pH/ROS dual-responsive supramolecular polypeptide prodrug nanomedicine based on host-guest recognition for cancer therapy

Supramolecular nanomedicine assembly combined with polypeptide prodrug could become a powerful strategy to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. Here, we developed a charge-reversal amphiphilic pillar[5]arene-modified polypeptide (P5-PLL-DMA), and reactive oxygen species (ROS)-sensitive polypeptide prodrug (P-PLL-DOX) including a ROS-cleavable thioketal (TK) linker between doxorubicin (DOX) and poly(_L-lysine) (PLL), which could assemble via pillar[5]arene host-guest recognition, and further encapsulate chlorin e6 (Ce6) to obtain a supramolecular polypeptide prodrug (SPP-DOX/Ce6). The chemical conjugation to load drugs of DOX and the negatively charge of SPP-DOX/Ce6 could prevent premature drug leakage, and reduce undesirable interaction with serum proteins to enhance stability under physiological conditions (pH 7.4). Simultaneously, the carried charge of SPP-DOX/Ce6 reversed from negative to positive could effectively enhance the cellular internalization for efficient DOX delivery under acidic tumor microenvironment (pH 6.5). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 rapidly cleaved the TK linker to release activated DOX, inducing the tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug based on pillar[5]arene host-guest recognition represents new avenues to develop stimulus responsive prodrug for enhanced cancer therapy with minimized the side effect. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS dual-sensitive supramolecular polypeptide prodrug (SPP-DOX/Ce6) was developed to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. The chemical conjugation to load drugs of DOX via a ROS-cleavable thioketal (TK) linker and the distinctive charge-reversal capacity of SPP-DOX/Ce6 significantly enhances the stability under physiological conditions (pH 7.4), while facilitates cellular uptake at tumor site (pH 6.8). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 induces the rapid cleavage of TK linker to release activated DOX, achieving a tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug SPP-DOX/Ce6 provides an effective strategy to construct stimulus responsive prodrug for enhanced cancer therapy.