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

描述(由申请人提供)：目前的方案是第一次研究两种有希望的抗癌药物--琥珀酰苯胺异羟肟酸(SAHA)和格尔达那霉素(GA)通过原始平台联合应用，用于体内抗侵袭性乳腺肿瘤的评估。这将分两个阶段完成：(1)设计良好的多功能纳米颗粒，用于通过笼状胶束共同输送药物(培训阶段)和(2)多功能纳米训练平台(独立阶段)，以评估不同联合疗法输送方法的可行性。长期目标是改善癌症患者侵袭性肿瘤的化疗消退。培训的目的是评估多功能笼状胶束中的SAHA和GA用于联合治疗啮齿动物体内的人乳腺癌异种移植模型。独立阶段的目标是比较评价纳米TRAINs中的SAHA和GA作为携带肿瘤的啮齿动物体内联合给药的替代平台。总体假设是，体内联合应用SAHA和GA将产生比单独药物更好的治疗效果和更低的剂量限制毒性，从而产生更好的抗肿瘤效果。由此产生的数据将通过提供对GA和SAHA的治疗组合的体内洞察以及对新的联合递送概念的洞察而具有重要意义。纳米TRAIN之所以重要，是因为对药物组合的新癌症研究表明，许多分子靶向药物也可以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取决于对癌细胞的全面生化了解(以便能够合理设计有希望的组合)，而且还取决于能够协同提供各种药物组合的多种平台。更广泛的影响是，与复杂的多功能纳米颗粒相比，纳米TRAIN可能提供更简单的联合给药解决方案，将有希望的联合治疗更快地带到临床，并具有用于治疗侵袭性癌症患者的个性化联合治疗的巨大潜力。 相关性：侵袭性癌症的治疗是一种药物的组合，然而，并不是所有的患者和癌症都对任何一种形式的药物联合治疗有反应。因此，在癌症治疗中有效的联合疗法将需要多功能的药物输送平台，能够为个别患者提供个性化的联合方案。

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.