Using Polymer Chemistry to Modulate the Delivery of Neurotrophic Factors from Degradable Microspheres: Delivery of BDNF
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Brain-derived neurotrophic factor (BDNF) plays an important role in neuroprotection and repair, but long-term delivery from polymer systems has been challenging. We investigated the role the chemistry of the polymer played in loading and delivery of BDNF via microspheres, which are suitable for minimally invasive administration.
We synthesized polymers based on PLGA and PEG to determine what components augmented loading and delivery. We characterized microspheres fabricated from these polymers using a battery of tests, including sizing, in vitro release, and bioactivity of the BDNF using PC12 cells engineered to express the trkB receptor.
We found that a triblock polymer of PLGA, PLL, and PEG led to the delivery of BDNF for periods of time greater than 60 days and that the BDNF delivered was bioactive. The microsphere size was amendable to injection via a 30 gauge needle, allowing minimally invasive delivery.
PLGA-PLL-PEG leads to greater loading and longer-term delivery of BDNF than PLGA or a blend of the polymers. We hypothesize that the introduction of an amphiphilic PLGA-based polymer increases the interaction of the BDNF with the polymer and leads to release that more closely correlates with the degradation of the polymer.
- Xu XM, Guénard V, Kleitman N, Aebischer P, Bunge MB. A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol. 1995;134:261–72. CrossRef
- Bamber NI, Li H, Oudega M, Aebischer P, Xu XM. Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J NeuroSci. 2001;13:257–68.
- Suzuki T, Ooto S, Akagi T, et al. Effects of prolonged delivery of brain-derived neurotrophic factor on the fate of neural stem cells transplanted into the developing rat retina. Biochem Biophys Res Commun. 2003;309:843–7. CrossRef
- Vicario-Abejon C, Collin C, Tsoulfas P, McKay RDG. Hippocampal stem cells differentiate into excitatory and inhibitory neurons. Eur J NeuroSci. 2000;12:677–88. CrossRef
- Nakamuraand M, Bregman BS. Differences in neurotrophic factor gene expression profiles between neonate and adult rat spinal cord after injury. Exp Neurol. 2001;169:407–15. CrossRef
- Vejsada R, Tseng J, Linsay R, Acheson A, Aebischer P, Kato A. Synergistic but transient rescue effects of BDNF and GDNF on axontomized neonatal motoneurons. Neuroscience. 1998;84:129–39. CrossRef
- Gillespie LN, Clark GM, Bartlett PF, Marzella PL. BDNF-induced survival of auditory neurons in vivo: cessation of treatment leads to accelerated loss of survival effects. J. Neurosci. Res. 2003;71:785–90. CrossRef
- BDNF Study group. A controlled trial of recombinant methionyl human BDNF in ALS. Neurology. 1999;52:1427–33.
- Lu P, Jones LL, Tuszynski MH. BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol. 2005;191:344–60. CrossRef
- Patist CM, Mulder MB, Gautier SE, Maquet V, Jerome R, Oudega M. Freeze-dried poly(D, L-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord. Biomaterials. 2004;25:1569–82. CrossRef
- Loh NK, Woerly S, Bunt SM, Wilton SD, Harvey AR. The regrowth of axons within tissue defects in the CNS is promoted by implanted hydrogel matrices that contain BDNF and CNTF producing fibroblasts. Exp Neurol. 2001;170:72–84. CrossRef
- Aszmann OC, Korak KJ, Kropf N, Fine E, Aebischer P, Frey M. Simultaneous GDNF and BDNF application leads to increased motoneuron survival and improved functional outcome in an experimental model for obstetric brachial plexus lesions. Plast Reconstr Surg. 2002;110:1066–72. CrossRef
- Comolli N, Neuhuber B, Fischer I, Lowman A. In vitro analysis of PNIPAAm-PEG, a novel, injectable scaffold for spinal cord repair. Acta Biomater. 2009;5:1046–55. CrossRef
- Winter JO, Gokhale M, Jensen RJ, Cogan SF, Rizzo JF. Tissue engineering applied to the retinal prosthesis: neurotrophin-eluting polymeric hydrogel coatings. Mater Sci Eng, C, Biomim Mater, Sens Syst. 2008;28:448–53.
