![onal adhesion molecule-1, occludin, and claudins) with cy-
mic accessory proteins (zonula occludens-1 and -2, cingulin,
and 7H6). They are linked to the actin cytoskeleton [9],
y forming the most intimate cell to cell connection. The TJ
ther strengthened and maintained by the interaction or
However, for almost all other substances, including essential mate-
rials such as glucose and amino acids, transport proteins (carriers),
specific receptor-mediated or vesicular mechanisms (adsorptive
transcytosis) are required to pass the BBB.
In the case of transport proteins or known as carrier-mediated
Fig. 1. Schematic representation of the blood–brain barrier (BBB) and other components of a neurovascular unit (NVU).
Reproduced with permission from reference [11].
Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665
Schematic representation of the blood–brain barrier (BBB)
REVIEWS© 2006 Nature Publi
*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: joan.abbott@kcl.ac.uk
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
in pathological conditions could lea
restorative therapies.
Neuroscience has traditionally focused on the
of the central and peripheral nervous system
increasingly, on their interactions with the gl
that support their function. It is now becomi
that neurons, glia and microvessels are organi
well-structured neurovascular units, which are i
in the regulation of cerebral blood flow1
.
this organization, further modular structure
detected; in particular, the proposed gliovascu
in which individual astrocytic glia support the f
of particular neuronal populations and territor
communicate with associated segments of the
vasculature2,3
. Several recent studies have high
the importance of the brain endothelial ce
form the blood–brain barrier (BBB) in this m
organization, and the physiology and pharm
of the signalling between glia and endothelium
involved in regulating the BBB. Here, we desc
properties of the brain endothelium that contr
its barrier function, and how cell–cell interacti
to induction of the specialized features of the B
associated cell types. We review work showing
BBB is a dynamic system, and discuss the ways i
BBB permeability and transport can be modula
then consider the important role of astrocytes
BBB in brain ion and volume regulation. Fin
discuss some of the pathologies that involve B
function, and the development of protective st
for the brain endothelium that may reduce sec
neural damage in both acute and chronic neur
conditions.
NATURE REVIEWS | NEUROSCIENCE
© 2006 Nature Publishing Group
*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: joan.abbott@kcl.ac.uk
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluidspaces(FIG. 1):theBBBformedbythecerebrovascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF5
. Individual neu-
ronsarerarelymorethan8–20µmfromabraincapillary6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia11,12
(FIG. 3). Small gaseous molecules such as O2
and CO2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41
© 2006 Nature Publishing Group
*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: joan.abbott@kcl.ac.uk
doi:10.1038/nrn1824
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
in the regulation of cerebral blood flow . Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
fluidspaces(FIG. 1):theBBBfo
endothelial cells between b
fluid (ISF), the choroid plexu
and ventricular CSF, and
between blood and subarach
ronsarerarelymorethan8–2
although they may be millim
CSF compartment. Hence, o
the BBB exerts the greatest
microenvironment of brain c
The blood–brain barrier
The BBB is a selective barrie
cells that line cerebral micro
‘physical barrier’ because com
adjacent endothelial cells fo
to take a transcellular route
moving paracellularly throu
endothelia11,12
(FIG. 3). Small g
and CO2
can diffuse freely th
and this is also a route of entr
including drugs such as bar
presence of specific transpo
and abluminal membranes r
traffic of small hydrophilic
NATURE REVIEWS | NEUROSCIENCE VO
Astrocyte–endothelial intera
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck‡
and Elisabeth Hansson‡
Abstract | The blood–brain barrier, which is formed by the endothe
cerebral microvessels, has an important role in maintaining a prec
microenvironment for reliable neuronal signalling. At present, the](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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- 1. 11/2015 :: National Institute of Science Education and Research :: Aman Kumar Naik Integrated M.Sc. Drug Delivery across the Blood–Brain Barrier(BBB)
- 2. onal adhesion molecule-1, occludin, and claudins) with cy- mic accessory proteins (zonula occludens-1 and -2, cingulin, and 7H6). They are linked to the actin cytoskeleton [9], y forming the most intimate cell to cell connection. The TJ ther strengthened and maintained by the interaction or However, for almost all other substances, including essential mate- rials such as glucose and amino acids, transport proteins (carriers), specific receptor-mediated or vesicular mechanisms (adsorptive transcytosis) are required to pass the BBB. In the case of transport proteins or known as carrier-mediated Fig. 1. Schematic representation of the blood–brain barrier (BBB) and other components of a neurovascular unit (NVU). Reproduced with permission from reference [11]. Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665 Schematic representation of the blood–brain barrier (BBB) REVIEWS© 2006 Nature Publi *Wolfson Centre for Age- Related Diseases, King’s College London, UK. ‡ Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. Correspondence to N.J.A. e-mail: joan.abbott@kcl.ac.uk doi:10.1038/nrn1824 Neurovascular unit A functional unit composed of groups of neurons and their associated astrocytes, interacting with smooth muscle cells and endothelial cells on the microvessels (arterioles) responsible for their blood supply, and capable of regulating the local blood flow. Gliovascular unit A proposed functional unit composed of single astrocytic glial cells and the neurons they surround, interacting with local segments of blood vessels, and capable of regulating blood flow at the arteriolar level and BBB functions at the capillary level. in pathological conditions could lea restorative therapies. Neuroscience has traditionally focused on the of the central and peripheral nervous system increasingly, on their interactions with the gl that support their function. It is now becomi that neurons, glia and microvessels are organi well-structured neurovascular units, which are i in the regulation of cerebral blood flow1 . this organization, further modular structure detected; in particular, the proposed gliovascu in which individual astrocytic glia support the f of particular neuronal populations and territor communicate with associated segments of the vasculature2,3 . Several recent studies have high the importance of the brain endothelial ce form the blood–brain barrier (BBB) in this m organization, and the physiology and pharm of the signalling between glia and endothelium involved in regulating the BBB. Here, we desc properties of the brain endothelium that contr its barrier function, and how cell–cell interacti to induction of the specialized features of the B associated cell types. We review work showing BBB is a dynamic system, and discuss the ways i BBB permeability and transport can be modula then consider the important role of astrocytes BBB in brain ion and volume regulation. Fin discuss some of the pathologies that involve B function, and the development of protective st for the brain endothelium that may reduce sec neural damage in both acute and chronic neur conditions. NATURE REVIEWS | NEUROSCIENCE © 2006 Nature Publishing Group *Wolfson Centre for Age- Related Diseases, King’s College London, UK. ‡ Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. Correspondence to N.J.A. e-mail: joan.abbott@kcl.ac.uk doi:10.1038/nrn1824 Neurovascular unit A functional unit composed of groups of neurons and their associated astrocytes, interacting with smooth muscle cells and endothelial cells on the microvessels (arterioles) responsible for their blood supply, and capable of regulating the local blood flow. Gliovascular unit A proposed functional unit composed of single astrocytic glial cells and the neurons they surround, interacting with local segments of blood vessels, and capable of regulating blood flow at the arteriolar level and BBB functions at the capillary level. Neuroscience has traditionally focused on the neurons of the central and peripheral nervous systems, and, increasingly, on their interactions with the glial cells that support their function. It is now becoming clear