Temperature-, pH-, and light-responsive reversibly cross-linked micelle assemblies for efficient DOX delivery

Abstract

Cancer is a global health concern, with millions diagnosed annually and over half dying. Traditional treatments struggle with low bioavailability, leading to toxicity. Solutions like hydrogels, liposomes, and polymeric micelles (PMs) are proposed. A series of stimuli-responsive PMs are fabricated for doxorubicin (DOX) delivery, allowing for efficient crosslinking and cleavage through controllable photodimerization of coumarin. The block copolymers are synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization where hydrophilic block is composed of poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA), and their hydrophobic block is composed of poly(7-acryloyloxy-4-methylcoumarin-co-methyl methacrylate) (P(AC-r-MMA)). DOX is efficiently delivered using these well-defined, nontoxic and multi-responsive PMs. The dynamic light scattering (DLS) data revealed that the size of the polymer assemblies altered in response to pH, temperature changes, and UV light irradiation. The LCST of PDMAEMA shifted from 54 to 59 °C after photodimerization of the coumarin group, indicating that the thermal behavior of PMs can be controlled by light. The Weibull mathematical model was used to study in vitro drug release kinetics from multi-responsive PMs, revealing sustained and controlled release patterns of DOX. DOX release can be controlled by various triggers, the cumulative release at pH = 4.5 is almost 20% higher than in neutral environment, due to the protonation of the PDMAEMA segment. Also, the cumulative DOX release faced a sharp drop of ~ 50% after UV light irradiation through cross-linked micelles. It is worth noting that a relatively low concentration of coumarin molecules resulted in highly efficient light-controlled drug release from the assemblies.

Graphical abstract