G23 peptide-mediated delivery of biodegradable nanocarriers across an in vitro blood-brain
barrier model
de Jong, Edwin
DOI:
10.33612/diss.132284892
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de Jong, E. (2020). G23 peptide-mediated delivery of biodegradable nanocarriers across an in vitro
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CHAPTER 1
General introduction and scope of the
thesis
Edwin de Jong
University of Groningen, University Medical Center Groningen, Department of Biomedical
Engineering, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands
THE BLOOD-BRAIN BARRIER
Brain homeostasis is largely dependent on proper functioning of the blood-brain barrier
(BBB), which is a cellular barrier that separates the circulating blood from the interstitial
fluid in the brain. The BBB is formed by a polarized layer of brain capillary endothelial
cells and supporting cell types, such as astrocytes and pericytes, that are located in close
proximity to the abluminal surface of brain capillaries [1, 2]. Neurons reside on average
about 10 to 30 µm from the nearest brain capillary [3−5]. Adjacent endothelial cells are
interconnected by transmembrane tight junction (TJ) proteins that are linked through
cytosolic scaffolding TJ proteins to the actin cytoskeleton and separate the plasma
membrane into a luminal (apical) and abluminal (basolateral) domain [6−8]. The TJ
complexes limit paracellular diffusion of biomolecules into the brain (Figure 1). Gaseous
lipophilic molecules, such as oxygen and carbon dioxide, are able to cross the plasma
membrane of brain endothelial cells by passive diffusion (Figure 1). The BBB actively
regulates the transcellular transport of biomolecules that can’t freely diffuse across the
endothelium in order to provide neurons with essential nutrients and metabolites while
preventing the passage of dangerous toxins and pathogens.
Figure 1. Transport across the blood-brain barrier. Gaseous lipophilic molecules are able to cross
the plasma membrane by passive diffusion. Tight junction complexes between adjacent endothelial
cells limit paracellular diffusion of biomolecules into the brain. Transporters and receptors facilitate
the translocation of specific biomolecules across the endothelium in order to provide the brain with
essential nutrients and metabolites.
The brain endothelium expresses transporters and receptors that facilitate the
translocation of specific biomolecules across the BBB. Carrier-mediated transport enables
BBB translocation of small hydrophilic molecules via membrane-embedded transporters
(Figure 1). The bidirectional glucose transporter GLUT1, which is present in both the
luminal and abluminal membrane domain of endothelial cells, mediates the delivery of
glucose to the brain by facilitated diffusion [7, 9, 10]. Other facilitative transporters that
enable transport of amino acids and lactate across both membrane domains of the brain
endothelium are the large neutral amino acid transporter LAT1 and the monocarboxylate
transporter MCT1, respectively [7, 10]. In contrast to facilitative transporters that mediate
translocation of molecules across the BBB in an energy-independent manner,
receptor-mediated transcytosis is an energy-dependent vesicular transport process that allows for
the delivery of relatively large molecules across the BBB (Figure 1). Upon interaction of a
ligand with the relevant membrane receptor, such as the transferrin receptor [11−13], the
low density lipoprotein (LDL) receptor [14, 15] or the insulin receptor [16−18], internalization
occurs via endocytosis. The uptake of iron-loaded transferrin is primarily facilitated by
clathrin-mediated endocytosis, a process which involves the formation of a clathrin-coated
pit at the plasma membrane that pinches off into the cytosol, forming clathrin-coated
vesicles. Caveolae-mediated endocytosis is the major route for internalization of LDL by
brain endothelial cells. Caveolae are invaginated membrane microdomains with a
flask-shaped morphology that bud from the plasma membrane and form caveolar vesicles upon
ligand-receptor interaction. After endocytosis of the ligands, subsequent intracellular
vesicular transport and exocytosis at the opposite cell surface of the brain endothelium
results in the transcellular transport of the ligands, e.g. nutrients and metabolites.
DRUG DELIVERY INTO THE BRAIN
Brain diseases have an enormous impact on the daily life of patients and pose a large
economic and social burden on society. The number of people diagnosed with a brain
disease, such as Alzheimer’s [19], continues to increase due to the ageing population.
The treatment of brain diseases is greatly hampered by the presence of the BBB, which
actively prevents the delivery of therapeutics from the blood into the brain. Temporary
disruption of TJ integrity upon intra-arterial infusion of a hyperosmolar solution, e.g.
mannitol, enables paracellular diffusion of chemotherapeutics through the BBB [20, 21].
However, besides the invasiveness of drug administration via the carotid or vertebral
artery, TJ disruption by mannitol is associated with the occurrence of seizures [22, 23].
Other highly invasive delivery techniques enable direct administration of a drug into
the brain via an injection or implant, but come with disadvantages such as the limited
volume of drug distribution, the potential increase of intracranial pressure and the risk
of infection [24, 25]. Intravenous administration of drugs that cross brain endothelial
cells without compromising BBB integrity is considered a less invasive alternative to treat
brain diseases.
