Dendron-Polymer Conjugate Based Cross-Linked Micelles: A Robust and Versatile Nanosystem for Targeted Delivery.

Abstract

Among various nanomedicine platforms, biodegradable polymeric micelles offer a viable approach to targeted cancer therapy. Herein, we report fabrication of core-cross-linked micelles using dendron-polymer conjugates as building blocks. Hydrophobic polyester dendrons containing peripheral alkene groups are conjugated to a hydrophilic poly(ethylene glycol) based copolymer bearing activated ester groups for appending an amine-containing peptide based targeting group, namely, cRGDfK. Micellar constructs assembled in aqueous media were cross-linked using a tetra-thiol molecule via the photochemical thiol-ene reaction. Cross-linked and non-cross-linked micelles were compared in terms of their critical micellar concentration, stability, drug loading, and drug release characteristics. It was observed that the cross-linked micelles were stable upon excessive dilution compared to their non-cross-linked counterparts. Importantly, the amount of passive drug release in neutral pH was considerably lower for the cross-linked micellar systems. Furthermore, treatment of MDA-MB-231 breast cancer cells with nontargeted and targeted cross-linked micelles demonstrated higher internalization of the targeted construct. In corroboration, in vitro assay revealed that drug loaded targeted micelles possessed higher cytotoxicity than the nontargeted ones. Facile fabrication of this modular platform which can carry a desired therapeutic agent and be conjugated with appropriate targeting units, along with the attributes necessary to serve as a viable drug delivery system, offers a platform with potential for addressing various challenges in the field of micellar drug delivery.