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

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 IC₅₀ 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.