负载替莫唑胺的纳米递释系统联合条件增殖腺病毒靶向治疗黑色素瘤的研究

Targeted cancer therapy delivers drugs directly to the tumor site. The safety and efficacy of vectors in targeting delivery are the key point. A recent study from our laboratory demonstrated synergistic action of temozolomide(TMZ)and a conditionally replicating adenovirus Ki67-ZD55-IL24 in melanoma cells. Based on the study, we will construct a nanoparticulate system-carrying temozolomide (TMZ-PAMAM) by utilizing the ErbB-3 mAb to target cancer cells. We will investigate whether a combination of ErbB3 mAb-TMZ-PAMAM mediated Nanoparticulate therapy and a chimeric conditionally replicating adenovirus F5/35-ZD55-IL24 accumulated to the tumor site, enhanced tumor local drug concentration, and limited its spread to other organizations. Thereby, this approach will enhance the safety and targeting of gene therapy and chemotherapy, and eventually form a multiple killing effect of drugs against melanoma, "kill two birds with one stone". Our research intends to combine chemotherapy-induced sensitization of cancer cells, molecular-targeted sensitization, and gene virotherapy from in vitro and animal model. This novel strategy may hold promising potentials for developing an effective approach to treat melanoma.

肿瘤靶向治疗致力于将药物定向浓集至肿瘤部位以消灭肿瘤细胞。高效靶向性、药物有效性是关键。我们已证明烷化剂替莫唑胺（TMZ）与携带IL-24的条件增殖腺病毒Ki67-ZD55-IL24体内外具有协同抑黑色素瘤效应。本研究在前期基础上，以TMZ为切入点，构建负载TMZ的PAMAM纳米递释系统，在ErbB-3单抗修饰下赋予其靶向性。同时联合纤毛改造的靶向条件增殖腺病毒F5/35-ZD55-IL24。使病毒和TMZ向肿瘤部位富集，提高肿瘤局部药物浓度，从而增强基因治疗与化疗的安全性，最终形成对黑色素瘤"一箭双雕"的靶向多重杀伤效应。本研究从体外细胞水平和体内动物模型两个层面，将化疗的细胞增敏、分子靶向增敏与病毒-基因治疗结合起来，为黑色素瘤的治疗提供新的策略与方法。

近年来黑素瘤化疗研究未取得明显进展，耐药性和毒副作用是面临的两大难题。如何提高黑素瘤细胞的化疗敏感性、靶向性是目前研究的热点与难点，也是提高黑素瘤整体疗效的关键。本项目成功构建了负载抗黑素瘤药物替莫唑胺（TMZ）的TMZ-PAMAM-PEG-GE11-HA靶向纳米递释系统，采用超声乳化法，成功包埋了TMZ，通过优化载药条件达到最适包封率和载药量，提高药物稳定性，并证明其具有良好的肿瘤细胞靶向性。本项目在原有基础上进一步发展，在PAMAM表面进一步修饰，转换成羧基，进一步合成了具有诊疗功能的靶向性纳米平台HA-PAMAM-ICG/TMZ，在细胞实验和动物实验证明其具有良好的肿瘤靶向性，并可以联合化疗与光热/光动力治疗杀伤黑素瘤。 本项目成功包装出携带IL-24基因的新型条件增殖型腺病毒F5/35-ZD55-IL-24，证明其有显著抑制黑素瘤细胞A375、MV3靶向性，并在细胞水平上成功证明F5/35-ZD55-IL-24可以联合化疗药物TMZ抑制黑素瘤细胞 A375、MV3增殖、促进凋亡的效应。本研究构建了具有良好靶向作用的纳米递释系统和条件增殖腺病毒，有效提高肿瘤局部药物浓度，并进一步发展了具有诊疗作用的纳米治疗平台，此外还将化疗与基因治疗结合起来，为黑素瘤的靶向治疗带来新的治疗策略与思路，本研究内容目前未见报道。