Synthesis Of CD44-targeted Nanocomposites Formed By Self-assembly Of Multiple Small Molecules And Their Applications In Cancer Therapy

Objective:Cancer is one of the major diseases that affect global human health,and chemotherapy has been one of the important method of cancer treatments.However,most of the chemotherapeutic agents used in clinic have the problems of low water solubility,poor stability,large side effects and lack of selectivity.In order to solve these problems,a novel CD44-targeted drug delivery system formed by self-assembly of multiple small molecules was synthesized based on low generation PAMAM(G0/G1 PAMAM)and hyaluronic acid.Methods:CD44-targeted drug delivery system loaded Doxorubicin(DOX@PAMAM/HA),erlotinib(EL@PAMAM/HA),ursolic acid(UA@PAMAM/HA)were synthesized by solvent exchange method,respectively.Then,the physical and chemical properties of DOX@PAMAM/HA,EL@PAMAM/HA and UA@PAMAM/HA were investigated respectively.The release of the nanocomposites under different pH conditions was investigated by UV spectrophotometry.The in vitro distribution of nanoparticles was investigated by confocal microscopy.The inhibition effect of DOX@PAMAM/HA on tumor cell A549,HeLa(CD44 over-expressing)and HepG2(CD44 negative expressing)was investigated by MTT assay and cell cycle assay.Finally,in vivo anti-tumor effect of CD44-targeted drug delivery system(DOX@PAMAM/HA)in nude mice was investigated by establishing a mouse tumor model.Results:The results of characterization and release experiments showed that the prepared CD44-targeted nanocomposites formed by self-assembly of multiple small molecules were not only uniform in size,but also had the characteristic of pH response.Under acidic pH conditions,the release rated of drug was significantly higher than that of neutral pH.MTT assay showed that the cytotoxicity of low generation PAMAM(G0/G1 PAMAM)was greatly reduced,and the nanocomposites encapsulated hyaluronic acid had greater cytotoxicity to CD44 over-expressing cells.This result was consistent with the cell apoptotic assay and the observation of confocal microscopy.Animal experiments suggested that anti-tumor effect in nude mice of CD44-targeted drug delivery system(DOX@PAMAM/HA)was more significant than free DOX.Conclusion:The CD44-targeted drug delivery system formed by self-assembly of multiple small molecules constructed in this study could encapsulate doxorubicin,erlotinib and ursolic acid,and the prepared nano drugs had the characteristics of pH response and targeting recognition of CD44 over-expressing tumor cells.The prepared CD44-targeted drug delivery system showed good anti-tumor effect both in vivo and in vitro experiments.Therefore,this study not only provides an alternative method for cancer therapy but also gives inspiration for the study of drug delivery system.