纳米载体共递送基因和化疗药物用于肿瘤治疗的研究进展

Progress in the Use of Nanocarriers for Co-delivery of Genes and Chemotherapeutic Agents for Cancer Therapy

化疗的应用前景目前受到肿瘤多药耐药性(Multidrug resistance,MDR)、药物分布的非特异性和系统性毒副作用等缺点限制。治疗性基因可通过适当载体运送至肿瘤细胞,通过下调耐药相关蛋白的表达或沉默其他调控肿瘤功能的基因以实现治疗的目的。因此,借助纳米载体将化疗与基因治疗联合应用可发挥两者的协同作用,改善化疗效果,是一种具有广阔前景的抗癌策略。沉默耐药相关基因是解决肿瘤MDR的主要思路,除此之外,尚需开发其他可协同化疗的基因治疗策略,通过调控肿瘤发生、发展的某个或某些环节以达到更显著的肿瘤治疗效果。与此同时,使用纳米颗粒(Nanoparticles,NPs)共递送基因和化疗药物对纳米载体提出了更高的要求。基因易被核酸酶降解,在血流中不稳定,细胞摄取差且转染效率低,因此亟需安全高效的共递送系统来克服诸多障碍,实现最大效率的药物共载和运送。依据所选择治疗基因靶点的不同,基因-化疗药物共递送的治疗策略可分为逆转肿瘤细胞MDR、促肿瘤细胞凋亡、抗肿瘤血管生成、化疗协同免疫治疗及清除肿瘤干细胞(Cancer stem cells,CSCs)等多种,递送的基因包括MDR-1 siRNA、Bcl-2 siRNA、p53 DNA、VEGF siRNA、PD-L1siRNA及miR-205等类型。用于共递送的理想纳米载体应符合安全性高、生物相容性好、具有可生物降解性、基因转染率高等条件。研究者们充分利用各类材料的特性优势,开发出聚合物纳米粒、纳米胶束、脂质体、无机纳米颗粒、病毒及核酸载体等不同类型的共递送载体。此外,通过对载体进行刺激响应性设计可实现依据肿瘤微环境或外部环境变化而靶向释放药物的效果,从而避免包裹药物的突释,保证肿瘤部位的药物分布,提高治疗效率的同时减轻药物对正常组织的毒副作用。本文归纳了纳米载体共递送基因和化疗药物的阶段性研究进展,分别对基因-化疗药物共递送策略及共递送载体等进行介绍,分析了各类型载体的特点,思考了纳米载体研发领域一些待解决的问题并展望其前景,以期为实现安全高效的基因-化学联合治疗提供参考。

The application prospect of chemotherapy is currently limited by the disadvantages of tumor multidrug resistance(MDR),non-specific drug distribution and systemic toxic side effects. Therapeutic genes can be transported to tumor cells by appropriate vectors to achieve therapeutic purposes by down-regulating the expression of resistance-associated proteins or silencing other genes that regulate tumor function.Therefore,the combination of chemotherapy and gene therapy with the help of nanocarriers can exert the synergistic effect of the two and improve the effect of chemotherapy,which is a promising anticancer strategy.Silencing drug resistance-related genes is the main idea to solve tumor MDR,and it is still necessary to explore other gene therapy strategies that can synergize with chemotherapy to achieve the purpose of cancer treatment for a wider range of targets by regulating one or some links in tumor development. In the meantime,the use of nanoparticles(NPs) to co-deliver genes and chemotherapeutic agents places higher demands on nanocarriers. Genes are easily degraded by nucleases,unstable in the bloodstream,poor cellular uptake and low transfection efficiency,so safe and efficient co-delivery systems are urgently needed to overcome many obstacles and achieve maximum efficiency of drug co-loading and transport.According to the different therapeutic gene targets selected,the therapeutic strategies of gene-chemotherapy drug co-delivery can be divided into various types such as reversing MDR in tumor cells,promoting tumor cell apoptosis,anti-tumor angiogenesis,chemotherapy synergistic immunotherapy and removing cancer stem cells(CSCs),and the delivered genes include MDR-1 siRNA,Bcl-2 siRNA,p53 DNA,VEGF siRNA,PD-L1 siRNA and miR-205. The ideal nanocarrier for co-delivery should meet the conditions of high safety, good biocompatibility,biodegradability,and high gene transfection rate. Researchers have made full use of the characteristic advantages of various materials to develop different types of co-delivery carriers such as polymer nanoparticles,nanomicelles,liposomes,inorganic nanoparticles,viruses and nucleic acid carriers. In addition,the effect of targeted release of drugs according to the changes in tumor microenvironment or external environment can be realized by stimulating responsive design of carriers,so as to avoid the sudden release of encapsulated drugs,ensure the drug distribution at the tumor site,improve the therapeutic efficiency and reduce the toxic side effects on normal tissues.In this review,the phased research progress of co-delivery of genes and chemotherapeutic drugs by nanocarriers is summarized,the codelivery strategies and co-delivery carriers of gene-chemotherapeutic drugs are introduced,the characteristics of various types of carriers are analyzed,some problems to be solved in the field of nanocarrier research are considered and their prospects are prospected. The above contents provide a reference for realizing safe and efficient gene-chemical combination therapy.