Multi-functional Nanocarrier against Canine Lymphoma

描述（申请人提供）：本项目开发的多功能胶束靶向纳米治疗药物为高浓度细胞毒性药物的递送提供了机会（如阿霉素），分子靶向药物（例如硼替佐米[Velcade（R）]，一种蛋白酶体抑制剂）以及治疗性放射性核素如131I到肿瘤部位，同时保留正常器官，从而大大增强了抗肿瘤作用，减轻了这些药物的全身副作用。因此，我们预计晚期非霍奇金淋巴瘤（T细胞和B细胞型）或实体瘤患者将受益于此类新型纳米疗法。此外，这种多功能纳米平台还可以用作肿瘤显像剂。 我们的纳米颗粒平台是独特的，由基于寡聚胆酸的胶束组成，其中载有药物，并装饰胶束表面的癌症靶向配体。我们相信，将淋巴瘤靶向配体LLP2A添加到纳米治疗剂中可以促进纳米载体在体内向肿瘤细胞的细胞内递送，因此将大大增强其抗肿瘤功效。在这项拟议的研究中，将在转基因小鼠淋巴瘤模型和自发性犬淋巴瘤中评估这种靶向纳米颗粒的生物分布特性（成像）和治疗功效。 这项研究将导致开发更有效和毒性更小的多功能靶向纳米制剂，包括硼替西泮（一种蛋白酶体抑制剂）、多柔比星（一种DNA嵌入物）和治疗性放射性核素131 I，所有这些都有望用于治疗许多癌症类型，包括非霍奇金淋巴瘤（NHL）。如果成功，这种治疗方法也可以应用于许多其他癌症类型，因此将对美国和世界各地癌症患者的生存产生重大影响。

DESCRIPTION (provided by applicant): The multifunctional micelle-based targeting nanotherapeutics to be developed in this project offer an opportunity to deliver high concentration of cytotoxic drugs (e.g. doxorubicine), molecularly targeted drugs (e.g. bortezomib [Velcade(R)], a proteosome inhibitor) as well as therapeutic radionuclides such as 131I to the tumor sites while sparing normal organs, thus greatly enhance the anti-tumor effects and lessen the systemic side effects of these drugs. As a result, we expect patients with advanced non- Hodgkin lymphoma (both T- and B-cell type) or solid tumors will benefit from such novel nanotherapies. In addition, such multifunctional nanoplatform can also be used as tumor imaging agents. Our nanotherapeutic platform is unique and comprised of oligocholic acid based micelles with drugs loaded inside and cancer targeting ligands decorating the micelle surface. We believe the addition of LLP2A, a lymphoma targeting ligand, to the nanotherapeutics can facilitate the intracellular delivery of the nanocarrier to the tumor cells in vivo and therefore will greatly enhance their anti-tumor efficacies. In this proposed research, biodistribution properties (imaging) and therapeutic efficacies of such targeting nanoparticles will be evaluated in both transgenic mouse lymphoma models and spontaneous canine lymphoma. This research will lead to the development of more efficacious and less toxic multifunctional targeting nanoformulations of bortexomib (a proteasome inhibitor), doxorubicin (a DNA intercalate), and therapeutic radionuclide 131I, all of which are expected to be useful in the treatment of many cancer types including non-Hodgkin lymphoma (NHL). If successful, this therapeutic approach can be applied to many other cancer types as well and therefore will have a great impact in the survival of cancer patients in the United States and around the world.