IGF::OT::IGF FAILED TUBULIN INHIBITOR REFORMULATED AS LOCALIZED ADJUVANT THERAPY FOR HEAD AND NECK CANCER

建议继续开发QR206，其中包括埃博酮D(EpoD)，一种高毒性的游离形式的化疗药物，重新配制成长效聚乳酸-乙醇酸微粒，在肿瘤和淋巴结内提供6-8周的缓释，用于治疗头颈部鳞状细胞癌(HNSCC)。瘤内(I.T.)注射QR206以多分散微粒的形式传递EpoD，这些微粒既有保留在肿瘤部位的大颗粒，也有通过利用吞噬细胞(如APC)的迁移扩散到区域和淋巴组织的小颗粒。建议的配方将减少治疗肿瘤所需的药量和全身暴露，从而减少副作用和全身毒性。拟议的启用IND的研究将包括在免疫活性BALB/c小鼠身上进行的剂量升级和生物分布研究，这些小鼠携带已确定的口腔同基因肿瘤(目标1和2)。在成功的小鼠研究之后，将进行剂量递增兽医试验，猫的口腔鳞状细胞癌将接受单剂量QR206(目标3)的治疗。预期结果包括在两个动物模型中建立疗效和安全性，并确认QR206的S靶向机制和预期的生物分布。

Proposed is a continued development of QR206, which comprises epothilone D (EpoD), a highly toxic chemotherapy in its free form, reformulated into long acting poly(lactic-co-glycolic) acid microparticles that provide 6-8 weeks of sustained release within tumors and lymph nodes, as treatment of head and neck squamous cell carcinoma (HNSCC). Intratumoral (i.t.) injection of QR206 delivers EpoD in poly-disperse microparticles spanning both large sizes that remain trapped at the tumor site and small sizes that spread into regional and lymphoid tissues by harnessing the migration of phagocytic cells, such as APCs. The proposed formulation will reduce the amount of drug required to treat the tumor and the systemic exposure to it, thus reducing side effects and systemic toxicity. The proposed IND-enabling studies will include dose escalation and biodistribution studies in immunocompetent BALB/c mice bearing established oral syngeneic tumors (Objectives 1 and 2, respectively). Successful murine studies will be followed by a dose escalation veterinary trial conducted where oral squamous cell carcinomas in cats will be treated with single doses of QR206 (Objective 3). The expected results include establishment of the efficacy and safety in two animal models and confirming QR206's targeting mechanism and anticipated biodistribution.