Most small-molecule drugs that are currently available for the treatment of brain-related
diseases cross the endothelium by passive diffusion. In addition to their low molecular
weight, the drug molecules must be moderately lipophilic and have a low
hydrogen-bonding potential to diffuse transcellularly [26]. However, the presence of ATP-binding
cassette (ABC) efflux transporters at the plasma membrane of brain endothelial cells
may prevent the transcellular transport of lipophilic molecules by exporting them
back into the circulation, and thereby reducing their delivery to the brain [27, 28]. The
polarized brain endothelium is characterized by an asymmetric distribution of efflux
transporters, including p-glycoprotein, between the luminal and abluminal membrane
domains [7]. P-glycoprotein, which is present in the luminal membrane domain, limits
the entry of various substrates, such as opiates, antipsychotics, antidepressants and
chemotherapeutics, into the brain [27, 28]. Although combined treatment with drugs and
inhibitors of ABC efflux transporters may stimulate drug transport across the BBB [29, 30],
the use of efflux pump inhibitors also increases the risk of concomitant entry of other,
potentially toxic, compounds from the blood into the brain.
Several hydrophilic small-molecule drugs, which are structurally similar to endogenous
substrates of the facilitative transporter LAT1 [31], are delivered across the brain
endothelium via LAT1-mediated transport. Alternatively, an endogenous substrate, e.g.
glucose, can be conjugated to the drug molecule in order to facilitate its BBB translocation
via a facilitative transporter, e.g. the GLUT1 transporter [32]. Also, the transport of certain
nanocarriers across the BBB is enhanced by conjugation of GLUT1-substrates [33−35].
However, transport via facilitative transporters is thought to be primarily suited for the
delivery of single hydrophilic drug molecules [36].
The treatment of brain diseases with therapeutic macromolecules, such as nucleic acids and
proteins, necessitates the development of delivery platforms to deliver these drugs into the
brain [37]. Nanocarriers are able to transport drugs across the BBB via the so-called
Trojan-horse mechanism whereby the nanoparticles cross the brain endothelium as passengers
on a vesicular transport route. Although adsorptive-mediated transcytosis enables
transendothelial transport of nanoparticles, e.g. cationic serum albumin-conjugated
polymersomes [38], it is considered to be a non-specific transport process. The conjugation
of ligands to nanoparticles that specifically target native receptors on the brain endothelium
and promote receptor-mediated transcytosis represents a more promising strategy for drug
delivery into the brain [39, 40]. Decoration of nanoparticles with moieties that target the
transferrin receptor, such as OX26 antibodies or B6 peptides, has been demonstrated to
enhance drug delivery across the BBB [41, 42]. Likewise, HIRMAb-functionalized liposomes,
which are targeted towards the insulin receptor, were shown to induce transendothelial
transport of macromolecular cargo into the brain [43]. Besides the transcytosis of targeted
nanoparticles across the endothelium, receptor-mediated transport may result in recycling
or degradation in lysosomes. The fate of a targeting ligand and its associated cargo is
affected by its capacity to dissociate from the receptor after internalization [44−46].
POLYMERSOMES FOR DRUG DELIVERY
Polymersomes are spherical bilayer structures composed of amphiphilic block copolymers
that protect the therapeutic cargo from degradation during systemic circulation. These
polymeric vesicles can accommodate hydrophilic and hydrophobic molecules within
their aqueous core and polymer bilayer (Figure 2), respectively. Decoration with targeting
ligands facilitates receptor-targeted delivery of drugs, e.g. peptides, proteins, siRNA and
doxorubicin, into the brain [41, 47−56]. Polymersomes are of great interest for biomedical
applications due to the high chemical versatility of block copolymers that allows for tuning
of nanoparticle properties, such as membrane thickness and stimulus-responsiveness [57].
The morphology of polymersomes closely resembles that of liposomes, which are bilayer
structures of amphiphilic phospholipids with a thickness of several nanometers. The thicker
membrane of polymersomes, in which the entanglement of block copolymers results in
low lateral diffusivity, contributes to a lower permeability and higher stability compared to
liposomes [57−59]. However, the superiority of polymersomes over liposomes in terms of
permeability and stability remains a matter of debate [60].
Figure 2. Different morphologies of diblock copolymer assemblies in aqueous solutions. Amphiphilic
block copolymers can self-assemble into various ordered structures depending on the ratio of the
hydrophilic and hydrophobic segments. As the hydrophilic fraction of the amphiphile decreases, the
morphology of the polymer assemblies generally shifts from spherical micelles to worm-like micelles
and eventually to polymersomes. Spherical and worm-like micelles can only encapsulate hydrophobic
cargo molecules. Polymersomes can accommodate both hydrophilic and hydrophobic cargo molecules
within their aqueous core and polymer bilayer, respectively.
