多模态成像导向的溶瘤病毒与化疗药物肿瘤协同治疗

The oncolytic viruses are reported as promising tools for tumor therapy due to the tumor-killing capability by selectively replicating in tumor cells other than normal cells. However, the strong immunogenicity, weak tumor-targeting and antitumor efficacy of oncolytic viruses limit their clinical application. In this project, a novel strategy will be designed for multi-modal imaging-guided tumor therapy via combining oncolytic virotherapy with chemotherapy. The surface of virions will be modified by tetrazine (Tz) and wrapped with calcium carbonate/manganese to form biomineralized nanoparticles. The mineral shells will protect viruses from removal of the host immune system, while the enhanced permeability and retention (EPR) effect will further improve the tumor-targeting of viral nanoparticles. When the viral nanoparticles reach the tumor tissue, the calcium carbonate/manganese mineral shells will be dissolved due to the low pH value in tumor microenvironment, resulting the viruses release. Furthermore, the process is expected to improve the tumor microenvironment and monitored by photoacoustic imaging (PAI), ultrasound (US) imaging and magnetic resonance imaging (MRI). Meanwhile, the released virions will activate the TCO-caged prodrug (TCO-Dox) with inverse electron-demand Diels-Alder chemistry (iEDDA). Hopefully, the synergism of oncolytic virotherapy with chemotherapy will improve the clinical application of oncolytic viruses.

溶瘤病毒可选择性杀伤肿瘤细胞，为肿瘤治疗提供了新的可能。然而由于肿瘤靶向性弱而免疫原性很强，以及抑瘤效果不理想等问题，使其实际应用仍面临许多挑战。本项目拟开展多模态成像导向下的溶瘤病毒和化疗药物协同抑瘤研究。在溶瘤腺病毒（OA）表面四嗪（Tz）修饰的基础上用碳酸钙/锰（MnCaCs）进行包封，形成病毒纳米颗粒（OA-Tz@MnCaCs），封闭病毒免疫原性增强体内循环能力的同时，通过肿瘤EPR效应使其靶向并富集于肿瘤组织；继而通过MnCaCs的低pH响应性定点释放OA-Tz，并调节肿瘤微环境，实现磁共振、超声、光声多模态成像，以对OA-Tz的富集与抑瘤效果进行实时监测；与此同时，制备反式环辛烯衍生的阿霉素前药（TCO-Dox），使其在肿瘤组织通过OA-Tz与TCO-Dox之间的逆电子效应Diels-Alder反应定点激活，实现OA与Dox对肿瘤的协同联合治疗，推进溶瘤病毒的临床应用。

溶瘤病毒可选择性杀伤肿瘤细胞，为肿瘤治疗提供了新的可能。然而由于肿瘤靶向性弱而免疫原性很强，以及抑瘤效果不理想等问题，使其实际应用仍面临许多挑战。本项目拟开展多模态成像导向下的溶瘤病毒和化疗药物协同抑瘤研究。在溶瘤腺病毒（OA）表面四嗪（Tz）修饰的基础上用碳酸钙/锰（MnCaCs）进行包封，形成病毒纳米颗粒（OA-Tz@MnCaCs），封闭病毒免疫原性增强体内循环能力的同时，通过肿瘤EPR效应使其靶向并富集于肿瘤组织；继而通过MnCaCs的低pH响应性定点释放OA-Tz，并调节肿瘤微环境，实现磁共振、超声、光声多模态成像，以对OA-Tz的富集与抑瘤效果进行实时监测；与此同时，制备反式环辛烯衍生的阿霉素前药（TCO-Dox），使其在肿瘤组织通过OA-Tz与TCO-Dox之间的逆电子效应Diels-Alder反应定点激活，实现OA与Dox对肿瘤的协同联合治疗，推进溶瘤病毒的临床应用。