血小板基双模式光热治疗纳米制剂与光活性全细胞肿瘤疫苗及其肿瘤治疗应用研究

This research plan is dedicated to explore dual-modal photothermal therapy theranostic nanoagents and whole-cell tumor vaccine for improved cancer therapy based on the combination of photothermal effects and the heat stress response of functional components in body. The target nanoagents will be constructed based on functionalization of platelet (PLT) with complex nanoparticles fabricated from copolymer with photothermal conversion (PTC) efficiency and copolymer with two-photon excited fluorescence (TPEF) feature. Upon NIR irradiation, such nanoagents, termed as PTC-TPEF@PLT, are expected to induce temperature increase at the lesion location via PTC effect and therefore the ablation of tumor cells. Additionally, temperature increase will trigger blood coagulation by activating PLT, which leads to the formation of PLT plug for blocking blood vessel at lesion sites and necrosis of tumor cells. Improved therapeutic effectiveness of tumor photothermal therapy based on such strategy with involvement of dual mechanism is highly expected. Additionally, TPEF feature of the nanoagents enables in vivo evaluation of the effectiveness of tumor photothermal therapy via TPEF imaging owing to its high resolution and ability of NIR light to penetrate the tissue. Upon NIR irradiation, PTC nanoparticles internalized in tumor cells is capable of inducing formation of heat shock protein (HSP), which is a kind of innate immune adjuvant for enhancing the immune function of the target vaccine, and the subsequent cell inactivation presents whole-cell tumor vaccine carrying all the tumor-associated antigens. For the obtained vaccine that are injected into the lesion location of tumor-bearing model mice, the joint action of HSP and photothermal nanoparticles, both functioning as immune adjuvant, and the tumor-associated antigens stimulate immunity of the body upon NIR irradiation. Owing to HSP’s nature as innate immune adjuvant together with the effective stimulation of NIR light capable of penetrating the tissue, the obtained whole-cell tumor vaccine is expected to generate strong immune response in the body’s immune system and therefore enhanced tumor killing effect on the tumor-bearing model mice.

拟基于光热效应与体内活性组份热应激响应性的结合，构建基于双重光热治疗机制的纳米制剂和能诱导机体免疫系统产生强应答的肿瘤疫苗。我们将合成光热转换（PTC）聚合物及双光子激发荧光（TPEF）共轭聚合物；制备集PTC和TPEF于一体的纳米颗粒并构建血小板(PLT)基、能进行在体荧光监测的光热治疗功能纳米制剂PTC-TPEF@PLT。载体经近红外光(NIR)辐照导致病灶部位温度升高、消融肿瘤细胞；PLT凝血能“封堵”肿瘤部位的血管，使血管下游肿瘤细胞坏死。肿瘤细胞内在化后的光热纳米颗粒经NIR光辐照在细胞内诱导生成具有天然免疫佐剂功能的热休克蛋白（HSP），细胞灭活后成为携带有肿瘤细胞全部抗原的肿瘤疫苗。经NIR光辐照，注射到荷瘤小鼠体病灶部位的疫苗内HSP和光热纳米颗粒作为佐剂与肿瘤细胞内的抗原共同激发机体的免疫作用，诱导免疫系统产生更强的应答、提高对肿瘤的杀伤效应，达到抑制肿瘤的效果。

本项目拟基于光热效应与体内活性组份热应激响应性的有机结合，构建基于双重光热治疗机制的复合诊疗载体和能诱导免疫系统产生相对强烈应答的肿瘤疫苗。我们将合成具有高效光热转换（PTC）性能的光热聚合物及具有双光子激发荧光发射（TPEF）特性的共轭聚合物；制备集PTC和TPEF于一体的纳米颗粒并以此构建血小板(PLT)基、能进行在体荧光监测的双重光热治疗功能诊疗载体PTC-TPEF@PLT。该载体经近红外光(NIR)辐照导致病灶部位温度升高、消融肿瘤细胞；升温导致的PLT凝血能“封堵”肿瘤部位的血管，使血管下游肿瘤细胞坏死；基于上述双重作用机制，提高肿瘤光热治疗效果。NIR光辐照经内在化过程进入肿瘤细胞内的光热纳米颗粒在细胞内诱导生成具有天然免疫佐剂功能的热休克蛋白（Heat shock protein, HSP），该细胞经灭活后即成为携带有肿瘤细胞全部抗原的全细胞肿瘤疫苗。经NIR光辐照，注射到荷瘤小鼠体病灶部位的疫苗内HSP和光热纳米颗粒将作为佐剂与肿瘤细胞内的抗原共同激发机体的免疫作用，诱导免疫系统产生更强的应答、从而提高对肿瘤病灶部位的杀伤效应，达到抑制肿瘤的效果。