Upon intravenous administration, nanoparticles are prone to be cleared from the
circulation by the mononuclear phagocyte system [61], thereby hampering the delivery
of drugs to the target site. Phagocytosis is triggered by opsonisation of the nanoparticle
surface with plasma proteins. Poly(ethylene glycol) (PEG) is a biocompatible and
hydrophilic polymer that is used to avoid opsonisation and subsequent degradation
of nanoparticles by opsonin-recognising cells [62]. Amphiphilic block copolymers,
in which PEG comprises the hydrophilic segment, allow for the assembly of 100%
pegylated polymersomes. Due to the potential immunogenicity of PEG following
repeated administration of pegylated liposomes [63−65], other synthetic polymers,
such as poly(vinylpyrrolidone) or poly(glycerol), as well as biopolymers, e.g. hyaluronic
acid, and poly(amino acids) have been applied to prolong the blood circulation time of
nanoparticles. However, the available alternatives for PEG are considered suboptimal for
application in drug delivery [66−68]. In contrast to the limited number of polymers for
the hydrophilic segment, a variety of polymers can comprise the hydrophobic segment of
block copolymers [57], enabling the assembly of polymersomes with specific membrane
properties. For polymersome-mediated drug delivery, biodegradable polymers, such
as poly(caprolactone) (PCL) and poly(trimethylene carbonate) (PTMC), are preferred
because of their susceptibility to hydrolytic and/or enzymatic degradation [69, 70].
Amphiphilic block copolymers can self-assemble in aqueous solutions into various
ordered structures depending on the ratio of the hydrophilic and hydrophobic
segments. In general, as the hydrophilic fraction of the amphiphile decreases, the
morphology of the polymer assemblies shifts from mostly spherical micelles to
worm-like micelles and eventually to polymersomes (Figure 2) [71−75]. Besides the chemical
composition of the block copolymers, the preparation method may have an effect on the
morphology of polymer assemblies [72]. The solvent displacement method and the thin
film rehydration method are widely used procedures for the formation of polymersomes.
Potential denaturation of the therapeutic cargo by organic solvents is a major drawback
of the solvent displacement method. The direct hydration method, which is a recently
developed procedure, does not involve the use of small molecular organic solvents
for the assembly of polymersomes. Instead, the block copolymers are blended with
oligo(ethylene glycol) prior to hydration. Furthermore, the direct hydration method has
demonstrated a higher encapsulation efficiency of cargo into polymersomes compared
to the thin film rehydration method [76].
G23 PEPTIDE-MEDIATED TRANSPORT ACROSS THE
BLOOD-BRAIN BARRIER
G23 peptide is a GM1 ganglioside-binding peptide [77] that can promote transendothelial
transport of different types of nanoparticles from the blood into the brain [77−81]. GM1 is
concentrated in caveolae at the luminal plasma membrane of endothelial cells [82]. The
enrichment of GM1 in these membrane microdomains suggests a possible involvement
of caveolae-mediated endocytosis in the transport of GM1-targeted nanoparticles
across the endothelium. In addition to GM1, the G23 peptide has binding affinity for
GT1b [77, 83, 84], which is described to promote binding of the peptide to neuronal
cells [84−88]. However, the affinity of the peptide for GT1b may also imply a role for this
trisialoganglioside in the transendothelial transport of G23-functionalized nanoparticles
across the BBB. Interestingly, in recent studies that focus on the neuronal-targeting
properties of the G23 peptide additional BBB-targeting ligands are used in order to form
dual-targeted nanoparticles for the delivery of therapeutics into the brain [52, 89, 90].
Conjugation of G23 peptide to non-biodegradable poly(ethylene
glycol)-block-poly(butadiene) (PEG-b-PBD) polymersomes has been demonstrated to enhance
polymersome transcytosis across the BBB, both in vitro and in vivo [77, 78]. Remarkably,
the PEG-b-PBD polymersomes also seemed to accumulate in the lung [78]. Other studies
have recently shown the use of the G23 peptide for brain-targeted delivery of
doxorubicin-loaded nanoparticles in glioblastoma tumour-bearing mice, and an RNA-binding protein
complexed with siRNA against β-secretase 1 in a mouse model for Alzheimer’s disease
[79−81]. The reduced levels of transcytosis observed with PEG-b-PBD polymersomes and
alginate-iron oxide nanoparticles that were decorated with scrambled versions of the
G23 peptide emphasise the significance of the peptide sequence for promoting transport
across the BBB [77−79]. Altogether, these observations make G23 a promising ligand for
drug delivery into the brain.
SCOPE OF THE THESIS
Effective delivery of therapeutic cargo from the blood into the brain necessitates nanocarriers
that are decorated with ligands, such as the G23 peptide, that allow for specific binding
to the brain endothelium and stimulate subsequent vesicular transport across the BBB.
In earlier work BBB translocation of non-biodegradable G23-PEG-b-PBD polymersomes
was shown. However, the inability to biologically degrade polymersomes composed of
PEG-b-PBD block copolymers severely limits their application in drug delivery. The aim
of the work described in this thesis was to design biodegradable polymersomes suitable
for the delivery of therapeutics into the brain, and to improve the transcytosis capacity
of G23 peptide-decorated nanocarriers across the BBB. First, we report the formation of
biodegradable PEG-b-PCL polymersomes by the direct hydration method in Chapter 2.