that neurons, glia and microvessels are organized into well-structured neurovascular units, which are involved in the regulation of cerebral blood flow1 . Within this organization, further modular structure can be detected; in particular, the proposed gliovascular units, in which individual astrocytic glia support the function of particular neuronal populations and territories, and communicate with associated segments of the micro- vasculature2,3 . Several recent studies have highlighted the importance of the brain endothelial cells that form the blood–brain barrier (BBB) in this modular organization, and the physiology and pharmacology of the signalling between glia and endothelium that is involved in regulating the BBB. Here, we describe the properties of the brain endothelium that contribute to its barrier function, and how cell–cell interactions lead to induction of the specialized features of the BBB and associated cell types. We review work showing that the BBB is a dynamic system, and discuss the ways in which BBB permeability and transport can be modulated. We then consider the important role of astrocytes and the BBB in brain ion and volume regulation. Finally, we discuss some of the pathologies that involve BBB dys- function, and the development of protective strategies for the brain endothelium that may reduce secondary neural damage in both acute and chronic neurological conditions. Barriers of the CNS The cerebral ventricles and subarachnoid space contain cerebrospinal fluid (CSF), which is secreted by choroid plexuses in the lateral, third and fourth ventricles4 . Three barrier layers limit and regulate molecular exchange at the interfaces between the blood and the neural tissue or its fluidspaces(FIG. 1):theBBBformedbythecerebrovascular endothelial cells between blood and brain interstitial fluid (ISF), the choroid plexus epithelium between blood and ventricular CSF, and the arachnoid epithelium between blood and subarachnoid CSF5 . Individual neu- ronsarerarelymorethan8–20µmfromabraincapillary6 , although they may be millimetres or centimetres from a CSF compartment. Hence, of the various CNS barriers, the BBB exerts the greatest control over the immediate microenvironment of brain cells. The blood–brain barrier The BBB is a selective barrier formed by the endothelial cells that line cerebral microvessels7–10 (FIG. 2). It acts as a ‘physical barrier’ because complex tight junctions between adjacent endothelial cells force most molecular traffic to take a transcellular route across the BBB, rather than moving paracellularly through the junctions, as in most endothelia11,12 (FIG. 3). Small gaseous molecules such as O2 and CO2 can diffuse freely through the lipid membranes, and this is also a route of entry for small lipophilic agents, including drugs such as barbiturates and ethanol. The presence of specific transport systems on the luminal and abluminal membranes regulates the transcellular traffic of small hydrophilic molecules, which provides NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41 © 2006 Nature Publishing Group *Wolfson Centre for Age- Related Diseases, King’s College London, UK. ‡ Institute of Clinical Neuroscience, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. Correspondence to N.J.A. e-mail: joan.abbott@kcl.ac.uk doi:10.1038/nrn1824 responsible for their blood supply, and capable of regulating the local blood flow. Gliovascular unit A proposed functional unit composed of single astrocytic glial cells and the neurons they surround, interacting with local segments of blood vessels, and capable of regulating blood flow at the arteriolar level and BBB functions at the capillary level. in the regulation of cerebral blood flow . Within this organization, further modular structure can be detected; in particular, the proposed gliovascular units, in which individual astrocytic glia support the function of particular neuronal populations and territories, and communicate with associated segments of the micro- vasculature2,3 . Several recent studies have highlighted the importance of the brain endothelial cells that form the blood–brain barrier (BBB) in this modular organization, and the physiology and pharmacology of the signalling between glia and endothelium that is involved in regulating the BBB. Here, we describe the properties of the brain endothelium that contribute to its barrier function, and how cell–cell interactions lead to induction of the specialized features of the BBB and associated cell types. We review work showing that the BBB is a dynamic system, and discuss the ways in which BBB permeability and transport can be modulated. We then consider the important role of astrocytes and the BBB in brain ion and volume regulation. Finally, we discuss some of the pathologies that involve BBB dys- function, and the development of protective strategies for the brain endothelium that may reduce secondary neural damage in both acute and chronic neurological conditions. fluidspaces(FIG. 1):theBBBfo endothelial cells between b fluid (ISF), the choroid plexu and ventricular CSF, and between blood and subarach ronsarerarelymorethan8–2 although they may be millim CSF compartment. Hence, o the BBB exerts the greatest microenvironment of brain c The blood–brain barrier The BBB is a selective barrie cells that line cerebral micro ‘physical barrier’ because com adjacent endothelial cells fo to take a transcellular route moving paracellularly throu endothelia11,12 (FIG. 3). Small g and CO2 can diffuse freely th and this is also a route of entr including drugs such as bar presence of specific transpo and abluminal membranes r traffic of small hydrophilic NATURE REVIEWS | NEUROSCIENCE VO Astrocyte–endothelial intera at the blood–brain barrier N. Joan Abbott*, Lars Rönnbäck‡ and Elisabeth Hansson‡ Abstract | The blood–brain barrier, which is formed by the endothe cerebral microvessels, has an important role in maintaining a prec microenvironment for reliable neuronal signalling. At present, the
- 3. g delivery typically involves either cationic proteins or cell- various CNS associated diseases. This section is focused on t ort routes across the blood–brain barrier. Pathways “a” to “f” are commonly for solute molecules; and the route “g” involves monocytes, macrophages an nd can be used for any drugs or drugs incorporated liposomes or nanoparticles. m reference [11]. Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665 Transport routes across the blood–brain barrier anced Drug Delivery Reviews 64 (2012) 640–665 nts lists available at SciVerse ScienceDirect ced Drug Delivery Reviews mepage: www.elsevier.com/locate/addr 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, au AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecule precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BC serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjuga diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experiment EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guano mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydr min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; IC interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprot vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipa MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mo tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotr PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-po methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycop PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor- acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activa growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nerv ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Austr E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Eng 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.11.010 e history: ved 6 August 2011 pted 21 November 2011 able online 28 November 2011 ords: d–brain barrier delivery ptor-mediated transport mediated transport particles omes ological conditions The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es- sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable, highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under- stood, particularly under different pathological conditions. This review will discuss the barrier issue from a biological and pathological perspective to provide a better insight to the challenges and opportunities asso- ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed. Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, and finally cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther- apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take into account BBB biology as well as the unique features associated with the pathological condition to be treated. