An implantable depot capable of in situ generation of micelles to achieve controlled and targeted tumor chemotherapy.

Abstract

Camptothecin (CPT)-containing promicelle polymers (PM_CPT) based on 4-armed poly(ethylene glycol) (PEG) were developed previously to self-assemble into folate-targeted and glutathione (GSH)-sensitive micelles (M_CPT). To address severe systemic toxicity and lack of tumor specificity implicated in the intravenous administration of M_CPT, a micelle-generating depot has been developed by blend electrospinning of PEG-poly(lactide) (PELA) copolymers, PM_CPT and polyethylene oxide (PEO). Upon implantation of the depot onto a tumor, PM_CPT are sustainably released to self-assemble into M_CPT on the tumor site. The release of PM_CPT is adjusted by varying PEO/PELA ratios and reaches in the range of 23-92% after 30 days of incubation. By making use of the aggregation-induced emission (AIE) features of tetraphenylethylene (TPE) derivatives, the release process of TPE-containing promicelle polymers (PM_TPE) from the depot and the spontaneous formation of micelles (M_TPE) have been monitored from the self-assembly-induced fluorescence light-up both in vitro and in vivo. Compared with intravenous injection of M_CPT, the micelle-generating depot has significantly enhanced micelle accumulation in the tumor for an extended period of time and resulted in stronger tumor inhibitory efficacy, reduced systemic toxicity and more effective inhibition of tumor metastasis, demonstrating great potential for targeted cancer therapy with sustained efficacy. The promicelle polymer-co-electrospun fibers are developed to form a micelle-generating depot after implantation onto the tumor. The promicelle polymers are continuously released and simultaneously self-assemble into folate-targeted and glutathione-sensitive micelles, ensuring sustained micelle delivery for more than 30 days. The process of micelle formation in the tumor tissue is visualized in vivo for the first time based on the mechanism of aggregation-induced emission. This in situ micelle formation also prevents premature drug release and rapid clearance from the bloodstream. In addition, these fibers deliver anti-cancer agents directly within tumor cells via dual selectivity (i.e. spatially selective accumulation in tumor tissues via implantation and selective internalization into tumor cells via folate receptor-mediated endocytosis) and on-demand drug release in response to cytosol GSH. They exhibit superior tumor inhibitory efficacy with minimal systemic toxicity, and prevent from malignant metastasis of cancer cells.