Polymer-based therapeutics show great promise in the treatment of cancer due to their versatile and tunable structures, which allow for sophisticated control over their properties and functions. Zwitterions have been widely investigated as alternatives to poly(ethylene glycol) (PEG) for enhancing water solubility and prolonging circulation time of therapeutics. A new class of polymeric biomaterials has been developed in our laboratory by incorporating extremely hydrophilic zwitterions with biodegradable functional polylactides (PLAs). In particular, zwitterionic polymer-drug conjugate (PDC) has been studied for sustained delivery of paclitaxel (PTX). Zwitterionic sulfobetaine (SB) and anticancer drug PTX were functionalized with thiol groups respectively, and then conjugated with PLA backbone by thiol-ene reactions with an allyl-functionalized PLA. The resulting PDC could form stable nanoparticles in aqueous solution. Complete enzymatic degradation and pH-sensitive hydrolytic sustained release of PTX were confirmed. In vitro studies demonstrated high anticancer efficacy and effective cellular uptake. Currently our research efforts on this project focus on development of other biodegradable zwitterionic polymer-based delivery systems for cancer therapy and diagnosis via multi-functionalization strategy. Both allyl-functionalized PLAs and acetylene-functionalized PLAs are adopted to serve as the precursors of polymer backbones. New types of hydrophilic zwitterions including SB and carboxybetaine (CB) are employed as solubilizing residues. The zwitterionic moieties and other functional groups such as anticancer drug, dye, targeting moieties, are grafted onto the functionalized PLAs via thiol-ene or azide-alkyne click chemistries. The resulting polymer conjugates could be used to develop nanoparticles, micelles, and nanocapsules for delivery of therapeutic agents and/or imaging agents. The integration of functional PLAs with hydrophilic zwitterions and other biomedical-relevant functionalities will generate a variety of novel biomaterials with significant application potentials in drug delivery, gene delivery, drug-gene co-delivery and imaging.

Biodegradable zwitterionic polylactide-based delivery systems for cancer treatment

255th National Meeting (2018)

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