Tweaking Unimolecular Micellar Nanoarchitecture for Drug Delivery in Tumor Xenograft Mice Models

Abstract Uncontrolled rapture of prodrug nano‐formulation under physiological concentration gradient is a bottleneck in the effective delivery of anticancer drugs to solid tumors in vivo. The present investigation reports macromolecular nano‐compartmentalization in single polymer chain micellar nanoparticle (or unimolecular micelle nanoparticle, UMNp) and demonstrates its therapeutic efficacies in pancreatic cancer xenograft mouse model. The UMNp is engineered in a six‐arm enzymatic‐biodegradable polycaprolactone star‐polymer by employing a divergent approach using identical chemical constituents but varying the arms‐lengths. The tiny <25 nm sized core–shell UMNp is found to be non‐toxic, non‐hemolytic, and highly efficient in loading 14% of clinical drug doxorubicin (DOX). UMNp undergoes biodegradation at the intracellular endo‐lysosomal compartments and exhibited substantial growth inhibition in multiple cancer cell lines such as MCF‐7 (breast cancer), MDA‐MB‐231 and MDA‐MB‐468 (triple‐negative breast cancers), and MIA PaCa 2 (pancreatic cancer) at very low IC ₅₀ values. Strikingly, the DOX delivered from the UMNp platform demonstrate more than a 90% reduction in tumor volume in MIA PaCa 2 tumor‐bearing mice. Biodistribution via IVIS‐imaging using deep tissue‐penetrable near‐infrared IR‐780‐loaded UMNp establish high tissue penetration and longer retention in tumor‐bearing mice and substantiate their excellent efficacy in solid tumor regression.