This preparation method is used throughout this thesis for the assembly of biodegradable
PEG-P(CL-g-TMC) polymersomes. Because the PEG-P(CL-g-TMC) polymersomes adhere to
the membrane filter of conventional Transwell
®culture systems, which are typically used
to prepare in vitro BBB models for the quantification of transendothelial transport, we
establish a filter-free in vitro BBB model to quantitatively study transcytosis of
G23-PEG-P(CL-g-TMC) polymersomes in Chapter 3. In addition, eight other GM1-binding peptides
are conjugated to the polymersomes and their transcytosis capacity is assessed using
the filter-free BBB model. In Chapter 4, we compare the transendothelial transport of
polymersomes decorated with either G23, or the transferrin receptor-targeting peptide
THR, or a combination of both peptides, using the filter-free in vitro BBB. In Chapter 5,
we report the identification of properties that the G23 peptide has in common with
cell-penetrating peptides. Finally, a summary of this thesis and future perspectives regarding
the delivery of nanocarriers across the BBB are presented in Chapter 6.
REFERENCES
[1] A. Villabona-Rueda, C. Erice, C.A. Pardo, M.F. Stins, The evolving concept of the blood brain barrier (BBB): from a single static barrier to a heterogeneous and dynamic relay center, Front. Cell Neurosci. 13 (2019) 405.
[2] T.M. Mathiisen, K.P. Lehre, N.C. Danbolt, O.P. Ottersen, The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction, Glia 58 (9) (2010) 1094−1103. [3] P.S. Tsai, J.P. Kaufhold, P. Blinder, B. Friedman, P.J. Drew, H.J. Karten, P.D. Lyden, D. Kleinfeld, Correlations of neuronal
and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels, J. Neurosci. 29 (46) (2009) 14553−14570.
[4] T. Mabuchi, J. Lucero, A. Feng, J.A. Koziol, G.J. Del Zoppo, Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels, J. Cereb. Blood Flow Metab. 25 (2) (2005) 257−266.
[5] K.E. Schlageter, P. Molnar, G.D. Lapin, D.R. Groothuis, Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties, Microvasc. Res. 58 (3) (1999) 312−328.
[6] S.M. Stamatovic, A.M. Johnson, R.F. Keep, A.V. Andjelkovic, Junctional proteins of the blood-brain barrier: new insights into function and dysfunction, Tissue Barriers 4 (1) (2016) e1154641.
[7] T. Worzfeld, M. Schwaninger, Apicobasal polarity of brain endothelial cells, J. Cereb. Blood Flow Metab. 36 (2) (2016) 340−362.
[8] R.F. Haseloff, S. Dithmer, L. Winkler, H. Wolburg, I.E. Blasig, Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects, Semin. Cell Dev. Biol. 38 (2015) 16−25.
[9] S.G. Patching, Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery, Mol. Neurobiol. 54 (2) (2017) 1046−1077.
[10] P. Campos-Bedolla, F.R. Walter, S. Veszelka, M.A. Deli, Role of the blood-brain barrier in the nutrition of the central nervous system, Arch. Med. Res. 45 (8) (2014) 610−638.
[11] D.F. Leitner, J.R. Connor, Functional roles of transferrin in the brain, Biochim. Biophys. Acta 1820 (3) (2012) 393−402. [12] L. Descamps, M.P. Dehouck, G. Torpier, R. Cecchelli, Receptor-mediated transcytosis of transferrin through
blood-brain barrier endothelial cells, Am. J. Physiol. 270 (4 Pt 2) (1996) H1149−H1158.
[13] R.L. Roberts, R.E. Fine, A. Sandra, Receptor-mediated endocytosis of transferrin at the blood-brain barrier, J. Cell. Sci. 104 (Pt 2) (1993) 521−532.
[14] P. Candela, F. Gosselet, F. Miller, V. Buee-Scherrer, G. Torpier, R. Cecchelli, L. Fenart, Physiological pathway for low-density lipoproteins across the blood-brain barrier: transcytosis through brain capillary endothelial cells in vitro, Endothelium 15 (5−6) (2008) 254−264.
[15] B. Dehouck, L. Fenart, M.P. Dehouck, A. Pierce, G. Torpier, R. Cecchelli, A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier, J. Cell Biol. 138 (4) (1997) 877−889.
[16] M. Konishi, M. Sakaguchi, S.M. Lockhart, W. Cai, M.E. Li, E.P. Homan, C. Rask-Madsen, C.R. Kahn, Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice, Proc. Natl. Acad. Sci. USA 114 (40) (2017) E8478−E8487.
[17] R.I. Meijer, S.M. Gray, K.W. Aylor, E.J. Barrett, Pathways for insulin access to the brain: the role of the microvascular endothelial cell, Am. J. Physiol. Heart Circ. Physiol. 311 (5) (2016) H1132−H1138.
[18] W.M. Pardridge, J. Eisenberg, J. Yang, Human blood-brain barrier insulin receptor, J. Neurochem. 44 (6) (1985) 1771−1778.
