Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy

TLDR

Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Here, we report a novel redox dual‑responsive prodrug‑nanosystem self‑assembled from hydrophobic paclitaxel–oleic acid conjugates. The thioether‑linked PTX‑S‑OA and dithioether‑inserted PTX‑2S‑OA conjugates are designed to respond to tumor redox heterogeneity. The PTX‑S‑OA nanoassemblies, with 57.4 % drug loading, release paclitaxel more rapidly and selectively under redox stimuli than PTX‑2S‑OAs, and exhibit potent antitumor activity in a human epidermoid carcinoma xenograft, thereby overcoming low loading and inefficient release issues of hydrophobic PTX prodrugs and enabling future redox‑dual‑sensitive delivery systems.

Abstract

Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.