Hybrid Homodimeric Prodrug Nanoassemblies for Low-Toxicity and Synergistic Chemophotodynamic Therapy of Melanoma.

Abstract

Synergistically active nanoparticles hold great promise for facilitating multimodal cancer therapy. However, strategies for their feasible manufacture and optimizing their formulations remain lacking. Herein, we developed hybrid homodimeric prodrug nanotherapeutics with tumor-restricted drug activation and chemophotodynamic pharmacology by leveraging the supramolecular nanoassembly of small molecules. The covalent dimerization of cytotoxic taxane chemotherapy via reactive oxygen species (ROS)-activated linker yielded a homodimeric prodrug, which was further coassembled with a ROS-generating dimeric photosensitizer. The nanoassemblies were readily refined in an amphiphilic PEGylation matrix for particle surface cloaking and in vivo intravenous injection. The nanoassemblies were optimized with favorable stability and combinatorial synergism to kill cancer cells. Upon near-infrared laser irradiation, the neighboring dimer photosensitizer generated ROS, subsequently triggering bond cleavage to facilitate drug activation, which in turn produced synergistic chemophotodynamic effects against cancer. In a preclinical model of melanoma, the intravenous administration of PEGylated nanoassemblies followed by near-infrared tumor irradiation led to significant tumor regression. Furthermore, animals treated with this efficient, photo-activatable nanotherapy exhibited low systemic toxicity even at high doses. This study describes a simple and cost-effective approach to integrate multimodal therapies by creating self-assembling small-molecule prodrugs for designing a combinatorial therapeutic nanosystem. We consider that this new paradigm holds substantial potential for advancing clinical translation.