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. ents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 bbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction; adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta rsor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; BSA-NP, bovine m albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced ion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide; cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide; ndothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider- rowth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu- HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL, eukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar es; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK, mitogen activated protein kinase; monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro- MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1; CA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF, PEGylated-recombinant ionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C; protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP, tor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123, rhodamine 123; SA, sialic esidue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmission electron microscopy; TER, transendothelial ical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial th factor; ZO, zonula occludens. his review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”. orresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: +61 8 9266 2738; fax. +61 89266 2769. -mail address: y.chen@curtin.edu.au (Y. Chen). Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University. -409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. 0.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ an Chen a, ⁎, Lihong Liu b,1 Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Modern methods for delivery of drugs across the blood–brain barrier☆ Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
- 4. Tight junction opening Biological stimuli Zonula occludens toxin (Zot) vasoactive compounds and inflammatory stimuli such as histamine, bradykinin and VEGF H2 receptors NO and cyclic GMP production Tight junction opening Chemical stimuli Arterial injection of hyperosmolar solution (e.g., mannitol, arabinose) Shrinkage of endothelial cells Opening gaps between cells Sodium dodecyl sulphate (SDS) anced Drug Delivery Reviews 64 (2012) 640–665 nts lists available at SciVerse ScienceDirect ced Drug Delivery Reviews mepage: www.elsevier.com/locate/addr 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, au AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecule precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; B serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjuga diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experiment EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guano mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydr min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; IC interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprot vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphip MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mo tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanot PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-po methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycop PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PT receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor- acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activa growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nerv ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Austr E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Eng 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.11.010 e history: ved 6 August 2011 pted 21 November 2011 able online 28 November 2011 ords: d–brain barrier delivery ptor-mediated transport mediated transport particles omes ological conditions The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es- sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable, highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under- stood, particularly under different pathological conditions. This review will discuss the barrier issue from a biological and pathological perspective to provide a better insight to the challenges and opportunities asso- ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed. Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, and finally cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther- apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take into account BBB biology as well as the unique features associated with the pathological condition to be treated. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. tents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 bbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction; adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta ursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; BSA-NP, bovine m albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced sion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide; cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide; ndothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider- growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu- HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL, eukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar les; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK, mitogen activated protein kinase; monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro- MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1; CA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF, PEGylated-recombinant ionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C; protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP, ptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123, rhodamine 123; SA, sialic residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmission electron microscopy; TER, transendothelial rical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial th factor; ZO, zonula occludens. This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”. orresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: +61 8 9266 2738; fax. +61 89266 2769. -mail address: y.chen@curtin.edu.au (Y. Chen). Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University. -409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. 0.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ an Chen a, ⁎, Lihong Liu b,1 Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Modern methods for delivery of drugs across the blood–brain barrier☆ Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
- 5. Physical stimuli * FUS = Focused Ultrasound Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain Hao-Li Liua,b,1 , Mu-Yi Huac,1 , Hung-Wei Yangc,1 , Chiung-Yin Huangd , Po-Chun Chua , Jia-Shin Wua , I-Chou Tsengd , Jiun-Jie Wange , Tzu-Chen Yenb,f , Pin-Yuan Chend,g,2,3 , and Kuo-Chen Weid,2,3 Departments of a Electrical Engineering, c Chemical and Material Engineering, and e Medical Image and Radiological Sciences and g Graduate Institute of C Medical Sciences, Chang-Gung University, Taoyuan 333, Taiwan; b Molecular Imaging Center and f Department of Nuclear Medicine, Chang-Gung Me Hospital, Taoyuan 333, Taiwan; and d Department of Neurosurgery, Chang-Gung University College of Medicine and Memorial Hospital, Taoyuan 333, T Edited by Ralph Weissleider, Harvard Medical School, Boston, MA, and accepted by the Editorial Board July 13, 2010 (received for review March 16, The superparamagnetic properties of magnetic nanoparticles (MNPs) allow them to be guided by an externally positioned magnet and also provide contrast for MRI. However, their therapeutic use in treating CNS pathologies in vivo is limited by insufficient local accumulation and retention resulting from their inability to traverse biological barriers. The combined use of focused ultrasound and magnetic targeting synergistically delivers therapeutic MNPs across the blood–brain barrier to enter the brain both passively and ac- tively. Therapeutic MNPs were characterized and evaluated both in vitro and in vivo, and MRI was used to monitor and quantify their distribution in vivo. The technique could be used in normal brains or in those with tumors, and significantly increased the deposition of therapeutic MNPs in brains with intact or compromised blood–brain barriers. Synergistic targeting and image monitoring are powerful techniques for the delivery of macromolecular chemotherapeutic agents into