一氧化氮供体和阿霉素的共递送系统用于逆转肿瘤低氧耐药研究

Co-delivery system of nitric oxide donor and DOX for reversing hypoxia-induced drug resistance in tumor

目的构建一种一氧化氮供体和阿霉素的共递送系统,以逆转肿瘤低氧耐药。方法利用酰胺反应合成一氧化氮供体单硝酸异山梨酯(IM)修饰的透明质酸(HA-IM),再通过硫化学作用将其嫁接于二硫化钼(MoS_(2))纳米片,制备出载体二硫化钼-单硝酸异山梨酯修饰的透明质酸(MoS_(2)-HA-IM),考察此载体的理化特性。通过疏水作用装载抗癌药阿霉素(DOX),构建一氧化氮供体和抗癌药物的共递送系统,并在细胞水平上考察此系统的抗肿瘤效果。结果二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素(MoS_(2)-HA-IM-DOX)可通过透明质酸受体介导的内吞作用有效地将装载的单硝酸异山梨酯和阿霉素输送到肿瘤细胞内,且在肿瘤弱酸性内环境和近红外光照射的双重刺激下迅速将药物释放出来,提高胞内游离药物的浓度。同时,装载的单硝酸异山梨酯能够逆转肿瘤细胞的低氧耐受性,进一步增强二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素的化疗效果,再联合基于二硫化钼材料产生的光热,共使肿瘤细胞的生长抑制率高达93.6%,明显高于其他组。结论二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素能够靶向输送一氧化氮供体和抗癌药物至肿瘤细胞内,双重响应控制药物释放,逆转肿瘤低氧耐药,最大限度地提高化疗效果,结合光热治疗,显示出优异的抗肿瘤效果。

Objective To construct a co-delivery system of nitric oxide donor and DOX,and reverse the hypoxia-induced drug resistance in tumor.Methods Hyaluronic acid(HA)modified with nitric oxide donor isosorbide mononitrate(IM)was synthesized by the amidation reaction,and then grafted onto molybdenum disulfide(MoS_(2))nanosheets by sulfur chemistry to prepare the carrier MoS_(2)-HA-IM.Meanwhile,the physicochemical properties of MoS_(2)-HA-IM nanosheets were investigated.The anticancer drug doxorubicin(DOX)was loaded onto the carrier by hydrophobic interaction,constructing a co-delivery system of a nitric oxide donor and DOX,and the antitumor effect of this system was investigated at the cellular level.Results MoS_(2)-HA-IM-DOX could effectively deliver the loaded IM and DOX into tumor cells via HA receptor-mediated endocytosis,and the drug was rapidly released under the dual stimulation of tumor acidic microenvironment and near-infrared light irradiation,obviously increasing the intracellular free drug concentration.Meanwhile,the loaded IM was able to reverse the hypoxic tolerance of tumor cells,further enhancing the chemotherapeutic effect of MoS_(2)-HA-IM-DOX.More importantly,the growth inhibition rate of tumor cells was up to 93.6%,significantly higher than other groups,mainly due to the combination of the chemotherapy and the MoS_(2)-based photothermal effect.Conclusion MoS_(2)-HA-IM-DOX can achieve the targeted delivery of nitric oxide donors and anticancer drugs into tumor cells,the control release of drugs under a dual-response stimulus,the reversal of hypoxia-induced drug resistance in tumors,maximizing the chemotherapy effect,and exhibit excellent antitumor effects in combination with photothermal therapy.