pH/近红外光响应脂质体的构建及其光热化疗抗肿瘤研究

Currently, it is difficult to achieve good therapeutic effect towards most tumor such as breast cancer using surgical treatment only. Besides, the therapeutic efficacy could be significantly affected by the side effects of chemotherapy drugs. Thus, the combination therapy for the treatment of cancer has become the better approach with high efficiency and low toxicity. In this project, we propose a novel liposome drug delivery system owning CO2 induced drug release and pH/near-infrared light double-responsive features through the encapsulation of near-infrared probe Cypate, epirubicin and CO2 initiator through NH4HCO3 gradient method. Cypate possess multiple functions such as fluorescence imaging and photothermal conversion induced by near-infrared light. Under near-infrared light irradiation, the photothermal agent could raise the temperature in order to kill tumor cells effectively. Then, the high temperature could simultaneously induce CO2 release from NH4HCO3 to promote the rapid release of anticancer drug in tumor site. Furthermore, the surface of liposome was shielded electrostatically with a pH-sensitive mPEG-PSD at pH 7.4, whereas mPEG-PSD was deshielded at tumor pH. It makes the carrier become long circulating in circulatory system but facilitate cellular uptake in tumor tissues. The photothermal chemotherapy could greatly improve the therapeutic effect towards cancer. In summary, we are devoted to investigate the cellular uptake, tissue distribution and antitumor effect of this multifunctional liposome with the influence of pH/NIR responsive and CO2 induced rapid release, reveal the combined anti-tumor mechanism between photothermal therapy and chemotherapy. We anticipate that this study could provide methodological and theoretical basis for high efficiency and low toxicity cancer therapy of liposome drug delivery system.

目前，多数肿瘤如乳腺癌通过单一手术治疗的方式无法根治，而化疗药物的毒副作用严重影响治疗效果。联合治疗协同抗肿瘤成为高效、低毒肿瘤治疗的发展方向。本项目通过将近红外探针Cypate与表阿霉素/NH4HCO3共负载，构建一种基于CO2气体介导的pH/近红外光双重响应多功能脂质体药物输送系统。Cypate具有近红外荧光成像与光热转换功能，既赋予脂质体肿瘤成像与热疗效应，也赋予其光热效应引发的CO2介导快速释药特性，实现光热化疗协同抗肿瘤；同时，利用具有肿瘤组织pH响应的磺胺衍生物（mPEG-PSD）与脂质体表面的静电吸附/解离，实现脂质体的长循环与促进肿瘤细胞摄取，达到其在肿瘤组织与细胞逐级递送的目的。本项目通过考察脂质体的近红外光响应性、pH响应性及CO2气体介导的快速释药对其细胞摄取、组织分布及体内外抑瘤效果的影响，揭示脂质体光热化疗协同抗肿瘤机制，为实现高效、低毒的肿瘤治疗提供依据。

化疗是治疗恶性肿瘤的主要手段之一，但由于化疗药物对肿瘤细胞缺乏选择性，导致其对正常组织产生严重的毒副作用，从而影响了疗效。如何促进肿瘤细胞对药物的摄取并实现药物在肿瘤组织的快速释放，已成为高效、低毒肿瘤治疗的研究热点与难点。本项目通过共载阿霉素、光敏剂Cypate和NH4HCO3，并将具有pH敏感性的聚磺胺二甲氧嘧啶静电吸附于阳离子脂质体表面，构建了具有pH/近红外光双重响应性的多功能脂质体用于光热化疗协同抗肿瘤研究。本项目考察了脂质体的pH敏感性及基于CO2气体介导的近红外光响应性快速释药行为，并研究了其示踪与体内外抑瘤效果。结果表明，制备的多功能脂质体具有肿瘤组织微环境pH敏感性和近红外光响应性快速释药特性，可有效促进肿瘤细胞的摄取及药物的快速释放，实现了药物的光热化疗协同抗肿瘤作用。此外，肿瘤细胞多药耐药性的产生已成为肿瘤治疗的一大障碍。因此，在上述研究基础上，本项目进一步开展了pH敏感电荷翻转/NO产生脂质体的构建及其逆转肿瘤多药耐药性的研究。通过包载NO供体DETA NONOate与紫杉醇，并将具有肿瘤组织pH敏感性的PEG-聚赖氨酸-二甲基马来酸酐静电吸附于阳离子脂质体表面，构建了pH敏感电荷翻转/NO产生脂质体，并研究了脂质体的pH敏感性电荷翻转、基于NO气体介导的pH响应性快速释药行为、药物的P-gp外排与富集情况及体内外抑瘤效果。结果证实，构建的NO产生脂质体具有肿瘤微环境pH敏感性和NO产生功能，既可促进肿瘤细胞对药物的摄取，促使药物在肿瘤部位快速释放，又可有效抑制P-gp的过表达，克服肿瘤细胞的多药耐药性，提高了疗效。综上所述，本项目制备的脂质体为实现高效、低毒的肿瘤治疗提供了依据。在项目执行期间，项目组已在Nanoscale、Int. J. Nanomed.、Colloid Surface B、ACS Appl. Mater. Inter.等杂志发表SCI论文11篇；申请国家发明专利4项，培养硕士生3名。