Investigation On PH-Responsive Release Of Drug-Conjugated Micelles From Electrospun Fiber Fragments

At present,various types of nanocarriers have been developed to target delivery and controlled release of chemotherapeutic drugs,but challenges remain in promoting the drug accumulation in tumors and alleviating the premature release in normal tissues.In the previous study,camptothecin(CPT)-conjugated promicelle polymers(PMCPT)were constructed with disulfide linkages for reduction-sensitive release and folate as targeting ligands.Acid-liable 2-propionic-3-methylmaleic anhydride(CDM)-linked poly(ethylene glycol)was used to initiate the ring-opening polymerization of lactide to prepare CDM/PELA copolymers.This study proposed a strategy to load the PMCPT into fiber fragments,realizing an acid-liable release and spontaneous self-assembly into MCPT,using electrospinning and freezing cutting technology.Dependent on the electrospinning capability and acid-liable degradation of copolymers,fiber fragments with 20%of PEG contents show the optimal cellular uptake,inhibition of tumor cell growth and induction of cell apoptosis.There is no apparent burst release of MCPT from fiber fragments and around 80%of accumulated releases after incubation in pH 6.5 buffers for 40 days.Compared to fresh MCPT prepared via solvent evaporation,the micelles released from fiber fragments revealed similar profiles,such as the average size and morphology,folate-mediated cellular uptake and glutathione-sensitive drug release.At the same time,(TPE)-conjugated promicelle polymers(PMTPE)with aggregation-induced excitation effect(AIE)was synthesized,flowed by inoculation of PMCPT into fiber fragments.Taking advantages of the AIE effect of tetraphenylethene(TPE),TPE-conjugated micelles(MTPE),showing similar sizes and release profiles to those of MCPT,have been initially employed to elucidate in situ micelle formation via self-assembly after release from fibers and subsequent cell internalization into cytosol.The intratumoral injection of fiber fragments generated spontaneous self-assembly of micelles,and strong fluorescence signals are detected during 14 days.Compared with intratumoral or intravenous injection of fresh MCPT,the sustained release of micelles from fiber fragments results in the optimal antitumor efficacy with respect to the inhibition of tumor growths,prolongation of animal survivals and induction of cell apoptosis in tumor tissues.Thus,the integration of double targeting strategies and double stimuli-responsive releases into fragmented fibers provides a feasible strategy to realize micelle release in response to acidic tumor extracellular environment and promote the therapeutic efficacy.