the CNS under the guidance of MRI. blood–brain barrier | brain drug delivery | focused ultrasound | magnetic nanoparticles | magnetic targeting Within the CNS, the blood–brain barrier (BBB) excludes larger (>400 Da) molecules from entering the brain pa- renchyma, protecting it from toxic foreign substances (1). How- ever, it also prohibits delivery of many potentially effective diagnostic or therapeutic agents and restricts the enhanced per- meability and retention (EPR) of therapeutic nanoparticles. Many factors affect EPR, including the pH, polarity, and size of the delivered substance. Even when pathologic processes com- promise the integrity or function of the BBB, EPR can be limited by microenvironmental characteristics such as hypovascularity, fibrosis, or necrosis (2–4). In the presence of microbubbles and with use of a low-energy burst tone, focused ultrasound (FUS) can increase the perme- ability of the BBB (5). This noninvasive procedure disrupts the BBB locally rather than systemically, minimizing off-target effects. Furthermore, the disruption is reversible within several hours, providing a window of opportunity to achieve local delivery of chemotherapeutic agents in brains with intact or compromised BBBs. However, drug delivery in such cases is passive, relying on the free diffusion of the agents across the barrier. Advancesinnanotechnologyand molecularbiologyhaveallowed development of novel nanomedical platforms (6–8). Such approaches allow simultaneous diagnostic imaging and drug de- liverymonitoringin vivo inrealtime (9, 10).Magneticnanoparticles (MNPs) have intrinsic magnetic properties that enable their use as contrast agents in MRI (8, 11). Because MNPs are also sensitive to external magnetic forces, magnetic targeting (MT) actively enhan- ces their deposition at the target site, increasing the therapeutic dose delivered beyond that obtainable by passive diffusion (12). This study combines FUS and MT of nanoparticles as a syn- ergistic delivery system for chemotherapeutic agents concurrent with MRI monitoring for treating CNS diseases. FUS creates the opportunity to deliver therapeutic MNPs by passive local and externally applied magnetic forces actively increase the MNP concentration. When combined, these techniques p the delivery of large molecules into the brain (Fig. 1). Fur more, the deposition of the therapeutic MNPs can be moni and quantified in vivo by MRI. Results Characterization of Therapeutic MNPs. The saturated magn tion, mean hydrodynamic size, and particle size of the mercially available MNP Resovist and the newly synthe MNPs generated for this study are summarized in Table S measured by transmission EM (TEM), MNP-3 had a mea ameter of 12.3 nm (Fig. 2A). This was significantly smaller the hydrodynamic sizes measured by dynamic light scatterin nm for Resovist, 74–83 nm for MNPs-1–3; Fig. S1A and T S1), although such differences could be attributable to so effects. The measured zeta potentials of all of the synthe MNPs were similar to that of Resovist (approximately 45 m Magnetization of MNPs is crucial for their utility in MT crystallinity significantly affects this parameter. During synt the crystallinity of the MNPs was manipulated by controllin reaction conditions. MNP-3 exhibited the best crystallinity a the MNPs tested (Fig. S1C) and also displayed the highest d of magnetization (Fig. S1B). Administration of the MNPs into biological tissues profo alters the spin–spin relaxation rate (R2), and thus can serve indicator of the MRI contrast agent. The R2, and hence th tection sensitivity, of MNP-3 was twice that of Resovist by (Fig. 2 E and F and Table S1). The polymer poly[aniline-co-N-(1-one-butyric acid)] a (SPAnH) was used to encapsulate iron oxide (Fe3O4). This cess decreases the aggregation typical of MNPs and imp their stability in aqueous solutions. Fourier transform IR (FT spectroscopy indicated that the surface of the Fe3O4 particle covered with a layer of the SPAnH polymer, and that the Author contributions: H.-L.L., M.-Y.H., H.-W.Y., P.-Y.C., and K.-C.W. designed re H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., and P.-Y formed research; H.-L.L., M.-Y.H., and H.-W.Y. contributed new reagents/analyti H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., P.-Y.C., and analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. R.W. is a guest editor invited by the E Board. Freely available online through the PNAS open access option. 1 H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work. 2 P.-Y.C. and K.-C.W. contributed equally to this work. 3 To whom correspondence may be addressed. E-mail: kuochenwei@adm.cgmh.or pinyuanc@adm.cgmh.org.tw. This article contains supporting information online at www.pnas.org/lookup/suppl 1073/pnas.1003388107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS | August 24, 2010 | vol. 107 | no. 34 | 15205 development of novel nanomedical platforms (6–8). Su approaches allow simultaneous diagnostic imaging and drug d liverymonitoringin vivo inrealtime (9,10).Magneticnanopartic (MNPs) have intrinsic magnetic properties that enable their use contrast agents in MRI (8, 11). Because MNPs are also sensitive external magnetic forces, magnetic targeting (MT) actively enha ces their deposition at the target site, increasing the therapeu dose delivered beyond that obtainable by passive diffusion (12). This study combines FUS and MT of nanoparticles as a s ergistic delivery system for chemotherapeutic agents concurre with MRI monitoring for treating CNS diseases. FUS creates t www.pnas.org/cgi/doi/10.1073/pnas.1003388107 development of novel nanomedical platforms (6–8). Such approaches allow simultaneous diagnostic imaging and drug de- liverymonitoringin vivo inrealtime (9,10).Magneticnanoparticles (MNPs) have intrinsic magnetic properties that enable their use as contrast agents in MRI (8, 11). Because MNPs are also sensitive to external magnetic forces, magnetic targeting (MT) actively enhan- ces their deposition at the target site, increasing the therapeutic dose delivered beyond that obtainable by passive diffusion (12). This study combines FUS and MT of nanoparticles as a syn- ergistic delivery system for chemotherapeutic agents concurrent with MRI monitoring for treating CNS diseases. FUS creates the analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. R.W. is a guest editor invited by the Editorial Board. Freely available online through the PNAS open access option. 1 H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work. 2 P.-Y.C. and K.-C.W. contributed equally to this work. 3 To whom correspondence may be addressed. E-mail: kuochenwei@adm.cgmh.org.tw or pinyuanc@adm.cgmh.org.tw. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1003388107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS | August 24, 2010 | vol. 107 | no. 34 | 15205–15210 MEDIC ultrasound/magneticnanoparticletargetin oftherapeuticagentstothebrain Hao-LiLiua,b,1 ,Mu-YiHuac,1 ,Hung-WeiYangc,1 ,Chiung-YinHuangd ,Po-ChunChua ,Jia-Shin Jiun-JieWange ,Tzu-ChenYenb,f ,Pin-YuanChend,g,2,3 ,andKuo-ChenWeid,2,3 Departmentsofa ElectricalEngineering,c ChemicalandMaterialEngineering,ande MedicalImageandRadiologicalScien MedicalSciences,Chang-GungUniversity,Taoyuan333,Taiwan;b MolecularImagingCenterandf DepartmentofNucl Hospital,Taoyuan333,Taiwan;andd DepartmentofNeurosurgery,Chang-GungUniversityCollegeofMedicineandMe EditedbyRalphWeissleider,HarvardMedicalSchool,Boston,MA,andacceptedbytheEditorialBoardJuly13,2010( Thesuperparamagneticpropertiesofmagneticnanoparticles (MNPs)allowthemtobeguidedbyanexternallypositionedmagnet andalsoprovidecontrastforMRI.However,theirtherapeuticusein treatingCNSpathologiesinvivoislimitedbyinsufficientlocal accumulationandretentionresultingfromtheirinabilitytotraverse biologicalbarriers.Thecombineduseoffocusedultrasoundand magnetictargetingsynergisticallydeliverstherapeuticMNPsacross theblood–brainbarriertoenterthebrainbothpassivelyandac- tively.TherapeuticMNPswerecharacterizedandevaluatedboth invitroandinvivo,andMRIwasusedtomonitorandquantifytheir distributioninvivo.Thetechniquecouldbeusedinnormalbrainsor inthosewithtumors,andsignificantlyincreasedthedepositionof therapeuticMNPsinbrainswithintactorcompromisedblood–brain barriers.Synergistictargetingandimagemonitoringarepowerful techniquesforthedeliveryofmacromolecularchemotherapeutic agentsintotheCNSundertheguidanceofMRI. blood–brainbarrier|braindrugdelivery|focusedultrasound|magnetic nanoparticles|magnetictargeting WithintheCNS,theblood–brainbarrier(BBB)excludes larger(>400Da)moleculesfromenteringthebrainpa- renchyma,protectingitfromtoxicforeignsubstances(1).How- ever,italsoprohibitsdeliveryofmanypotentiallyeffective