Facile Functionalization of Polyesters through Thiol-yne Chemistry for the Design of Degradable, Cell-Penetrating and Gene Delivery Dual-Functional Agents

Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
Biomacromolecules (Impact Factor: 5.75). 10/2012; 13(11). DOI: 10.1021/bm301333w
Source: PubMed


Synthesis of polyesters bearing pendant amine groups with controlled molecular weights and narrow molecular weight distributions was achieved through ring-opening polymerization of 5-(4-(prop-2-yn-1-yloxy)benzyl)-1,3-dioxolane-2,4-dione, an O-carboxyanhydride derived from tyrosine, followed by thiol-yne "click" photochemistry with 2-aminoethanethiol hydrochloride. This class of biodegradable polymers displayed excellent cell penetration and gene delivery properties with low toxicities.

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Available from: Yanbing Lu, Oct 06, 2014
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    • "Along with the development of polymer chemistry, the applicability of CPs in gene delivery has been enhanced by incorporating biodegradability within their macromolecular structures. A variety of biodegradable CPs such as poly(b-amino ester)s [14e17], poly[a- (4-aminobutyl)-L-glycolic acid] [18], poly(4-hydroxy-L-proline ester) [19], poly(D-glucaramidoamine) [20], cationic poly(a-hydroxy acid) [21], and cationic cyclodextrin [22] have been successfully synthesized and used in gene delivery studies. In addition to protecting therapeutic genes from nuclease degradation, synthetic design of CPs can be directed to optimize their biodegradability and improve their biocompatibility for repeated administration of gene-based therapies [23] [24]. "
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    ABSTRACT: Representing a new type of biodegradable cationic block copolymer, well-defined poly(ethylene glycol)-block-cationic polylactides (PEG-b-CPLAs) with tertiary amine-based cationic groups were synthesized by thiol-ene functionalization of an allyl-functionalized diblock precursor. Subsequently the application of PEG-b-CPLAs as biodegradable vectors for the delivery of plasmid DNAs (pDNAs) was investigated. Via the formation of PEG-b-CPLA:pDNA nanocomplexes by spontaneous electrostatic interaction, pDNAs encoding luciferase or enhanced green fluorescent protein were successfully delivered to four physiologically distinct cell lines (including macrophage, fibroblast, epithelial, and stem cell). Formulated nanocomplexes demonstrated high levels of transfection with low levels of cytotoxicity and hemolysis when compared to a positive control. Biophysical characterization of charge densities of nanocomplexes at various polymer:pDNA weight ratios revealed a positive correlation between surface charge and gene delivery. Nanocomplexes with high surface charge densities were utilized in an in vitro serum gene delivery inhibition assay, and effective gene delivery was observed despite high levels of serum. Overall, these results help to elucidate the influence of charge, size, and PEGylation of nanocomplexes upon the delivery of nucleic acids in physiologically relevant conditions.
    Biomaterials 09/2013; 34(37). DOI:10.1016/j.biomaterials.2013.08.063 · 8.56 Impact Factor
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    ABSTRACT: Well-defined cationic polylactides (CPLAs) with tertiary amine groups were synthesized by thiol-ene click functionalization of an allyl-functionalized polylactide to yield polymers with tunable charge densities. CPLAs have not previously been utilized in the context of DNA delivery. Thus, plasmid DNA (pDNA) encoding luciferase was delivered to two physiological distinct cell lines (macrophage and fibroblast) via formation of CPLA/pDNA nanoplexes by electrostatic interaction. The formulated nanoplexes demonstrated high levels of transfection with low levels of cytotoxicity. Biophysical characterization of charge densities at various CPLA/pDNA weight ratios revealed a positive correlation between surface charge and gene delivery. Overall, these results help to elucidate the influence of nanoplex charge and size upon the delivery of nucleic acid and support future gene delivery applications using this next-generation biomaterial.
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    ABSTRACT: We developed camptothecin (CPT)-conjugated, core-cross-linked (CCL) micelles that are subject to redox-responsive cleavage of the built-in disulfide bonds, resulting in disruption of the micellar structure and rapid release of CPT. CCL micelles were prepared via co-precipitation of disulfide-containing CPT-poly(Tyrosine(alkynyl)-OCA) conjugate and monomethoxy poly(ethylene glycol)-b-poly(Tyrosine(alkynyl)-OCA), followed by cross-linking of the micellar core via azidealkyne click chemistry. CCL micelles exhibited excellent stability under physiological conditions while underwent rapid dissociation in reduction circumstance, resulting in burst release of CPT. These redox-responsive CCL micelles showed enhanced cytotoxicity against human breast cancer cells in vitro.
    Biomacromolecules 09/2013; 14(10). DOI:10.1021/bm401086d · 5.75 Impact Factor
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