Thermoresponsive Graft Copolymers of N‑Isopropylacrylamide and Hyperbranched Polyglycerol as Thermally Induced Drug Delivery and Release Nanoformulation Systems for Curcumin with High Colloidal Stability and Enhanced Anticancer Effect.

The poor solubility, stability issues, and restricted bioavailability of numerous drugs and potential pharmaceutical compounds highlight the critical need for the development of polymeric nanoparticles as effective drug delivery systems. Ideal polymers for such applications must be biocompatible, provide controlled drug loading and release, and maintain the high colloidal stability of the nanoformulation. In this study, LCST-type thermoresponsive poly-(N-isopropylacrylamide)-g-(hyperbranched polyglycerol) (PNiPAAm-g-HbPG) graft copolymers, composed of two biocompatible components, were synthesized by grafting amino-monofunctional HbPG, prepared by multibranching anionic ring-opening polymerization, onto PNiPAAm chains containing succinimide active ester groups. In both aqueous solutions and phosphate-buffered saline, these graft copolymers undergo reversible aggregation and disaggregation in response to temperature changes, with linear increase of the critical solution temperature (CST) as a function of grafting density. The architecture of the copolymers enables efficient encapsulation of curcumin, a natural anticancer agent, by a simple mixing process at elevated temperatures, and the hydrophilic HbPG side chains provide excellent colloidal stability for the polymer-drug nanoformulations. Sustained release of curcumin from the PNiPAAm-g-HbPG aggregates was found, which depends on the grafting density, and the release rate can be externally triggered by decreasing the temperature. The potential biocompatibility of the PNiPAAm-g-HbPG graft copolymers was demonstrated in vitro, with no evidence of cytotoxicity or hemolytic activity against human cells. The nanoformulations of curcumin with these new graft copolymers enhanced its internalization into HT-29 human colorectal adenocarcinoma cells and significantly improved its cytostatic effect against colon cancer cells. These properties of the novel PNiPAAm-g-HbPG graft copolymers make them superior candidates for advanced drug encapsulation and delivery systems.