仿血小板脂质体智能递送PDL1抗体治疗肿瘤切除术后复发和转移的研究

Surgical resection is the main treatment option for most solid tumors, but post-surgical tumor recurrence and metastasis caused by tiny residual tumors and circulating tumor cells remain a serious threat to human health. Although the immune checkpoint blockade (ICB) antibodies have achieved exciting results in treating various types of tumors, they still have many limitations including low objective response rate, poor stability in vivo and autoimmune disorders caused by the off-targeting effect. Therefore, in this project, a platelet-mimicking liposome drug delivery system is developed by integrating platelet membrane proteins into thrombin-sensitive liposomes using anti-PDL1 antibody as the model drug, and post-surgical tumor recurrence and metastasis of highly metastatic breast cancer and melanoma as the disease model. Through mimicking the natural homing to wounds and tumor metastasis of platelets, platelet-mimicking liposomes deliver PDL1 antibodies to residual tumors and tumor metastasis, release them by the cleavage of the local thrombin, and improve the immunotherapy of post-surgical tumor recurrence and metastasis. This therapeutic strategy and the constructing mode of this biomimetic liposome system have never been reported in domestic and abroad, which present high-level research value and innovation significance.

手术切除是目前大部分实体瘤的主要治疗手段，但术后残留微小肿瘤和循环肿瘤细胞所导致的肿瘤复发和转移严重威胁人类的健康。免疫检查点阻断（ICB）抗体在多种肿瘤的免疫治疗方面虽已取得显著成效，但仍存在客观有效率较低、体内稳定性较差、脱靶效应导致自身免疫性疾病发生率高等问题。据此，本项目以高转移性乳腺癌和黑色素瘤的术后肿瘤复发与转移为疾病模型，以PDL1抗体为模型药物，将血小板膜蛋白与对凝血酶敏感的脂质体融合，构建载PDL1抗体的仿血小板脂质体智能递药系统，通过模仿血小板对伤口和肿瘤转移部位天然趋向的行为，将PDL1抗体递送至术后残留肿瘤和肿瘤转移部位，同时利用高度特异表达于伤口和肿瘤转移部位的凝血酶的切割作用，将PDL1抗体定点释放，提高肿瘤的复发与转移的免疫治疗效果。该治疗策略及仿生纳米递药系统的构建模式目前国内外未见报道，具有较高的创新意义和研究价值。

手术切除是目前大部分实体瘤的主要治疗手段，但术后残留微小肿瘤和循环肿瘤细胞所导致的肿瘤复发和转移严重威胁人类的健康。免疫检查点阻断（ICB）抗体在多种肿瘤的免疫治疗方面虽已取得显著成效，但仍存在客观有效率较低、脱靶效应导致自身免疫性疾病发生率高等问题。据此，本项目以高转移性乳腺癌的术后肿瘤复发与转移为疾病模型，以PDL1抗体为模型药物，将血小板膜蛋白与对凝血酶敏感的脂质体融合，构建载PDL1抗体的仿血小板脂质体智能递药系统PL-TS-αPDL1，通过模仿血小板对伤口和肿瘤转移部位天然趋向的行为，将PDL1抗体递送至术后残留肿瘤和肿瘤转移部位，同时利用高度特异表达于伤口和肿瘤转移部位的凝血酶的切割作用，将PDL1抗体定点释放，提高术后肿瘤复发与肿瘤转移的免疫治疗效果。研究结果表明，与载αPDL1的血小板泡囊和普通脂质体相比，静脉注射后PL-TS-αPDL1在术后残留肿瘤部位的分布分别提高了90.2倍和3.7倍，在肿瘤肺转移部位的分布分别提高了2.03倍和1.87倍。药效学结果表明，PL-TS-αPDL1可以显著抑制术后肿瘤的复发和肿瘤的肺转移，延长动物的生存期，且安全性良好。上述结果表明，PL-TS-αPDL1是一种优良的抗体药物靶向递送系统，对术后肿瘤的复发和转移治疗有潜在的应用价值。该研究结果为肿瘤的免疫治疗提供了相关的研究方法和实验参考，具有较高的研究意义和社会效益。