Preparation Of Histone Based Photothermal-Chemotherapeutic Nanomedicine For Killing Of Drug Resistant Breast Tumor Cells

Nanomedicine with photothermal-chemotherapy(PCT)have potential in the treatment of drug-resistant tumors,which can reverse drug resistance by inhibiting the expression of drug-resistant genes through high temperature while delivering drugs.However,PCT usually has low therapeutic efficiency and poor penetration depth.To improve the therapeutic efficiency of PCT against drug-resistant tumors,we constructed a histone based PCT agent that can target the nucleus.Histones are a kind of basic proteins in the nucleus.Starting from the biological functions of histones,we designed and prepared a PCT agent of DIR825@histone by using histone,small molecule photothermal agent(IR825)and chemotherapeutic drug doxorubicin(DOX),which can target the cell nucleus and making the PCT therapeutic effect precisely ourred in cell nucleus,leading to a efficient inhibition of drug-resistant cancer cells in vitro.IR825@histone with different particle sizes can be formed by chemical coupling of IR825 and histone at different mass ratios.When the mass ratio of IR825 to histone was 1:10,IR825@histone NPs could reach a relative small size.PCT agent of DIR825@histone was prepared by mixing DOX with IR825@histone at a mass ratio of 1:10 and in which DOX loading was 5.9%.Under simulated physiological conditions(pH 7.4,37℃),DIR825@histone showed slow DOX release rate(41.2%within 48 h),but under laser irradiation(1 W/cm2,10 min),the cumulative release rate of DOX within 2 h was 40.8%,showing photothermal triggered drug release.In vitro study showed that DIR825@histone can be ingested and localized in the nucleus of breast cancer(MCF-7/ADR)resistant cells with high P-gp expression.Due to the delivery of DOX across the cytoplasmic membrane to the nucleus,DIR825@histone exhibited the nearly the same inhibitory activity against MCF-7 and MCF-7/ADR cells with IC50 of 1.98±0.15μg/mL and 2.69±0.26 μg/mL,respectively.Due to the nuclear targeting properties,DIR825@histone showed stronger photothermal therapeutic effects,including direct destruction of the nucleus,induced apoptosis and significant down-regulation of P-gp and Hsp-90.These results suggest that DIR825@histone mediated nuclear targeted PCT can not only effectively kill drug-resistant cells,but also significantly down-regulate genes related to tumor progression.Therefore,DIR825@histone and its mediated nuclear targeted thermochemotherapy have potential in the treatment of drug-resistant tumors.