| During the treatment of cancer,chemotherapy has been confronted with two major challenges: drug side effects on normal cells and inefficiency of drugs.However,the emergence of nano drug delivery systems provides a novel way to solve these problems.By using the differences of microenvironment between malignant tumor tissues and normal tissues,we can construct the stimuli-responsive nano drug delivery systems to realize the controlled release of antineoplastic drugs in cancer cells.At the same time,the systems have significant advantages to increase the drug stability,improvement of therapeutic efficiency,prolong the blood circulation times and reduce toxicity to healthy tissues.However,single stimulus response nano drug delivery system is difficult to achieve rapid drug release,due to the complicated intracellular environment of cancer cells.Therefore,our paper proposes to construct a multi-stimulus responsive supramolecular nano based on the ability of molecular recognition and molecular assembly of pillararene which is the fifth generation macrocyclic molecule.It can combine curcumin,a broad-spectrum anticancer drug,to construct a pH-GSH stimulus response nano prodrug system which can load doxorubicin hydrochloride and achieve combined treatment.In this paper,nano prodrug system was constructed with amphiphile molecules by borate of curcumin and supramolecular materials which was formed by water-soluble carboxylate functionalized pillar[5]arene(WP5)and phenylboronic acid derivative with disulfide bonds and pyridinium salts(G).The structure of the synthesized compounds was confirmed by NMR data and high resolution mass spectrometry.The assembly of host molecule and guest molecule in 1:1 ratio and the bonding of curcumin with supramolecular material were demonstrated by NMR shift and UV-Vis absorption spectra.The results of SEM,TEM and nano laser particle size analyzer showed that supramolecular vesicles with an average particle size of 190.1 nm were formed in water.These vesicles can be used to pack the water-soluble anti-cancer drug doxorubicin hydrochloride.Drug loading capacity of curcumin and doxorubicin hydrochloride were 15.2% and 30.4%,respectively.The simulated release experiments in vitro showed that the carriers exhibited pH and GSH stimulus responsiveness.At pH = 5.0,the release rate of curcumin was about 75% and the release rate of doxorubicin hydrochloride was about 60% in 8 h.The release rate of doxorubicin hydrochloride was about 66% at 5.0 mM GSH,86% at pH = 5.0 and 5.0 mM GSH in 4 h.The highest release rate of doxorubicin hydrochloride was about 90% in 24 hours.The laser scanning confocal microscope experiments showed that the nano drug delivery system can effectively deliver antineoplastic drugs to cells.By testing the cell viability of the normal cells,it is demonstrated that the carriers have good biocompatibility to normal cells.At the same time,it can effectively reduce the side effects of doxorubicin hydrochloride on 293T cells.The cytotoxicity experiments of HepG2 cells showed that the prodrug carriers have the ability to kill cancer cells.Compared with curcumin and doxorubicin hydrochloride,the nano drug delivery system can enhance the killing ability of cancer cells and achieve the effect of two anti-cancer drugs in the treatment of cancer.In conclusion,a novel pH-GSH stimulus-response nano prodrug system was constructed,which can self-assemble into supramolecular vesicles and load doxorubicin hydrochloride simultaneously in water.The system can deliver antineoplastic drugs to cancer cells and reduce the toxic side effects of anti-tumor drugs on normal cells effectively.At the same time,it can improve the efficiency of drugs and realize the joint treatment of two drugs,which is significant in the field of nanomedicine. |
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