- Peymanand GA, Ganiban GJ. Delivery systems for intraocular routes. Adv Drug Deliv Rev. 1995;16:107–23. CrossRef
- Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol. 2001;19:1029–34. CrossRef
- Kaigler D, Krebsbach PH, Polverini PJ, Mooney DJ. Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells. Tissue Eng. 2003;9:95–103. CrossRef
- Lavik EB, Hrkach JS, Lotan N, Nazarov R, Langer R. A simple synthetic route to the formation of a block copolymer of poly(lactic-co-glycolic acid) and polylysine for the fabrication of functionalized, degradable structures for biomedical applications. J. Biomed. Mater. Res. 2001;58:291–4. CrossRef
- Bertram JP, Jay SM, Hynes SR, Robinson R, Criscione JM, Lavik, EB. Functionalized poly(lactic-co-glycolic acid) enhances drug delivery and provides chemical moieties for surface engineering while preserving biocompatibility. Acta Biomaterialia. 2009;5:2860–71.
- Ford MC, Bertram JP, Hynes SR, et al. A macroporous hydrogel for the coculture of neural progenitor and endothelial cells to form functional vascular networks in vivo. Proc Natl Acad Sci USA. 2006;103:2512–7. CrossRef
- Elisseeff J, McIntosh W, Fu K, Blunk T, Langer R. Controlled-release of IGF-I and TGF-beta 1 in a photopolymerizing hydrogel for cartilage tissue engineering. J Orthop Res. 2001;19:1098–104. CrossRef
- Pean JM, Boury F, Venier-Julienne MC, Menei P, Proust JE, Benoit JP. Why does PEG 400 co-encapsulation improve NGF stability and release from PLGA biodegradable microspheres? Pharm Res. 1999;16:1294–9. CrossRef
- Ward MS, Khoobehi A, Lavik EB, Langer R, Young MJ. Neuroprotection of retinal ganglion cells in DBA/2 J mice with GDNF-loaded biodegradable microspheres. J. Pharm. Sci. 2007;96:558–68. CrossRef
- Fu K, Harrell R, Zinski K, et al. A potential approach for decreasing the burst effect of protein from PLGA microspheres. J. Pharm. Sci. 2003;92:1582–91. CrossRef
- Bilati U, Allemann E, Doelker E. Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles. Eur J Pharm Biopharm. 2005;59:375–88. CrossRef
- Perez C, Castellanos IJ, Costantino HR, Al-Azzam W, Griebenow K. Recent trends in stabilizing protein structure upon encapsulation and release from bioerodible polymers. J Pharm Pharmacol. 2002;54:301–13. CrossRef
- van de Weert M, Hennink W, Jiskoot W. Protein instability in poly(lactic-co-glycolic acid) microparticles. Pharm Res. 2000;17:1159–67. CrossRef
- Smith PK, Krohn RI, Hermanson GT, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150:76–85. CrossRef
- Cohen S, Yoshioka T, Lucarelli M, Hwang LH, Langer R. Controlled delivery systems for proteins based on poly(lactic glycolic acid) microspheres. Pharm Res. 1991;8:713–20. CrossRef
- Deng C, Chen X, Yu H, Sun J, Lu T, Jing X. A biodegradable triblock copolymer poly(ethylene glycol)-b-poly(l-lactide)-b-poly(l-lysine): synthesis, self-assembly, and RGD peptide modification. Polymer. 2007;48:139–49. CrossRef
- Khang G, Lee SJ, Lee JH, Kim YS, Lee HB. Interaction of fibroblast cells on poly(lactide-co-glycolide) surface with wettability chemogradient. Biomed Mater Eng. 1999;9:179–87.
