Multi-functional Nanocarrier against Canine Lymphoma

描述(申请人提供)：本项目将开发的基于胶束的多功能靶向纳米疗法提供了一个机会，将高浓度的细胞毒性药物(例如阿霉素)、分子靶向药物(例如蛋白酶体抑制剂Bortezomib[VELCADE(R)])以及治疗性放射性核素(如131I)输送到肿瘤部位，同时保留正常器官，从而极大地增强抗肿瘤效果并减少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细胞型和B细胞型)或实体瘤的患者将从这种新型纳米疗法中受益。此外，这种多功能纳米平台还可以用作肿瘤显像剂。我们的纳米治疗平台是独一无二的，由内部装载药物的基于低聚胆酸的胶束和装饰胶束表面的癌症靶向配体组成。我们相信，在纳米治疗中加入淋巴瘤靶向配体LLP2A，可以促进纳米载体在体内的细胞内递送到肿瘤细胞，从而大大增强其抗肿瘤效果。在这项拟议的研究中，这种靶向纳米颗粒的生物分布特性(成像)和治疗效果将在转基因小鼠淋巴瘤模型和自发性犬淋巴瘤模型中进行评估。这项研究将导致更有效和毒性更低的多功能靶向纳米制剂的开发，这些纳米制剂包括蛋白酶体抑制剂Bortex omib、DNA嵌入物阿霉素和治疗性放射性核素131I，所有这些都有望用于治疗包括非霍奇金淋巴瘤(NHL)在内的多种癌症类型。如果成功，这种治疗方法也可以应用于许多其他类型的癌症，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.