| Chemotherapy is one of the three major means to treat cancer,although always companied by severe adverse effects,because most anticancer drugs are associated with a number of drawbacks,including lack of targeting capability,multi-drug resistance(MDR)and poor water solubility.Drug carrier technology is believed an effective way to circumvent these hurdles and is widely concerned.The polymer nano-micelle system has a good application prospect as a drug carrier system,due to its high drug loading capacity,good stability,easy modification,and long-time circulation in vivo.In the application of drug carrier materials,biocompatibility and biodegradability are the most important issues to be considered,so the polyamino acid carriers attracted much attention.Poly(aspartic acid)(PASP)is a kind of long-chain amino acids with carboxyl side chains,which has good biocompatibility and biodegradability.Therefore,in order to prepare a drug carrier system to solve the defects of chemotherapeutic drugs,a multifunctional amphiphilic micellar polyamino acid drug carrier was prepared based on PASP in this study.PASP was modified with hydrophobic tyrosine(Tyr)to prepare an amphiphilic poly(amino acids).When the amphiphilic polypeptide chains self-assembled in water to form nano micelles,hydrophobic drugs were encapsulated into hydrophobic core,while hydrophilic drugs are bound to hydrophilic shell,creating a dual-drug delivery system.After that,hyaluronic acid(HA),which is a recognized target ligand that can specifically bind to CD44 receptor over expressed on tumor cells surface,was grafted into PASP-Tyr,resulting in an HEPT carrier with active targeting.~1H NMR and FT-IR outcomes suggested the synthesis of HA-modified polyamino acid carrier HEPT.The loading capacity was up to 68.8%for CUR and 53.0%for DOX.On the one hand,the loading rate of hydrophobic drugs was significantly increased,the difficulty of loading and delivering hydrophobic drugs solved,and the co-delivery was conducive to the synergistic effect.The effect of graft rate on drug loading capacity was discussed in detail,that is,the increased grafting rate resulted in improved drug loading capacity especially for CUR owing to the special micellar structure.The morphology of micelle nanoparticles was observed by TEM and SEM,which displayed nearly spherical shape under neutral condition.DLS showed the average particle size was about142.9±11.4 nm,which was beneficial for nanoparticles to pass through the gaps in vascular walls of solid tumor by EPR effect.In vitro release experiments showed an obvious p H-response effect.At 24 h,CUR showed slow release at p H7.4,but fast release at p H 5.4 with a 2.35-fold increase.The releasing weight ratio of CUR and DOX was close to 2:1,providing a better synergistic effect.In vitro anticancer activity evaluation revealed that the co-loaded(DOX+CUR)@HEPT nanoparticles presented higher cytotoxicity against human colon cancer cells(HCT-116)compared with that of free combination of(DOX+CUR),indicating improved antitumor efficacy,which is related to the obvious p H-response,targeting and synergistic effect of drugs.Such a polyamino acid-based co-delivery system which encapsulated both hydrophobic CUR and hydrophilic DOX,integrated p H-response,passive and active targeting into one nanoplatform facilitated the understanding of drug loading mechanism,and open a pathway for research and applications of new anti-cancer vehicles. |
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