[19] Alzheimer’s Association, 2019 Alzheimer’s disease facts and figures, Alzheimers Dement. 15 (3) (2019) 321−387. [20] L. Angelov, N.D. Doolittle, D.F. Kraemer, T. Siegal, G.H. Barnett, D.M. Peereboom, G. Stevens, J. McGregor, K. Jahnke,
C.A. Lacy, N.A. Hedrick, E. Shalom, S. Ference, S. Bell, L. Sorenson, R.M. Tyson, M. Haluska, E.A. Neuwelt, Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience, J. Clin. Oncol. 27 (21) (2009) 3503−3509.
[21] D. Fortin, A. Desjardins, A. Benko, T. Niyonsega, M. Boudrias, Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: the Sherbrooke experience, Cancer 103 (12) (2005) 2606−2615.
[22] N.M. Elkassabany, J. Bhatia, A. Deogaonkar, G.H. Barnett, M. Lotto, M. Maurtua, Z. Ebrahim, A. Schubert, S. Ference, E. Farag, Perioperative complications of blood brain barrier disruption under general anesthesia: a retrospective review, J. Neurosurg. Anesthesiol. 20 (1) (2008) 45−48.
[23] N. Marchi, L. Angelov, T. Masaryk, V. Fazio, T. Granata, N. Hernandez, K. Hallene, T. Diglaw, L. Franic, I. Najm, D. Janigro, Seizure-promoting effect of blood-brain barrier disruption, Epilepsia 48 (4) (2007) 732−742.
[24] D. Furtado, M. Björnmalm, S. Ayton, A.I. Bush, K. Kempe, F. Caruso, Overcoming the blood-brain barrier: the role of nanomaterials in treating neurological diseases, Adv. Mater. 30 (46) (2018) e1801362.
[25] C.T. Lu, Y.Z. Zhao, H.L. Wong, J. Cai, L. Peng, X.Q. Tian, Current approaches to enhance CNS delivery of drugs across the brain barriers, Int. J. Nanomedicine 9 (2014) 2241−2257.
[26] J.L. Mikitsh, A.M. Chacko, Pathways for small molecule delivery to the central nervous system across the blood-brain barrier, Perspect. Medicin. Chem. 6 (2014) 11−24.
[27] A. Mahringer, G. Fricker, ABC transporters at the blood-brain barrier, Expert Opin. Drug Metab. Toxicol. 12 (5) (2016) 499−508.
[28] D. Gomez-Zepeda, M. Taghi, J.M. Scherrmann, X. Decleves, M.C. Menet, ABC transporters at the blood-brain interfaces, their study models, and drug delivery implications in gliomas, Pharmaceutics 12 (1) (2019) E20. [29] M. Bauer, R. Karch, M. Zeitlinger, C. Philippe, K. Römermann, J. Stanek, A. Maier-Salamon, W. Wadsak, W. Jäger, M.
Hacker, M. Müller, O. Langer, Approaching complete inhibition of p-glycoprotein at the human blood-brain barrier: an (R)-[11C]verapamil PET study, J. Cereb. Blood Flow Metab. 35 (5) (2015) 743−746.
[30] W.C. Kreisl, R. Bhatia, C.L. Morse, A.E. Woock, S.S. Zoghbi, H.U. Shetty, V.W. Pike, R.B. Innis, Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar, J. Nucl. Med. 56 (1) (2015) 82−87.
[31] N. Singh, G.F. Ecker, Insights into the structure, function, and ligand discovery of the large neutral amino acid transporter 1, LAT1, Int. J. Mol. Sci. 19 (5) (2018) E1278.
[32] Q. Chen, T. Gong, J. Liu, X. Wang, H. Fu, Z. Zhang, Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery, J. Drug Target. 17 (4) (2009) 318−328.
[33] Y. Anraku, H. Kuwahara, Y. Fukusato, A. Mizoguchi, T. Ishii, K. Nitta, Y. Matsumoto, K. Toh, K. Miyata, S. Uchida, K. Nishina, K. Osada, K. Itaka, N. Nishiyama, H. Mizusawa, T. Yamasoba, T. Yokota, K. Kataoka, Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain, Nat. Commun. 8 (1) (2017) 1001.
[34] K. Shao, Y. Zhang, N. Ding, S. Huang, J. Wu, J. Li, C. Yang, Q. Leng, L. Ye, J. Lou, L. Zhu, C. Jiang, Functionalized nanoscale micelles with brain targeting ability and intercellular microenvironment biosensitivity for anti-intracranial infection applications, Adv. Healthc. Mater. 4 (2) (2015) 291−300.
[35] Z. Hao, Y. Cui, M. Li, D. Du, M. Liu, H. Tao, S. Li, F. Cao, Y. Chen, X. Lei, L. Wang, D. Zhu, H. Peng, C. Jiang, Liposomes modified with p-aminophenyl-α-D-mannopyranoside: a carrier for targeting cerebral functional regions in mice, Eur. J. Pharm. Biopharm. 84 (3) (2013) 505−516.
