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

描述（由申请人提供）：本提案首次研究了两种有前途的抗癌药物辛二酰苯胺异羟肟酸（SAHA）和格尔德霉素（GA）通过原始平台的共同递送，用于体内评价侵袭性乳腺肿瘤。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递送药物（训练阶段）和（2）多功能nanoTRAIN平台（独立阶段），以评估联合治疗的不同递送方法的可行性。长期目标是改善癌症患者中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用于针对啮齿动物中的人乳腺癌异种移植模型的联合治疗。独立阶段的目的是比较评估在nanoTRAIN中递送的SAHA和GA作为在携带肿瘤的啮齿动物中共同递送药物的替代平台。总体假设是，由于比单独药物更高的治疗功效和更低的剂量限制毒性，SAHA和GA的体内共递送将导致上级抗肿瘤作用。由此产生的数据将是显着的，通过提供在体内的洞察GA和SAHA的治疗组合，以及洞察到一个新的共同交付的概念。NanoTRAIN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用于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物化学理解（以合理设计有希望的组合），而且依赖于能够协调递送各种药物组合的通用平台。更广泛的影响是，与复杂的多功能纳米颗粒相比，nanoTRAIN可以提供更简单的共同递送解决方案，用于更快地将有前途的组合治疗带到临床，并且具有治疗侵袭性癌症患者的个性化组合治疗的巨大潜力。 相关性：侵袭性癌症用药物组合治疗，然而并非所有患者和癌症都对任何一种形式的药物组合疗法有反应。因此，治疗癌症的有效组合疗法将需要能够为个体患者个性化组合方案的通用药物递送平台。

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.