diagnosticortherapeuticagentsandrestrictstheenhancedper- meabilityandretention(EPR)oftherapeuticnanoparticles. ManyfactorsaffectEPR,includingthepH,polarity,andsizeof thedeliveredsubstance.Evenwhenpathologicprocessescom- promisetheintegrityorfunctionoftheBBB,EPRcanbelimited bymicroenvironmentalcharacteristicssuchashypovascularity, fibrosis,ornecrosis(2–4). Inthepresenceofmicrobubblesandwithuseofalow-energy bursttone,focusedultrasound(FUS)canincreasetheperme- abilityoftheBBB(5).Thisnoninvasiveproceduredisruptsthe BBBlocallyratherthansystemically,minimizingoff-target effects.Furthermore,thedisruptionisreversiblewithinseveral hours,providingawindowofopportunitytoachievelocaldelivery ofchemotherapeuticagentsinbrainswithintactorcompromised BBBs.However,drugdeliveryinsuchcasesispassive,relyingon thefreediffusionoftheagentsacrossthebarrier. Advancesinnanotechnologyandmolecularbiologyhaveallowed developmentofnovelnanomedicalplatforms(6–8).Such approachesallowsimultaneousdiagnosticimaginganddrugde- liverymonitoringinvivoinrealtime(9,10).Magneticnanoparticles (MNPs)haveintrinsicmagneticpropertiesthatenabletheiruseas contrastagentsinMRI(8,11).BecauseMNPsarealsosensitiveto externalmagneticforces,magnetictargeting(MT)activelyenhan- cestheirdepositionatthetargetsite,increasingthetherapeutic dosedeliveredbeyondthatobtainablebypassivediffusion(12). ThisstudycombinesFUSandMTofnanoparticlesasasyn- ergisticdeliverysystemforchemotherapeuticagentsconcurrent withMRImonitoringfortreatingCNSdiseases.FUScreatesthe opportunitytodelivertherapeut andexternallyappliedmagneticf MNPconcentration.Whencom thedeliveryoflargemoleculesi more,thedepositionofthethera andquantifiedinvivobyMRI. Results CharacterizationofTherapeuticM tion,meanhydrodynamicsize, merciallyavailableMNPResov MNPsgeneratedforthisstudya measuredbytransmissionEM( ameterof12.3nm(Fig.2A).Th thehydrodynamicsizesmeasured nmforResovist,74–83nmforM S1),althoughsuchdifferencesc effects.Themeasuredzetapote MNPsweresimilartothatofRe MagnetizationofMNPsiscru crystallinitysignificantlyaffectsth thecrystallinityoftheMNPswas reactionconditions.MNP-3exhib theMNPstested(Fig.S1C)anda ofmagnetization(Fig.S1B). AdministrationoftheMNPsin altersthespin–spinrelaxationrat indicatoroftheMRIcontrastag tectionsensitivity,ofMNP-3was (Fig.2EandFandTableS1). Thepolymerpoly[aniline-co- (SPAnH)wasusedtoencapsulat cessdecreasestheaggregation theirstabilityinaqueoussolution spectroscopyindicatedthatthesu coveredwithalayeroftheSPA Authorcontributions:H.-L.L.,M.-Y.H.,H.-W. H.-L.L.,M.-Y.H.,H.-W.Y.,C.-Y.H.,P.-C.C.,J.-S formedresearch;H.-L.L.,M.-Y.H.,andH.-W.Y H.-L.L.,M.-Y.H.,H.-W.Y.,C.-Y.H.,P.-C.C.,J.-S.W analyzeddata;andH.-L.L.,M.-Y.H.,H.-W.Y., Theauthorsdeclarenoconflictofinterest. ThisarticleisaPNASDirectSubmission.R.W Board. FreelyavailableonlinethroughthePNASop 1 H.-L.L.,M.-Y.H.,andH.-W.Y.contributedeq 2 P.-Y.C.andK.-C.W.contributedequallytoth 3 Towhomcorrespondencemaybeaddressed pinyuanc@adm.cgmh.org.tw. Thisarticlecontainssupportinginformationo 1073/pnas.1003388107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1003388107PNAS|August24,2010 Electromagnetic field (EMF) Pulse Protein kinase C signalling Translocation of tight junction's Protein ZO-1 Tight Junction Opening Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Nanoparticles Liposomes Pathological conditions a in tr Contents 1. Introduction . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain 3. Transport routes across the blood–brain ba 4. Biological and pathological properties of BB 4.1. Physical barrier . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amylo AMT, adsorptive-mediated transport; AMP, adenosine mo precursor protein; ApoE, Apolipoprotein E; ATP, adenosine serum albumin conjugated nanoparticles; cAMP, cyclic AM diffusion; CHP, hydrophobic cholesterol groups; CMC, crit CRM, cross reacting material; CSF, cerebrospinal fluid; DT, EC, endothelial cell; EMF, electromagnetic fields; FBP, fusi mal growth factor; HIRMAb, human insulin receptor mono min; HSP-96, heat shock protein 96; HUVEC, human um interleukin; INF, interferon; JAM, junction adhesion mol vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein rece MCP, monocyte chemotactic protein; MHC, major histoc tein; MS, multiple sclerosis; NOS, nitric oxide synthes PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(but methionyl human granulocyted colony stimulating facto PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolid receptor associated protein; RES, reticuloendothelial sy acid residue; SBP, sequence signal-based peptide; SUV, sma electrical resistance; TfR, transferrin receptor; TJ, tight junc growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Rev ⁎ Corresponding author at: School of Pharmacy, Curtin E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctora 0169-409X/$ – see front matter. Crown Copyright © 2011 doi:10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain b Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore a b s t r a c ta r t i c l e i n f o Article history: Received 6 August 2011 Accepted 21 November 2011 Available online 28 November 2011 Keywords: Blood–brain barrier Drug delivery Receptor-mediated transport Cell-mediated transport Nanoparticles Liposomes Pathological conditions The blood–brain barrier (BBB) is a highly regulated and efficient ba brain. It is designed to regulate brain homeostasis and to permit selec sential for brain function. Unfortunately, drug transport to the brain is h highly selective and well coordinated barrier. With progress in molec stood, particularly under different pathological conditions. This review biological and pathological perspective to provide a better insight to t ciated with the BBB. Modern methods which can take advantage of Applications of nanotechnology in drug transport, receptor-mediate cell-mediated drug transport will also be covered in the review. The ch apy to the brain is formidable; solutions will likely involve concerted into account BBB biology as well as the unique features associated treated. Crown Copyright © 2011 Publish Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunod AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitax precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood– serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PL diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central ner CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimm EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monop mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hy min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracere interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein recepto vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptid MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear p tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolact methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein ty receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated tr acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissio electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vasc growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: + E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Cu 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ Yan Chen a, ⁎, Lihong Liu b,1 Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 64 Contents lists available at SciVe Advanced Drug Deliv journal homepage: www.elsevi Modern methods for delivery of drugs a Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, S Advanced Drug Deliver Contents lists availab Advanced Drug journal homepage: ww