[36] J. Barar, M.A. Rafi, M.M. Pourseif, Y. Omidi, Blood-brain barrier transport machineries and targeted therapy of brain diseases, Bioimpacts 6 (4) (2016) 225−248.
[37] W.M. Pardridge, Blood-brain barrier and delivery of protein and gene therapeutics to brain, Front. Aging Neurosci. 11 (2020) 373.
[38] Z. Pang, H. Gao, J. Chen, S. Shen, B. Zhang, J. Ren, L. Guo, Y. Qian, X. Jiang, H. Mei, Intracellular delivery mechanism and brain delivery kinetics of biodegradable cationic bovine serum albumin-conjugated polymersomes, Int. J. Nanomedicine 7 (2012) 3421−3432.
[39] F. Fang, D. Zou, W. Wang, Y. Yin, T. Yin, S. Hao, B. Wang, G. Wang, Y. Wang, Non-invasive approaches for drug delivery to the brain based on the receptor mediated transport, Mater. Sci. Eng. C Mater. Biol. Appl. 76 (2017) 1316−1327. [40] J.V. Georgieva, D. Hoekstra, I.S. Zuhorn, Smuggling drugs into the brain: an overview of ligands targeting transcytosis
for drug delivery across the blood-brain barrier, Pharmaceutics 6 (4) (2014) 557−583.
[41] Z. Pang, W. Lu, H. Gao, K. Hu, J. Chen, C. Zhang, X. Gao, X. Jiang, C. Zhu, Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26, J. Control. Release 128 (2) (2008) 120−127.
[42] S. Fan, Y. Zheng, X. Liu, W. Fang, X. Chen, W. Liao, X. Jing, M. Lei, E. Tao, Q. Ma, X. Zhang, R. Guo, J. Liu, Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer’s disease, Drug Deliv. 25 (1) (2018) 1091−1102.
[43] Y. Zhang, F. Schlachetzki, W.M. Pardridge, Global non-viral gene transfer to the primate brain following intravenous administration, Mol. Ther. 7 (1) (2003) 11−18.
[44] A.S. Haqqani, G. Thom, M. Burrell, C.E. Delaney, E. Brunette, E. Baumann, C. Sodja, A. Jezierski, C. Webster, D.B. Stanimirovic, Intracellular sorting and transcytosis of the rat transferrin receptor antibody OX26 across the blood-brain barrier in vitro is dependent on its binding affinity, J. Neurochem. 146 (6) (2018) 735−752.
[45] N. Bien-Ly, Y.J. Yu, D. Bumbaca, J. Elstrott, C.A. Boswell, Y. Zhang, W. Luk, Y. Lu, M.S. Dennis, R.M. Weimer, I. Chung, R.J. Watts, Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants, J. Exp. Med. 211 (2) (2014) 233−244.
[46] Y.J. Yu, Y. Zhang, M. Kenrick, K. Hoyte, W. Luk, Y. Lu, J. Atwal, J.M. Elliott, S. Prabhu, R.J. Watts, M.S. Dennis, Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target, Sci. Transl. Med. 3 (84) (2011) 84ra44.
[47] H. Qin, Y. Jiang, J. Zhang, C. Deng, Z. Zhong, Oncoprotein inhibitor rigosertib loaded in ApoE-targeted smart polymersomes reveals high safety and potency against human glioblastoma in mice, Mol. Pharm. 16 (8) (2019) 3711−3719.
[48] Y. Shi, Y. Jiang, J. Cao, W. Yang, J. Zhang, F. Meng, Z. Zhong, Boosting RNAi therapy for orthotopic glioblastoma with nontoxic brain-targeting chimaeric polymersomes, J. Control. Release 292 (2018) 163−171.
[49] Y. Jiang, J. Zhang, F. Meng, Z. Zhong, Apolipoprotein E peptide-directed chimeric polymersomes mediate an ultrahigh-efficiency targeted protein therapy for glioblastoma, ACS Nano 12 (11) (2018) 11070−11079.
[50] Y. Jiang, W. Yang, J. Zhang, F. Meng, Z. Zhong, Protein toxin chaperoned by LRP-1-targeted virus-mimicking vesicles induces high-efficiency glioblastoma therapy in vivo, Adv. Mater. 30 (30) (2018) e1800316.
[51] F. Lu, Z. Pang, J. Zhao, K. Jin, H. Li, Q. Pang, L. Zhang, Z. Pang, Angiopep-2-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats, Int. J. Nanomedicine 12 (2017) 2117−2127.
[52] T. Jia, Z. Sun, Y. Lu, J. Gao, H. Zou, F. Xie, G. Zhang, H. Xu, D. Sun, Y. Yu, Y. Zhong, A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice, Int. J. Nanomedicine 11 (2016) 3765−3775.
