一种近红外光热协同增强的癌症基因免疫治疗微针的研究

Cancer immunotherapy has been regarded as the next generation of cancer treatment strategy due to its great potential to inhibit metastases and prevent tumour relapses via stimulating the inherent immunological systems of the body to attack tumour cells. However, until now, most of those immune-therapeutic strategies still have limitations such as the possible immunotoxicity, individual variations in therapeutic responses, etc..We explore in the project to develop a new platform to enhance immunotherapy effect for melanoma by combining microneedle patch-assisted gene delivery with NIR photothermal therapy. A bioinspired nanocarrier encapsulated with IR820, a photothermal agent, and plasmid pPD-1 is designed to be delivered into the subcutaneous melanoma via a physiologically soluable microneedle patch. The near-infrared (NIR) irradiation will be explored as a "kill two birds with one stone" strategy to enhance immunotherapy effect: Firstly, the NIR photothermal effect will enhance membrane permeability of the cultured cells and the high­efficiency delivery of plasmid pPD-1 into cells, which will promote the in situ transfection of pPD-1 and effectively block the PD-1 / PDL-1 immune checkpoint pathways; Secondly, The NIR-triggered photothermal ablation of cancer cell can explore to generate tumour-associated antigens, which can show vaccine-like functions to generate anti-tumour immunological effects. The new cancer immunotherapy by combining microneedle patch-assisted gene delivery with NIR photothermal therapy might provide a new promises way to eliminate primary tumours, inhibit metastases, and prevent tumour relapses.

本项目针对癌症免疫治疗的关键难题，将仿病毒基因载体、近红外光热效应和聚合物微针贴片技术的优势有机结合，探索制备一种近红外光热协同增强的癌症基因免疫治疗微针贴片。研究将采用可溶解聚合物微针为平台，实现负载近红外光染料IR820和pPD-1质粒的仿病毒纳米载体在皮下黑色素瘤中的定位传递；并利用近红外光热辅助手段实现“一石二鸟”的近红外光热协同增强免疫治疗模式：一方面，通过本课题组特色性的近红外光热辅助跨膜技术增强pPD-1质粒的原位转染，有效阻断PD-1/PDL-1免疫检测点通路，解除肿瘤细胞的免疫“隐身”逃避能力；另一方面，深入研究近红外光热效应对肿瘤特异性抗原表达的影响规律，探索实现免疫检测点阻断和光热诱导增强抗癌免疫应答二元协同增强的可能性，为提高癌症免疫治疗的临床有效性提供切实可行的途径。

本项目针对具有高度侵袭性的黑色素瘤的治疗，将仿病毒基因载体、近红外光热效应和聚合物微针贴片技术的优势有机结合，制备了近红外光热协同增强的基因治疗微针贴片。利用聚多巴胺纳米粒子的近红外光热转换能力，制备了基于聚多巴胺纳米粒子的非病毒基因载体，探究了纳米粒子的尺寸及刺激响应特性对基因传递效率的影响；制备了共负载抑癌基因和光热剂IR 820的快速可溶微针，验证了近红外光热与基因协同增强的肿瘤治疗效果；制备了以光热剂聚多巴胺纳米粒子为基因载体的可溶解微针，利用近红外光热辅助跨膜技术增强基因的原位转染，实现了光热增强的基因治疗效果；进一步拓展了气体协同治疗的聚合物微针贴片的研究，携氧跳跳糖微针能显著促进药物渗透扩散，通过改善乏氧微环境，能有效抑制黑色素瘤的转移；采用可工业化的超声喷涂技术制备了基因涂层微针，为基于微针经皮传递的黑色素瘤的治疗提供了切实可行的途径。