- 6. Transport system-mediated drug delivery Nanocarriers for brain drug delivery mdpi.com • Nontoxic, biodegradable and biocompatible • Particle size less than 100 nm • Stable in blood (no aggregation and dissociation) • Non-immunogenic • BBB-targeted moiety • Applicable to carry small molecules, proteins, peptides or nucleic acids Nano carriers May be Liposomes, Micelles, Polymeric Gels, Amphiphilic Gels anced Drug Delivery Reviews 64 (2012) 640–665 nts lists available at SciVerse ScienceDirect nced Drug Delivery Reviews mepage: www.elsevier.com/locate/addr Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; A AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiope precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under cu serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum a diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, c CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, s mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human imm min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprot vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamell MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, my tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neu PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethy methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, pr receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evapo acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 t electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rig doi:10.1016/j.addr.2011.11.010 treated. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. ntents . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 . Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 . Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 . Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction; T, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta ursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; BSA-NP, bovine m albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced usion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide; M, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide; endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider- growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu- ; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL, rleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar cles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK, mitogen activated protein kinase; P, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro- ; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1; CA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF, PEGylated-recombinant hionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C; , protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP, ptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123, rhodamine 123; SA, sialic residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmission electron microscopy; TER, transendothelial trical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial wth factor; ZO, zonula occludens. This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”. Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: +61 8 9266 2738; fax. +61 89266 2769. E-mail address: y.chen@curtin.edu.au (Y. Chen). L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University. 9-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. 10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ an Chen a, ⁎, Lihong Liu b,1 Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Modern methods for delivery of drugs across the blood–brain b Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
- 7. Transport vectors Drugs Molecular structure mimicking the endogenous nutrients Prodrugs BBB Drugs dvanced Drug Delivery Reviews 64 (2012) 640–665 ents lists available at SciVerse ScienceDirect nced Drug Delivery Reviews omepage: www.elsevier.com/locate/addr Crown Copyright © 2011 Published by Else Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency sy AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, A precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospi serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanopart diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimmune enceph EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; H mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic ba min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricu interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactof vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK, m MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plas PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG- methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein k PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kin receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmission electron m electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endoth growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”. ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: +61 8 9266 2 E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin Univer 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.11.010 an Chen a, ⁎, Lihong Liu b,1 chool of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia nstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore a b s t r a c tr t i c l e i n f o icle history: ceived 6 August 2011 cepted 21 November 2011 ailable online 28 November 2011 ywords: ood–brain barrier ug delivery ceptor-mediated transport ll-mediated transport noparticles osomes thological conditions The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es- sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable, highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under- stood, particularly under different pathological conditions. This review will discuss the barrier issue from a biological and pathological perspective to provide a better insight to the challenges and opportunities asso- ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed. Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, and finally cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther- apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take into account BBB biology as well as the unique features associated with the pathological condition to be treated. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. ntents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction; MT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta ecursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; BSA-NP, bovine um albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced fusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide; M, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide; endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider- al growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu- n; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL, erleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar sicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK, mitogen activated protein kinase; CP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro- n; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1; DCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF, PEGylated-recombinant ethionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C; G, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP, ceptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123, rhodamine 123; SA, sialic d residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmission electron microscopy; TER, transendothelial ctrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial owth factor; ZO, zonula occludens. This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”. Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: +61 8 9266 2738; fax. +61 89266 2769. E-mail address: y.chen@curtin.edu.au (Y. Chen). L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University. 69-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. i:10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Modern methods for delivery of drugs across the blood–brain barrier☆ Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Dopamine Levodopa Dopaminelevodopa Decarboxylase CNS Type 1 l-type Amino-acid transporter Levodopa contains the carboxyl and α-amino groups
- 8. Adsorptive-mediated transcytosis journals.cambridge.org/ Cell-penetrating peptides (CPPs) The application of CPPs is based on the prem active cargo can be attached to CPPs and translo link between the CPPs and cargo is most comm and seldom in non-covalent bond. A large va cules/materials have been effectively delivered i cluding small molecules, proteins, peptides, liposomes and nanoparticles [204]. Some can ent dothelia cells or are even translocated into the br amples are highlighted here. Table 3 Principle features of the selected cell penetrating peptides ( Peptide name Sequence MAP KLALKLALKALKAALKLA pAntp43–68 RQIKIWFQNRRMKWKK Transportan GWTLNSAGYLLGKINLKALAALAKKIL SBP MGLGLHLLVLAAALQGAWSQPKKKRKV FBP GALFLGWLGAAGSTMGAWSQPKKKRKV TAT48–60 GRKKRRQRRRPPQ SynB1 RGGRLSYSRRRFSTSTGR SynB3 RRLSYSRRRF MAP: model amphipathic peptide; Antp: Antennapedia; SB peptide; FBP, fusion sequence-based peptide; TAT, HIV-1 tra The peptide residues in this table are expressed with one- leucine; A—alanine; R—arginines; Q—glutamine; I—isoleu phenylalanine; N—asparagine; M—methionine; G—glycines; S was collected from references [204,206,221,222,312–314]. 654 Y. Ch The major dogma has been that CPPs enter cells by a receptor and energy- independent process but the exact mechanisms are not yet fully understood SynB1, SynB1 TAT derived CPPs Lipid raft-mediated macropinocytosis Endosomal transport All are having Net Positive Charge but Internalization differed in each case.
