Construction Of Doxorubicin And MiR-34a Simultaneously Delivered By Stearylated Polypeptide Micelle And The Study On Treatment Of Prostate Cancer

Prostatic cancer is the most common malignant tumor of the reproductive system in the European and American countries.With the improvement of people's living standard,the incidence of prostate cancer in our country is increased.Early prostate cancer is hormone-dependent,in which case the general use of endocrine therapy.Hormone-dependent prostate cancer gradually transformed into hormone refractory prostate cancer during the treatment.The combination of chemotherapy drugs and gene drug combination is currently popular direction of cancer treatment.In this paper,we study the anti-hormone refractory prostate cancer of doxorubicin and miR-34 a which is mediated by novel polypeptide micelles in vitro and vivo.The first part of this study reported polypeptide monomer synthesized by solid phase synthesis containing poly-arginine,histidine,and stearic acid.The product was purified by preparative HPLC and analyzed by mass spectrometry.The polymer polypeptides formed by a disulfide bond from the oxidation reaction of utilizing cysteine at low concentration of hydrogen peroxide.1H-NMR and GPC shows the polymer polypeptides synthesized successfully.Then the formation of a polypeptide micelles by self-assembling peptide polymers and doxorubicin and miR-34 a were entrapped by hydrophobic cavity and poly-arginine.The polypeptide micelle diameter and potential is about 160 nm and 20 mV and drug loading content is 22.81 %.The second part of this paper reported the treatment of hormone refractory prostate cancer by co-delivery DOX and miR-34 a via novel polypeptide micelles in vitro.There is a high uptake rate of miR-34 a medicated by polypeptide micelles and doxorubicin released into the nucleus efficiently on hormone-independent DU145 prostate cancer cells.SIRT1 expression is inhibited by the expression of miR-34 a,which is mediated by polypeptide micelles.The synergistic effect is appeared during the anti-androgen-independent prostate cancer cell proliferation in DU145 cells and promotion of apoptosis by doxorubicin and miR-34 a in vitro.The third part of this study was to verify the efficacy the anti-tumor effect of doxorubicin and miR-34 a mediated by polypeptide micelles.Fluorescence marked polypeptide micelles can escape from RES effect and target at the tumor site on model of DU145 prostate cancer xenografts in nude mice.Doxorubicin and miR-34 a medicated by polypeptide micelles synergistically inhibit the tumor growth observed by HE stainingand tumor tissue inhibition experiment.Safety Results show that there is no systemic side effects of polypeptide micelles which can reduce the damage of doxorubicin to heart tissue.In this paper,novel polypeptide micelle is employed as a carrier to entrap chemotherapy drug and gene therapeutic agent,which is not only for clinical treatment of hormone-independent prostate cancer,but also provides a useful reference for the treatment of other cancers.