The tumor microenvironment imposes strong barriers to passive paracellular diffusion of molecules, blocking the movement of nanomedicines in tumor tissue and making distal cells inaccessible. Tumor penetration is therefore an unresolved obstacle to effective anticancer drug delivery. To this end, we demonstrate an active tumor-penetration nanomedicine that exploits transcytosis among tumor cells to distribute throughout the tumor tissue, overcoming the paracellular diffusion obstacle and leading to significantly enhanced therapeutic efficacy. The nanomedicine is a γ-glutamyl transpeptidase (GGT)-responsive cationizing macromolecular drug, γ-glutamyl-based polymer–camptothecin (CPT) conjugate, which is zwitterionic and has a long blood circulation. When the drug conjugate passes on the luminal endothelial cells of tumor blood-vessels or extravasates into the tumor cell interstitium, the overexpressed GGT on the cell membrane cleaves off the conjugate’s γ-glutamyl moieties to generate primary amines, turning it positively charged. The resulting cationic conjugate undergoes fast caveolae-mediated endocytosis and transcytosis, enabling transendothelial and transcellular transport of the conjugate and uniform distribution throughout the tumor. As a result, this conjugate shows much more potent antitumor activity than non-GGT-sensitive controls, leading to complete eradication of small solid tumors (~100 mm3) and dramatic regression of large established tumors of clinically relevant sizes (~500 mm3). It also significantly extends the survival of mice bearing orthotopic pancreatic tumors compared to the first-line drug gemcitabine. Thus, the active tumor penetration provides an effective approach for anticancer nanomedicine to circumvent the tumor passive diffusion barriers and enhance their therapeutic efficacies.

Enzyme-responsive actively tumor-penetrating nanomedicine overcomes tumor diffusion barriers and produces potent anticancer efficacy

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.