Tumor microenvironment-activated therapeutic peptide-conjugated prodrug nanoparticles for enhanced tumor penetration and local T cell activation in the tumor microenvironment.

Abstract

Nanomedicine-based chemoimmunotherapy has shown a great potential for cancer therapies application in recent years. However, most nanoparticles still face a problem of low accumulation and limited penetration of chemotherapeutic drugs and immunotherapeutic drugs into solid tumors. Here, we developed a tumor microenvironment (TME)-activable therapeutic peptide-conjugated prodrug nanoparticle for enhanced tumor penetration and synergistic antitumor effects of chemotherapy and immune checkpoint blockade therapy. The prodrug nanoparticle is composed of a short D-peptide antagonist of PD-L1 (^DPPA) conjugated doxorubicin (DOX) prodrug and a PEGylated DOX prodrug, which can dissociate into small DOX nanoparticles (<30 nm) and release ^DPPA antagonist in TME. The prodrug nanoparticles could co-deliver DOX and ^DPPA antagonist by one nanocarrier and improve tumor accumulation and penetration of the prodrug nanoparticels via a transcytosis process. It is demonstrated that co-delivery of DOX and ^DPPA antagonist directly killed tumor cells, promoted the tumor-infiltrating cytotoxic T lymphocytes, reduced the tumor-infiltrating regulatory T cells, and elicited a long-term immune memory effect to prevent tumor recurrence and metastasis. This TME-activable prodrug nanoparticle holds promise as a co-delivery nanoplatform for the improved chemoimmunotherapy of solid tumors.