Acid-Labile Degradation of Injectable Fiber Fragments to Release Bioreducible Micelles for Targeted Cancer Therapy

Cancer chemotherapy is confronted with difficulties enhancing the tumor accumulation, improving the bioavailability, and relieving the adverse effect of chemotherapeutic agents. To address the challenges, this study proposes a feasible strategy to realize a sustained release of drug-loaded micelles from fiber fragments after intratumoral injection. Camptothecin (CPT) is grafted on hyaluronic acid (HA) via 3,3′-dithiodipropionic acid to obtain reduction-sensitive promicelle polymers (PMCPT), which are conjugated with poly­(d,l-lactide) via 2-propionic-3-methylmaleic anhydride (CDM) to obtain acid-labile copolymers for the preparation of injectable fiber fragments. Fiber fragments show remarkable acid-sensitive degradation, and the released PMCPT are spontaneously self-assembled into micelles, followed by subsequent HA-mediated internalization into tumor cells and reduction-sensitive release of drugs in the cytosol. Compared to fresh micelles prepared by ultrasonication, the micelles released via the degradation of fiber fragments display similar behaviors, such as the size and morphology, glutathione-sensitive drug release, cellular uptake efficiency, and cytotoxicity. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethene (TPE), the micelle release, cellular uptake, and tumor accumulation have been elucidated from the self-assembly induced fluorescence light-up in vitro and after intratumoral injection. Compared to the intratumoral injection of free micelles, sustained micelle release from fiber fragments resulted in significantly higher antitumor efficacy with respect to the inhibition of tumor growths, prolonging of animal survivals, and induction of cell apoptosis in tumor tissues. Thus, the micelle-releasing fiber fragments integrated with double targeting capabilities and double stimuli responsiveness have demonstrated a superior capacity to sustainably deliver chemotherapeutic agents directly within tumor cells.