- 9. Endogenous receptor-mediated transcytosis Receptor-ligand binding Endocytosis at the luminal (blood) side Movement through the endothelia cytoplasm Exocytosis of the drug or ligand-attached drug or cargo at the abluminal (brain) side mdpi.com Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Contents 1. Introduction . . . . . . . . . . . . . 2. Physiology and biology of the blood–brai 3. Transport routes across the blood–brain b 4. Biological and pathological properties of B 4.1. Physical barrier . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amy AMT, adsorptive-mediated transport; AMP, adenosine m precursor protein; ApoE, Apolipoprotein E; ATP, adenosi serum albumin conjugated nanoparticles; cAMP, cyclic diffusion; CHP, hydrophobic cholesterol groups; CMC, c CRM, cross reacting material; CSF, cerebrospinal fluid; D EC, endothelial cell; EMF, electromagnetic fields; FBP, fu mal growth factor; HIRMAb, human insulin receptor mo min; HSP-96, heat shock protein 96; HUVEC, human u interleukin; INF, interferon; JAM, junction adhesion m vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein re MCP, monocyte chemotactic protein; MHC, major hist tein; MS, multiple sclerosis; NOS, nitric oxide synth PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(b methionyl human granulocyted colony stimulating fa PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glyco receptor associated protein; RES, reticuloendothelial acid residue; SBP, sequence signal-based peptide; SUV, sm electrical resistance; TfR, transferrin receptor; TJ, tight ju growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery R ⁎ Corresponding author at: School of Pharmacy, Curt E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdocto 0169-409X/$ – see front matter. Crown Copyright © 20 doi:10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore a b s t r a c ta r t i c l e i n f o Article history: Received 6 August 2011 Accepted 21 November 2011 Available online 28 November 2011 Keywords: Blood–brain barrier Drug delivery Receptor-mediated transport Cell-mediated transport Nanoparticles Liposomes Pathological conditions The blood–brain barrier (BBB) is a highly regulated and efficient brain. It is designed to regulate brain homeostasis and to permit se sential for brain function. Unfortunately, drug transport to the brain highly selective and well coordinated barrier. With progress in m stood, particularly under different pathological conditions. This re biological and pathological perspective to provide a better insight ciated with the BBB. Modern methods which can take advantage Applications of nanotechnology in drug transport, receptor-medi cell-mediated drug transport will also be covered in the review. Th apy to the brain is formidable; solutions will likely involve concert into account BBB biology as well as the unique features associat treated. Crown Copyright © 2011 Pub Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Physiology and biology of the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Transport routes across the blood–brain barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Biological and pathological properties of BBB for drug transport . . . . . . . . . . . . . . . . . . . . . 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abbreviations: a2M, alpha-2 macroglobulin; Aβ, amyloid β; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmu AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of pac precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blo serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central CRM, cross reacting material; CSF, cerebrospinal fluid; DT, diphtheria toxin; DTR, diphtheria toxin receptor; EAE, experimental autoim EC, endothelial cell; EMF, electromagnetic fields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine mo mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic– min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intrac interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein rece vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic pep MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononucle tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferr PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycapro methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, prote receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediate acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmi electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, growth factor; ZO, zonula occludens. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous Sys ⁎ Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel E-mail address: y.chen@curtin.edu.au (Y. Chen). 1 L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering 0169-409X/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.11.010 Modern methods for delivery of drugs across the blood–brain barrier☆ Advanced Drug Delivery Reviews 64 (2012) 640–665 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Advanced Drug Delivery Reviews Contents lists available at Sci Advanced Drug Del journal homepage: www.else Modern methods for delivery of drugs Yan Chen a, ⁎, Lihong Liu b,1 a School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Weste b Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 13866 Advanced Drug Del Contents lists avai Advanced Dru journal homepage: w
- 10. - f - - h - . tyrosine. An alternative pathway is surface deiodination of the intact peptide, possibly by ectoenzymes on the endothelial sur- face of organ capillary beds. Evidence for this pathway is the observation that the systemic clearance (C1, Table I) for the 125 I-bio-Ab1–40 /OX26-SA conjugate, 2.6 ml/min/kg, is approxi- mately fourfold greater than the systemic clearance of the un- conjugated 125 I-83-14 mAb in rhesus monkeys, 0.39–1.00 ml/ Figure 11. Scheme depicting the multifunctionality and three do- mains of the peptide radiopharmaceutical conjugated to the BBB de- livery system. The imaging agent is comprised of amyloid-binding do- main, a linker domain, and a BBB transport domain, the last constituted by the mAb to the HIR. The HIR is localized in human brain capillary endothelium (reference 21), which forms the BBB in vivo. DrugTargeting of a Peptide Radiopharmaceutical through the Prima Barrier In Vivo with a Monoclonal Antibody to the Human Insulin Re Dafang Wu, Jing Yang, and William M. Pardridge Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095-1682 Abstract Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled to un- dergo transport through the blood–brain barrier (BBB) in vivo. Radiolabeled Ab1–40 images brain amyloid in tissue sections of Alzheimer’s disease autopsy brain, but this pep- tide radiopharmaceutical cannot be used to image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125 I-Ab1–40 was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain tar- geting system comprised of a complex of the 83-14 mono- clonal antibody (mAb) to the human insulin receptor, which is tagged with streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125 I-bio-Ab1–40 was ob- served after conjugation to the 8314-SA delivery system at 3 h after intravenous injection. In contrast, no measurable brain uptake of 125 I-bio-Ab1–40 was observed in the absence of a BBB drug delivery system. The peptide radiopharma- ceutical was degraded in brain with export of the iodide ra- dioactivity, and by 48 h after intravenous injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for imaging amyloid or other brain disorders. (J. Clin. Invest. 