Abstract
Polymeric micelles have found a growing interest as gene vectors due to the serious safety concerns associated with viral vectors. In particular, the cationic polymer polyethylene imine (PEI) has shown relatively high condensation and transfection efficiencies. Additionally, polyethylene glycol (PEG) modification of polymeric gene vectors has dramatically improved their biological properties, including enhanced biocompatibility, prolonged circulation time, and increased bio-distribution. However, PEG grafting of PEI for subsequent condensation of nucleic acids (NAs) does not necessarily result in the formation of a PEI/NAs core with a PEG corona. But often times, the presence of PEG interferes with PEI’s electrostatic interaction with NAs. We describe here a facile method to prepare multilayered biodegradable micelles which address some of the critical drawbacks associated with current PEI-based systems. The polyplex micelles have superb stability and stealth properties. Moreover, we describe a method to prepare fully biodegradable and biocompatible injectable hydrogels for use in localized gene therapy.
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References
Langer R, Tirrell DA (2004) Designing materials for biology and medicine. Nature 428(6982):487–492
Vagner J, Qu HC, Hruby VJ (2008) Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol 12(3):292–296
Mavromoustakos T, Durdagi S, Koukoulitsa C, Simcic M, Papadopoulos MG, Hodoscek M, Grdadolnik SG (2011) Strategies in the rational drug design. Curr Med Chem 18(17):2517–2530
Singh V (2014) Recent advancements in synthetic biology: current status and challenges. Gene 535(1):1–11
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCcormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint BG, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302(5644):415–419
Wiseman JW, Goddard CA, McLelland D, Colledge WH (2003) A comparison of linear and branched polyethylenimine (PEI) with DCChol/DOPE liposomes for gene delivery to epithelial cells in vitro and in vivo. Gene Ther 10(19):1654–1662
Chollet P, Favrot MC, Hurbin A, Coll JL (2002) Side-effects of a systemic injection of linear polyethylenimine-DNA complexes. J Gene Med 4(1):84–91
Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A (2005) A two-stage poly(ethylenimine)-mediated cytotoxicity: Implications for gene transfer/therapy. Mol Ther 11(6):990–995
Breunig M, Lungwitz U, Liebl R, Goepferich A (2007) Breaking up the correlation between efficacy and toxicity for nonviral gene delivery. Proc Natl Acad Sci U S A 104(36):14454–14459
Merkel OM, Urbanics R, Bedocs P, Rozsnyay Z, Rosivall L, Toth M, Kissel T, Szebeni J (2011) In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. Biomaterials 32(21):4936–4942
Moret I, Peris JE, Guillem VM, Benet M, Revert F, Dasi F, Crespo A, Alino SF (2001) Stability of PEI-DNA and DOTAP-DNA complexes: effect of alkaline pH, heparin and serum. J Control Release 76(1-2):169–181
Petersen H, Fechner PM, Fischer D, Kissel T (2002) Synthesis, characterization, and biocompatibility of polyethylenimine-graft-poly(ethylene glycol) block copolymers. Macromolecules 35(18):6867–6874
Kunath K, von Harpe A, Petersen H, Fischer D, Voigt K, Kissel T, Bickel U (2002) The structure of PEG-modified poly(ethylene imines) influences biodistribution and pharmacokinetics of their complexes with NF-kappa B decoy in mice. Pharm Res 19(6):810–817
Bauhuber S, Liebl R, Tomasetti L, Rachel R, Goepferich A, Breunig M (2012) A library of strictly linear poly(ethylene glycol)-poly(ethylene imine) diblock copolymers to perform structure-function relationship of non-viral gene carriers. J Control Release 162(2):446–455
Barratt G (2003) Colloidal drug carriers: achievements and perspectives. Cell Mol Life Sci 60(1):21–37
Mintzer MA, Simanek EE (2009) Nonviral vectors for gene delivery. Chem Rev 109(2):259–302
Lee JI, Kim HS, Yoo HS (2009) DNA nanogels composed of chitosan and Pluronic with thermo-sensitive and photo-crosslinking properties. Int J Pharm 373(1-2):93–99
Giano MC, Ibrahim Z, Medina SH, Sarhane KA, Christensen JM, Yamada Y, Brandacher G, Schneider JP (2014) Injectable bioadhesive hydrogels with innate antibacterial properties. Nat Commun 5:9
Lei P, Padmashali RM, Andreadis ST (2009) Cell-controlled and spatially arrayed gene delivery from fibrin hydrogels. Biomaterials 30(22):3790–3799
Krebs MD, Salter E, Chen E, Sutter KA, Alsberg E (2010) Calcium alginate phosphate-DNA nanoparticle gene delivery from hydrogels induces in vivo osteogenesis. J Biomed Mater Res A 92A(3):1131–1138
Li ZH, Ning W, Wang JM, Choi A, Lee PY, Tyagi P, Huang L (2003) Controlled gene delivery system based on thermosensitive biodegradable hydrogel. Pharm Res 20(6):884–888
Kasper FK, Seidlits SK, Tang A, Crowther RS, Carney DH, Barry MA, Mikos AG (2005) In vitro release of plasmid DNA from oligo(poly(ethylene glycol) fumarate) hydrogels. J Control Release 104(3):521–539
Abebe DG, Kandil R, Kraus T, Elsayed M, Merkel OM, Fujiwara T (2015) Three-layered biodegradable micelles prepared by two-step self-assembly of PLA-PEI-PLA and PLA-PEG-PLA triblock copolymers as efficient gene delivery system. Macromol Biosci 15(5):698–711
Abebe DG, Fujiwara T (2012) Controlled thermoresponsive hydrogels by stereocomplexed PLA-PEG-PLA prepared via hybrid micelles of Pre-mixed copolymers with different PEG lengths. Biomacromolecules 13(6):1828–1836
Patil YB, Toti US, Khdair A, Ma L, Panyam J (2009) Single-step surface functionalization of polymeric nanoparticles for targeted drug delivery. Biomaterials 30(5):859–866
Acknowledgments
OMM acknowledges the Wayne State University Start-Up grant. The Electron Microscopy Core Facility at Wayne State University is partially supported by NSF-MRI grant 0216084 and NSF-MRI grant 0922912. We are grateful to Dr. Zhi Mei for expert support with the TEM imaging of our samples.
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Abebe, D.G., Kandil, R., Kraus, T., Elsayed, M., Fujiwara, T., Merkel, O.M. (2016). Biodegradable Three-Layered Micelles and Injectable Hydrogels. In: Candiani, G. (eds) Non-Viral Gene Delivery Vectors. Methods in Molecular Biology, vol 1445. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3718-9_11
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DOI: https://doi.org/10.1007/978-1-4939-3718-9_11
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