- Beletsi A, Leontiadis L, Klepetsanis P, Ithakissios DS, Avgoustakis K. Effect of preparative variables on the properties of poly(dl-lactide-co-glycolide) methoxypoly(ethyleneglycol) copolymers related to their application in controlled drug delivery. Int J Pharm. 1999;182:187–97. CrossRef
- Patapoutinand A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11:272–80. CrossRef
- Greeneand LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth-factor. Proc Natl Acad Sci USA. 1976;73:2424–8. CrossRef
- Putneyand SD, Burke PA. Improving protein therapeutics with sustained-release formulations. Nat Biotechnol. 1998;16:153–7. CrossRef
- Krewson CE, Dause R, Mak M, Saltzman WM. Stabilization of nerve growth factor in controlled release polymers and in tissue. J Biomater Sci Polym Ed. 1996;8:103–17. CrossRef
- Maysinger D, Krieglstein K, FilipovicGrcic J, Sendtner M, Unsicker K, Richardson P. Microencapsulated ciliary neurotrophic factor: physical properties and biological activities. Exp Neurol. 1996;138:177–88. CrossRef
- Pean JM, Venier-Julienne MC, Filmon R, Sergent M, Phan-Tan-Luu R, Benoit JP. Optimization of HSA and NGF encapsulation yields in PLGA microparticles. Int J Pharm. 1998;166:105–15. CrossRef
- Péan J-M, Venier-Julienne MC, Boury F, Menei P, Denizot B, Benoit JP. NGF release from poly(D, L-lactide-co-glycolide) microspheres. E.B. J Contr Release. 1998;56:175–87. CrossRef
- Thote AJ, Chappell JT, Gupta RB, Kumar R. Reduction in the initial-burst release by surface crosslinking of PLGA microparticles containing hydrophilic or hydrophobic drugs. Drug Dev Ind Pharm. 2005;31:43–57.
- Park T. Degradation of poly(D, L-lactic acid) microspheres: effect of molecular weight. J Contr Release: official journal of the Controlled Release Society. 1994;30:161–73.
- Park TG. Degradation of poly(lactic-co-glycolic acid) microspheres - effect of copolymer composition. Biomaterials. 1995;16:1123–30. CrossRef
- Blanco MD, Sastre RL, Teijon C, Olmo R, Teijon JM. Degradation behaviour of microspheres prepared by spray-drying poly(D, L-lactide) and poly(D, L-lactide-co-glycolide) polymers. Int J Pharm. 2006;326:139–47. CrossRef
- Zolnikand BS, Burgess DJ. Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres. J Contr Release. 2008;127:137–45. CrossRef
- Alder J, Thakker-Varia S, Bangasser DA, et al. Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J. Neurosci. 2003;23:10800–8.
- Soppet D, Escandon E, Maragos J, et al. the neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkb tyrosine kinase receptor. Cell. 1991;65:895–903. CrossRef
- Wood MD, Borschel GH, Sakiyama-Elbert SE. Controlled release of glial-derived neurotrophic factor from fibrin matrices containing an affinity-based delivery system. J Biomed Mater Res Part A. 2009;89A:909–18. CrossRef
- Devakumarand J, Mookambeswaran V. A novel affinity-based controlled release system involving derivatives of dextran with enhanced osmotic activity. Bioconjug Chem. 2007;18:477–83. CrossRef
- Maxwell DJ, Hicks BC, Parsons S, Sakiyama-Elbert SE. Development of rationally designed affinity-based drug delivery systems. Acta Biomater. 2005;1:101–13. CrossRef
- Thatipartiand T, von Recum H. Cyclodextrin Complexation for Affinity-Based Antibiotic Delivery. Macromol Biosci:epub. 2009.
- Using Polymer Chemistry to Modulate the Delivery of Neurotrophic Factors from Degradable Microspheres: Delivery of BDNF
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- 1. Department of Biomedical Engineering, Yale University, 55 Prospect Street, Malone Engineering Center, New Haven, Connecticut, 06520, USA
- 2. Department of Anesthesiology, Columbia University Medical Center, New York, New York, 10032, USA
- 3. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, 44106, USA