[53] Y.C. Chen, C.F. Chiang, L.F. Chen, P.C. Liang, W.Y. Hsieh, W.L. Lin, Polymersomes conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery system, Biomaterials 35 (13) (2014) 4066−4081. [54] Y. Yu, Z. Pang, W. Lu, Q. Yin, H. Gao, X. Jiang, Self-assembled polymersomes conjugated with lactoferrin as novel
drug carrier for brain delivery, Pharm. Res. 29 (1) (2012) 83−96.
[55] Z. Pang, H. Gao, Y. Yu, L. Guo, J. Chen, S. Pan, J. Ren, Z. Wen, X. Jiang, Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin-conjugated biodegradable polymersomes loaded with doxorubicin, Bioconjug. Chem. 22 (6) (2011) 1171−1180.
[56] Z. Pang, L. Feng, R. Hua, J. Chen, H. Gao, S. Pan, X. Jiang, P. Zhang, Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats, Mol. Pharm. 7 (6) (2010) 1995−2005.
[57] C.G. Palivan, R. Goers, A. Najer, X. Zhang, A. Car, W. Meier, Bioinspired polymer vesicles and membranes for biological and medical applications, Chem. Soc. Rev. 45 (2) (2016) 377−411.
[58] E. Rideau, R. Dimova, P. Schwille, F.R. Wurm, K. Landfester, Liposomes and polymersomes: a comparative review towards cell mimicking, Chem. Soc. Rev. 47 (23) (2018) 8572−8610.
[59] L. Messager, J. Gaitzsch, L. Chierico, G. Battaglia, Novel aspects of encapsulation and delivery using polymersomes, Curr. Opin. Pharmacol. 18 (2014) 104−111.
[60] S. Matoori, J.C. Leroux, Twenty-five years of polymersomes: lost in translation?, Mater. Horiz. (2020).
[61] H.H. Gustafson, D. Holt-Casper, D.W. Grainger, H. Ghandehari, Nanoparticle uptake: the phagocyte problem, Nano Today 10 (4) (2015) 487−510.
[62] J.S. Suk, Q. Xu, N. Kim, J. Hanes, L.M. Ensign, PEGylation as a strategy for improving nanoparticle-based drug and gene delivery, Adv. Drug Deliv. Rev. 99 (Pt A) (2016) 28−51.
[63] P.H. Kierstead, H. Okochi, V.J. Venditto, T.C. Chuong, S. Kivimae, J.M. Fréchet, F.C. Szoka, The effect of polymer backbone chemistry on the induction of the accelerated blood clearance in polymer modified liposomes, J. Control. Release 213 (2015) 1−9.
[64] T. Ishida, M. Ichihara, X. Wang, K. Yamamoto, J. Kimura, E. Majima, H. Kiwada, Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes, J. Control. Release 112 (1) (2006) 15−25.
[65] E.T. Dams, P. Laverman, W.J. Oyen, G. Storm, G.L. Scherphof, J.W. Van Der Meer, F.H. Corstens, O.C. Boerman, Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes, J. Pharmacol. Exp. Ther. 292 (3) (2000) 1071−1079.
[66] N. d’Avanzo, C. Celia, A. Barone, M. Carafa, L. Di Marzio, H.A. Santos, M. Fresta, Immunogenicity of polyethylene glycol based nanomedicines: mechanisms, clinical implications and systematic approach, Adv. Therap. 3 (3) (2020) 1900170.
[67] T.T. Hoang Thi, E.H. Pilkington, D.H. Nguyen, J.S. Lee, K.D. Park, N.P. Truong, The importance of poly(ethylene glycol) alternatives for overcoming PEG immunogenicity in drug delivery and bioconjugation, Polymers (Basel) 12 (2) (2020) E298.
[68] K. Knop, R. Hoogenboom, D. Fischer, U.S. Schubert, Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives, Angew. Chem. Int. Ed. Engl. 49 (36) (2010) 6288−6308.
[69] F. Ahmed, D.E. Discher, Self-porating polymersomes of PEG-PLA and PEG-PCL: hydrolysis-triggered controlled release vesicles, J. Control. Release 96 (1) (2004) 37−53.
[70] C. Sanson, C. Schatz, J.F. Le Meins, A. Brûlet, A. Soum, S. Lecommandoux, Biocompatible and biodegradable poly(trimethylene carbonate)-b-poly(L-glutamic acid) polymersomes: size control and stability, Langmuir 26 (4) (2010) 2751−2760.
[71] C. Lebleu, L. Rodrigues, J.M. Guigner, A. Brûlet, E. Garanger, S. Lecommandoux, Self-assembly of PEG-b-PTMC copolymers: micelles and polymersomes size control, Langmuir 35 (41) (2019) 13364−13374.
[72] M. Dionzou, A. Morère, C. Roux, B. Lonetti, J.D. Marty, C. Mingotaud, P. Joseph, D. Goudounèche, B. Payré, M. Léonetti, A.F. Mingotaud, Comparison of methods for the fabrication and the characterization of polymer self-assemblies: what are the important parameters?, Soft Matter 12 (7) (2016) 2166−2176.
[73] J.S. Lee, J. Feijen, Polymersomes for drug delivery: design, formation and characterization, J. Control. Release 161 (2) (2012) 473−483.
