Functionalized PCL-PEG-PCL Block Copolymer Nanoparticle Thermosensitive Hydrogel For In-situ Anticancer Drug Delivery

Chemotherapy is one of the main treatment methods for cancer.Anticancer drugs commonly are administrated by oral or intravenous injection.However,due to lack of targeting,the drug bioavailability is low and has obvious toxic and side effects.Therefore,improving drug targeted delivery is the key issue for enhancing chemotherapy efficiency.Injectable thermosensitive hydrogels self-supported by polycaprolactone（PCL）-polyetnylene glycol（PEG）-PCL triblock copolymer nanoparticles（NPs）provided convenient local nanodrug delivery platforms for tumor therapy,but their lower cell uptake and slower intracellular drug release serious limited the antitumor efficiency.In this paper,by introducing pendant amino groups on poly（ε-caprolactone）（PCL）segments and optimizing the hydrophobic-hydrophilic balance,we successfully prepared a kind of pendant amino-modified PCL-PEG-PCL triblock copolymers（PECN）.PECN self-assembly nanoparticles（NPs）took about～90 nm size and slightly positive charge（7.3m V）.We investigated the gelation and drug delivery efficiency of PTX loaded PECN（PTX/PECN）NPs in vitro and in vivo.PTX/PECN NPs kept the thermo-sensitive gelation behavior that the injectable PTX/PECN NPs aqueous solution（25 wt%）at ambient temperature could fast gelation at 37^oC after a quenching treatment and sustain release PTX/PECN NPs for 10 days.More importantly,without obvious toxicity,the PECN NPs could enhance the drug loading capacity,improve the cell uptake and p H-sensitively trigger the intracellular fast drug release.Thus,PTX/PECN NPs presented lower IC50 of 3.138μg/m L than that of PTX（4.128μg/m L）.Moreover,through peritumoral injection,the PTX/PECN hydrogel showed 94.27%inhibition of tumor growth on day 19,higher than the PTX/PECT hydrogel（72.28%）and Taxol^?（47.03%）.Although PECN NPs hydrogel showed excellent local anticancer efficiency,one problem is that a quenching process needed for preparing the PECN NPs thermosensitive hydrogel,which is not convenient for application.To solve this problem,we studied a co-assembly strategy by PECN and PECT to obtain a PECN/PECT co-assemble NPs.The PECN/PECT NPs aqueous solution could directly gelation when the temperature increased to the critical gel transition temperature without quenching treatment.At the same time,PECN/PECT NPs remained the p H-sensitive drug release ability.Finally,by using the reactivity of the-NH₂ groups on PECN,we further conjugated2,3-dimethylene maleic anhydride on the amino group of PECN to prepare–COOH modified PECN triblock copolymer（PECD）.PECD nanoparticles facilitated the loading of dugs containing amino groups and enhanced the intracellular drug release.Therefore,PECN hydrogel provided a more significant injectable platform to enhance local cancer chemotherapy,and also provided further functionalization possibility by the reactive amino groups.