PEG-based polymeric biomaterials for controlled intratumoral chemotherapy and vaginal microbicide delivery

Abstract

Overview of thesis: development of PEG based biomaterials for intratumoral delivery of chemotherapeutic agents and microbicide delivery for HIV-1 prevention. (A) This section illustrates the development of hydrazone linkage-based PEG hydrogels and Xanthan-PEG hydrogels with injectable and self-healing properties facilitating the intratumoral delivery of a chemotherapeutic agent (doxorubicin). (B) This section illustrates the development of a mucoadhesive hydrogel system (hybrid imine and hydrazone linkage) which can form a uniform layer over vaginal mucosa owing to its in-situ formation along with providing a controlled release of tenofovir (microbicide). (C) this section illustrates the development of a polymeric micelle system from a mannose functionalized PEG-PCL copolymer. The polymeric micelles loaded with microbicide agent can provide prophylactic prevention from HIV-1 infection by actively targeting the viral reservoir cells (dendritic cells and Langerhans cells) The release of drugs from an optimized formulation at a predetermined rate has been the biggest challenge in drug delivery, in particular for controlled delivery of chemotherapeutic agents to treat cancer and microbicides to prevent HIV-1 infection in women. Hydrogels are water-insoluble network of hydrophilic polymers formed by covalent crosslinking of polymer chains, with the ability to absorb water and swell. These networks allow molecules to diffuse in and out of the matrix. Owing to their excellent biocompatibility along with tunable physicochemical characteristics and biodegradability, hydrogels have emerged as smart delivery systems capable of providing spatiotemporal control over the release of macromolecular as well as small molecule therapeutics1. Hydrogels have been extensively explored for intratumoral chemotherapy2 and vaginal microbicide3 delivery but without much success so far as product development is concerned. The present work aims to develop novel PEG-based biodegradable hydrogels to address these challenges. The first platform developed were PEG-based hydrogels formed utilizing glyoxylic hydrazone linkages between a glyoxylic aldehyde-terminated 8-arm PEG and hydrazine-terminated 8-arm PEG. Similarly, xanthan-based hydrogels were developed utilizing hydrazone linkages formed between free aldehydes in partially oxidized xanthan and hydrazine-terminated 8-arm PEG4. Both hydrogels exhibited fast gelation and excellent mechanical robustness along with slow in vitro degradation and doxorubicin (DOX) release spanning over a month. Also, the hydrogels were found to be compatible with mammalian cells. Although these hydrogels exhibited excellent drug release properties, the lack of inherent mucoadhesive characteristics makes them unsuitable for vaginal microbicide delivery. Therefore, we developed imine/hydrazone linkage-based hybrid hydrogels from PEG and chitosan. Presence of chitosan is expected to provide significant mucoadhesion. These hydrogels provided a pH-responsive sustained release of tenofovir for over a week in in vitro simulated vaginal environment with degradation time ranging from a week to a month and found to be compatible with mammalian fibroblasts and non-irritant towards reconstitute human vaginal epithelium 3D model (in vitro). The microbicide released from hydrogels developed in the present work is likely to be restricted to vaginal lumen, with no ability to reach virus reservoirs, such as Langerhans and dendritic cells, in submucosal regions5. Therefore, we developed mucopenetrating mannose-grafted polymeric micelles composed of PEG-PCL block copolymers6. The polymeric micelles were found in the range of 50-100 nm and Multiple Particle Tracking studies of mannosylated and unmodified polymeric micelles showed similar diffusivity in porcine intestinal mucus (Cardiff Mucus). In conclusion, an array of polymeric biomaterials were developed from synthetic and biopolymers, which can be fine tuned in terms of drug release, biodegradation, mucopenetration, and mechanical characteristics pertaining to a variety of drug delivery challenges apart from being biocompatible towards mammalian cells.