[74] D.J. Adams, C. Kitchen, S. Adams, S. Furzeland, D. Atkins, P. Schuetz, C.M. Fernyhough, N. Tzokova, A.J. Ryan, M.F. Butler, On the mechanism of formation of vesicles from poly(ethylene oxide)-block-poly(caprolactone) copolymers, Soft Matter 5 (16) (2009) 3086−3096.
[75] D.A. Christian, S. Cai, D.M. Bowen, Y. Kim, J.D. Pajerowski, D.E. Discher, Polymersome carriers: from self-assembly to siRNA and protein therapeutics, Eur. J. Pharm. Biopharm. 71 (3) (2009) 463−474.
[76] C.P. O’Neil, T. Suzuki, D. Demurtas, A. Finka, J.A. Hubbell, A novel method for the encapsulation of biomolecules into polymersomes via direct hydration, Langmuir 25 (16) (2009) 9025−9029.
[77] J.V. Georgieva, R.P. Brinkhuis, K. Stojanov, C.A. Weijers, H. Zuilhof, F.P. Rutjes, D. Hoekstra, J.C. Van Hest, I.S. Zuhorn, Peptide-mediated blood-brain barrier transport of polymersomes, Angew. Chem. Int. Ed. Engl. 51 (33) (2012) 8339−8342.
[78] K. Stojanov, J.V. Georgieva, R.P. Brinkhuis, J.C. Van Hest, F.P. Rutjes, R.A. Dierckx, E.F. De Vries, I.S. Zuhorn, In vivo biodistribution of prion- and GM1-targeted polymersomes following intravenous administration in mice, Mol. Pharm. 9 (6) (2012) 1620−1627.
[79] C.H. Su, C.Y. Tsai, B. Tomanek, W.Y. Chen, F.Y. Cheng, Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications, Nanoscale 8 (15) (2016) 7866−7870.
[80] M.M. Haroon, K. Saba, V.H. Boddedda, J.M. Kumar, A.B. Patel, V. Gopal, Delivery of BACE1 siRNA mediated by TARBP-BTP fusion protein reduces β-amyloid deposits in a transgenic mouse model of Alzheimer’s disease, J. Biosci. 44 (1) (2019) 1.
[81] M.M. Haroon, G.H. Dar, D. Jeyalakshmi, U. Venkatraman, K. Saba, N. Rangaraj, A.B. Patel, V. Gopal, A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain, J. Control. Release 228 (2016) 120−131. [82] J.E. Schnitzer, D.P. McIntosh, A.M. Dvorak, J. Liu, P. Oh, Separation of caveolae from associated microdomains of
GPI-anchored proteins, Science 269 (5229) (1995) 1435−1439.
[83] T. Federici, J.K. Liu, Q. Teng, J. Yang, N.M. Boulis, A means for targeting therapeutics to peripheral nervous system neurons with axonal damage, Neurosurgery 60 (5) (2007) 911−918.
[84] J.K. Liu, Q. Teng, M. Garrity-Moses, T. Federici, D. Tanase, M.J. Imperiale, N.M. Boulis, A novel peptide defined through phage display for therapeutic protein and vector neuronal targeting, Neurobiol. Dis. 19 (3) (2005) 407−418. [85] A.S. Davis, T. Federici, W.C. Ray, N.M. Boulis, D. O’Connor, K.R. Clark, J.S. Bartlett, Rational design and engineering of a
modified adeno-associated virus (AAV1)-based vector system for enhanced retrograde gene delivery, Neurosurgery 76 (2) (2015) 216−225.
[86] J. Zhang, X. Zhou, Q. Yu, L. Yang, D. Sun, Y. Zhou, J. Liu, Epigallocatechin-3-gallate (EGCG)-stabilized selenium nanoparticles coated with Tet-1 peptide to reduce amyloid-β aggregation and cytotoxicity, ACS Appl. Mater. Interfaces 6 (11) (2014) 8475−8487.
[87] E.J. Kwon, J. Lasiene, B.E. Jacobson, I.K. Park, P.J. Horner, S.H. Pun, Targeted nonviral delivery vehicles to neural progenitor cells in the mouse subventricular zone, Biomaterials 31 (8) (2010) 2417−2424.
[88] I.K. Park, J. Lasiene, S.H. Chou, P.J. Horner, S.H. Pun, Neuron-specific delivery of nucleic acids mediated by Tet1-modified poly(ethylenimine), J. Gene Med. 9 (8) (2007) 691−702.
[89] Q. Guo, S. Xu, P. Yang, P. Wang, S. Lu, D. Sheng, K. Qian, J. Cao, W. Lu, Q. Zhang, A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer’s disease mice, J. Control. Release 320 (2020) 347−362. [90] P. Wang, X. Zheng, Q. Guo, P. Yang, X. Pang, K. Qian, W. Lu, Q. Zhang, X. Jiang, Systemic delivery of BACE1 siRNA
through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease, J. Control. Release 279 (2018) 220−233.