1997. 100:1804–1812.) Key words: Alzhei- mer’s disease • amyloid • monoclonal antibody • insulin re- ceptor • avidin Introduction Peptide radiopharmaceuticals have potential for diagnostic im- aging (1). The somatostatin receptor is overexpressed in cer- tain neuroendocrine tumors, as well as brain tumors such as meningiomas or gliomas, and 125 I- or 111 In-labeled octreotide, a somatostatin peptide analog, has been used to image these tu- mors (2, 3). Owing to the small size of the peptide radiophar- maceutical, octreotide readily crosses the porous capillaries perfusing tumors in the periphery, or certain brain tumors such as meningiomas, which lack a bloo However, well-differentiated gliomas somatostatin receptors, have an intac to image these tumors with octreotide does not cross the BBB in vivo (5). In addition to tumors, it should a other medical disorders with peptid such as amyloid. The deposition of heimer’s disease correlates with the d disorder (6, 7). Extracellular amyloid comprised of two types: senile (neur amyloid (8–12). Both types of amyloi are comprised of a 43–amino acid am nated Ab1–43 . There are as well Ab1– the abnormal proteolysis of a normal loid peptide precursor (13). The Ab amyloid of tissue section autopsy brain can be identified with or with antibodies directed against Ab1–42/43 peptide (14). However, the A tions may also be identified in vitro 125 I-Ab1–40 , a peptide containing the f Ab1–42/43 peptide that deposits with hi ing Ab amyloid (15). Therefore, rad tential peptide radiopharmaceutical neurodiagnostic quantitation of the Alzheimer’s disease brain of living su ternal detection methodologies, such computed tomography or positron However, 125 I-Ab1–40 does not cross vector-mediated BBB drug delivery amyloid does not deposit in the brai form in the brain of New World pri (15–20 yr) squirrel monkey, as vascu duced in the brain of Old World pr (27–30 yr) rhesus monkey, in neuritic These studies use 125 I-Ab1–40 adap ery system that enables the peptide blood to a high degree, allowing for im of the peptide radiopharmaceutical in (intravenous, i.v.) injection. The goa fold: first, to prepare radiolabeled pep jugated to the BBB delivery system; that the deposition of 125 I-Ab1–40 on Address correspondence to William M. Pardridge, M.D., Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095- 1682. Phone: 310-825-8858; FAX: 310-206-5163; E-mail: wpardrid@ 11/17/2015 Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human ins J Clin Invest. 1997 Oct 1; 100(7): 1804–1812. doi: 10.1172/JCI119708 PMCID: PMC508366 Drug targeting of a peptide radiopharmaceutical through the primate bloodbrain barrier in vivo with a monoclonal antibody to the human insulin receptor. D Wu, J Yang, and W M Pardridge Department of Medicine, UCLA School of Medicine, Los Angeles, California 900951682, USA. Copyright notice This article has been cited by other articles in PMC. Abstract Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled to undergo transport through the bloodbrain barrier (BBB) in vivo. Radiolabeled Abeta140 images brain amyloid in tissue sections of Alzheimer's disease autopsy brain, but this peptide radiopharmaceutical cannot be used to image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125IAbeta140 was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain targeting system comprised of a complex of the 8314 monoclonal antibody (mAb) to the human insulin receptor, which is tagged with streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125IbioAbeta140 was observed after conjugation to the 8314SA delivery system at 3 h after intravenous injection. In contrast, no measurable brain uptake of 125IbioAbeta140 was observed in the absence of a BBB drug delivery system. The peptide radiopharmaceutical was degraded in brain with export of the iodide radioactivity, and by 48 h after intravenous injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for imaging amyloid or other brain disorders. Full Text The Full Text of this article is available as a PDF (354K). Insulin receptor Amyloid-β- peptide 125I-Abeta1–40 conjugated to 83–14 monoclonal antibody (mAb) Insulin receptor Diagnostic probe for ADReceptor mediated Endocytosis 11/17/2015 Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human in J Clin Invest. 1997 Oct 1; 100(7): 1804–1812. doi: 10.1172/JCI119708 PMCID: PMC508366 Drug targeting of a peptide radiopharmaceutical through the primate bloodbrain barrier in vivo with a monoclonal antibody to the human insulin receptor. D Wu, J Yang, and W M Pardridge Department of Medicine, UCLA School of Medicine, Los Angeles, California 900951682, USA. Copyright notice This article has been cited by other articles in PMC. Abstract Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled t undergo transport through the bloodbrain barrier (BBB) in vivo. Radiolabeled Abeta140 images brain amyloi in tissue sections of Alzheimer's disease autopsy brain, but this peptide radiopharmaceutical cannot be used to image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125IAbeta140 was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain targeting system comprised of a complex of the 8314 monoclonal antibody (mAb) to the human insulin receptor, which is tagged with streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125IbioAbeta140 was observed after conjugation to the 8314SA delivery system at 3 h after intravenous injection. In contrast, no measurable brain uptake of 125IbioAbeta140 was observed in the absence of a BBB drug delivery system. The peptide radiopharmaceutical was degraded in brain with export of the iodide radioactivity, and by 48 h after intravenou injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for imaging amyloid or other brain disorders. Full Text The Full Text of this article is available as a PDF (354K). Low-density lipoprotein receptor related proteins 1 and 2 (LRP1 and LRP2 receptors) ApoE (Apolipoprotein E) Tissue plasminogen activator (tPA) Plasminogen activator inhibitor 1(PAI-1) Amyloid precursor protein (APP) Lactoferrin Melanotransferrin α2 macroglobulin (α2 M) Receptor associated protein (RAP) HIV-1 TAT protein Heparin cofactor II Heat shock protein 96 (HSP-96) Engineered angiopeps Binds to Specific LRP1 and LRP2 receptors in BBB Receptor-mediated transcytosis