Hyaluronic Acid-decorated Micellar Delivery System:the Role Of Hydrophobic Groups And The Application In The Combination Therapy Of Tamoxifen And Docetaxel

Micellar drug delivery system is widely used as suitable nano-carriers for a variety of therapeutic applications due to its small particle size,high specific surface area and good stability.Exploring the role of hydrophobic groups on the properties of the amphiphilic carrier and micelles were the aim of this study.Using hyaluronic acid(HA),cholesterol(CHOL)and octadecanoic acid(OA),two amphiphilic polymers were prepared and fully characterized by 1H NMR,FTIR,DSC and PXRD.Measurement of critical micellar concentration experiment proved that the hydrophobic groups affected the CMC of the amphiphilic copolymers.Evenmore,hydrophobic groups had a certain influence on the particle size,encapsulation efficiency(EE)of docetaxel(DTX)-loaded micelles and had a degree of selectivity for drugs.In vitro cytotoxic experiments showed that HA-SA-CYS-OA micelles were generally more cytotoxic to A549 and S-180 cells on account of the toxicity of octadecanoic acid while in vivo animal experiments confirmed that HA-SA-CYS-CHOL micelles exhibited better tumor-targeting properties and antitumor effects.From these preliminary evaluations,it is possible to conclude that hydrophobic groups not only affect the stability and drug-loading capacity of the amphiphilic carriers,but also influence the distribution,metabolism and ultimately,the effect of DTX-TMX combination therapy.Compared with HA-SA-CYS-OA,HA-SA-CYS-CHOL had a lower critical micellar concentration(CMC)producing docetaxel(DTX)-loaded micelles of a smaller particle size and better tumor targeting.So HA-SA-CYS-CHOL has better use and development prospects.Therefore,we further applied the cholesterol-modified amphiphilic carrier to the combination therapy to investigate the role of the micelle delivery system.Docetaxel(DTX)and tamoxifen(TMX)are first-line drugs used to treat breast cancer.However when used in combination,they produce antagonism on estrogen receptor positive cells and synergism on estrogen receptor negative cells.In order to prevent this antagonism,HA-SA-CYS-CHOL amphiphilic carrier was used for investigating the co-delivery of TMX and DTX.DSC and PXRD experiment revealed that the Co-NPs were thermal stability and distributed in an amorphous state.In vitro drug release experiment of the Co-encapsulated(encapsulated DTX+TMX)nanoparticles(Co-NPs)revealed that NPs with the release mechanism of pH dependence can markedly reduce the release of these drugs in the circulatory system.However,when reaching in cell,TMX can release rapidly to prevent DTX from coming into contact with metabolizing enzymes.In vitro cytotoxicity experiment revealed that the Co-NPs exhibited a significant synergistic effect for inhibiting the proliferation of the cancer cell lines A549,MCF7 and S180.Cell apoptosis assay revealed that one of the synergistic mechanisms was that Co-NPs could mediate cell sensitization to cytotoxic agent,resulted in a remarkable cell apoptosis.As an in vivo treatment of xenograft tumors involving 180 cells,the Co-NPs displayed a clear tumor targeting and inhibiting effect compared to free drugs.And,there was a significant difference in tumor volume between the Co-NPs group and the DTX-NPs,TMX-NPs groups at low does.After stopping the administration,the tumors in the DTX-NPs and TMX-NPs groups relapsed rapidly wheras Co-NPs’ not.Immunohistochemistry experiments have shown that another synergistic mechanism was that the Co-NPs could downregulated the expression of P-gp level to play a better anti-tumor effect.