Tumor pH-Responsive Release of Drug-Conjugated Micelles from Fiber Fragments for Intratumoral Chemotherapy.

The tumor accumulation of micelles is essential to enhance the cellular uptake and extend the release of chemotherapeutic agents. In the previous study camptothecin (CPT)-conjugated micelles (M) were constructed with disulfide linkages and folate moieties for reduction-sensitive release and cell-selective uptake. This study proposes a strategy to integrate the promicelle polymers (PM) into fiber fragments for intratumoral injection, realizing acid-liable release of PM in response to acidic tumor microenvironment and spontaneous self-assembly into M. Acid-liable 2-propionic-3-methylmaleic anhydride (CDM)-linked poly(ethylene glycol) initiates the ring-opening polymerization of dl-lactide as the fiber matrix. There is no apparent burst release of M from fiber fragments and around 80% of accumulated releases after incubation in pH 6.5 buffers for 40 days. Compared to M freshly prepared via solvent evaporation, the micelles released from fiber fragments reveal similar profiles, such as folate-mediated cellular uptake and glutathione-sensitive drug release. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethylene (TPE) derivatives, TPE-conjugated micelles (M) have been successfully been used to track the self-assembly into micelles after release from fibers and subsequent cell internalization into cytosol. The self-assembly induced fluorescence light-up was also detected after intratumoral injection of fiber fragments. Compared with CPT-loaded fiber fragments and intratumoral or intravenous injection of free M, the sustained release from fiber fragments and high accumulation of micelles in tumors result in significantly higher inhibition of tumor growths, prolongation of animal survival, and induction of tumor cell apoptosis. Thus, the integration of double targeting and double stimuli responsiveness into fragmented fibers provides a feasible strategy to realize the sustained micelle release from fibers and promote the therapeutic efficacy.