Multifunctional Co-delivery Systems for In Vivo Combination Therapy in Cancer

描述（由申请人提供）：目前的提案是第一个通过原始平台研究两种有前景的抗癌药物，亚酰苯胺羟肟酸（SAHA）和格尔达霉素（GA）的共同递送，用于体内评估对侵袭性乳腺肿瘤的作用。这将分两个阶段完成：(1)设计一个精心设计的多功能纳米颗粒，用于通过笼状胶束共同递送药物（训练阶段）；(2)一个多功能纳米列车平台（独立阶段），以评估不同递送方法在联合治疗中的可行性。长期目标是改善癌症患者侵袭性肿瘤的化疗消退。培训的目的是评估SAHA和GA在多功能笼状胶束中联合治疗啮齿动物人类乳腺癌异种移植模型的效果。独立阶段的目的是比较评估以纳米列车递送的SAHA和GA作为载瘤啮齿动物共同递送药物的替代平台。总体假设是，与单独用药相比，SAHA和GA在体内共给药具有更高的治疗效果和更低的剂量限制性毒性，因此具有更好的抗肿瘤效果。通过提供GA和SAHA联合治疗的体内洞察以及对新的共同递送概念的洞察，所得数据将具有重要意义。纳米列车很重要，因为对药物组合的新兴癌症研究表明，许多分子靶向药物也可以被利用来使耐药癌症对以前失败的标准化疗药物敏感。因此，有效的癌症治疗不仅依赖于对癌细胞的全面生化理解（以便合理设计有希望的组合），而且还依赖于多功能平台，以便协调各种药物组合的递送。更广泛的影响是，与复杂的多功能纳米颗粒相比，纳米列车可能提供更简单的共同递送解决方案，将有希望的联合治疗更快地带到诊所，并且在治疗侵袭性癌症患者的个性化联合治疗方面具有巨大的潜力。

DESCRIPTION (provided by applicant): The current proposal is the first to investigate the co-delivery of two promising anticancer agents, suberoylanilide hydroxamic acid (SAHA) and geldanamycin (GA) via original platforms for in vivo evaluations against aggressive breast tumors. This will be accomplished in two phases: (1) a well-designed multifunctional nanoparticle for co-delivery of drugs through caged micelles (training phase) and (2) a multifunctional nanoTRAIN platform (independent phase) to assess the feasibility of the different delivery approaches for combination therapy. The long term goal is to improve chemotherapeutic regressions of aggressive tumors in cancer patients. The objective of the training is to evaluate SAHA and GA in multifunctional caged micelles for combination therapy against a xenograft model of human breast cancer in rodents. The objective of the independent phase is to comparatively evaluate SAHA and GA delivered in nanoTRAINs as the alternative platform for co-delivery of drugs in tumor-bearing rodents. The overall hypothesis is that in vivo co-delivery of SAHA and GA will lead to superior antitumor effects due to greater therapeutic efficacy and lower dose limiting toxicities than individual drugs. The resulting data will be significant by providing in vivo insights into the therapeutic combination of GA and SAHA as well as insights into a new co-delivery concept. NanoTRAINs are important because emerging cancer research into drug combinations has demonstrated that many molecularly targeted drugs can also be exploited to sensitize drug-resistant cancers to standard chemotherapeutics that had previously failed. Therefore, effective cancer treatments would rest not only on a comprehensive biochemical understanding of the cancer cell (to enable the rational design of promising combinations), but also on versatile platforms that would enable for concerted delivery of a variety of drug combinations. The broader impact is that nanoTRAINs may provide simpler co-delivery solutions, in contrast to complicated multifunctional nanoparticles, for bringing promising combination treatments more rapidly to the clinics, and have immense potential to personalize combination therapy for treating aggressive cancers, patients. RELEVANCE: Aggressive cancers are treated with, a combination of drugs, however not all patients and cancers respond to any one form of drug combination therapy. Effective combination therapy in the treatment of cancer will therefore require versatile drug delivery platforms capable of personalizing combination regimens for individual patients.