LIGHT ACTIVATED ANTI-CANCER DRUGS

描述（由申请人提供）：该提案描述了一种高度创新的癌症治疗方法。癌症治疗的主要方式之一涉及使用化疗剂。虽然有用，但所有这些药物都表现出相当大的副作用。因此，它们的使用需要在一方面根除癌症和另一方面造成长期细胞损伤之间进行权衡。在这里，我们建议使用“笼”（非活性）药物，可以“uncaged”（激活）的长波长光在特定的位置的方式来解决上述问题;这样的药物可以专门针对肿瘤和备用正常组织。这种创新策略是基于双光子可去除保护基团（包括Bhc，BHQ和NDBF）领域的最新化学发展。这些部分可以通过使用聚焦红光（800 nm）的双光子激发来去除。由于长波长的光可以有效地穿透组织，这种解开策略可以用于在皮肤下的肿瘤内选择性地释放抗癌药物，而不会影响周围组织。这不仅可以减少化疗的副作用，而且在某些情况下还可以减少手术切除肿瘤的需要。然而，在实施这种方法之前，必须解决的关键问题是：在什么深度光激活（通过双光子激发，2 PE）可以产生生物有用的药物水平？这个问题，在应用于Ras驱动的癌症的背景下，是这里提出的研究的重点。因此，在目标1中，我们将合成并研究笼状荧光团模型和蛋白质异戊二烯基转移酶的笼状抑制剂的性质，包括笼状法尼基转移酶抑制剂（FTI）、笼状香叶基香叶基转移酶抑制剂（GGTI）和笼状双异戊二烯化抑制剂（DPI）在溶液和细胞培养模型中的性质。在目标2中，将使用体模组织模型来评估荧光团和蛋白质异戊二烯基转移酶的笼状抑制剂在不同深度的释放效率。最后，在目的3中，我们将测试笼状FTI、笼状GGTI和笼状DPI的位点特异性撑开在小鼠皮肤癌模型和体内异种移植模型中抑制H-Ras和K-Ras刺激的转化和肿瘤形成的功效。如果成功，这种方法可能是改善癌症治疗的革命性一步。

DESCRIPTION (provided by applicant): This proposal describes a highly innovative approach for the treatment of cancer. One of the primary modalities for cancer treatment involves the use of chemotherapeutic agents. While useful, all of these drugs manifest substantial side effects. Thus, their use requires a tradeoff between eradicating the cancer on the one hand and causing long term cellular damage on the other. Here we propose to address the above problem using "caged" (inactive) drugs that can be "uncaged" (activated) by long wavelength light in a site-specific manner; such drugs could specifically target the tumor and spare normal tissue. This innovative strategy is based on recent developments in chemistry in the area of two photon removable protecting groups (including Bhc, BHQ and NDBF). These moieties can be removed by two-photon excitation using focused red (800 nm) light. Since long wavelength light can efficiently penetrate tissue, this uncaging strategy could be used to selectively release anti-cancer drugs within a tumor below the skin without affecting the surrounding tissue. Not only would this reduce the side effects from chemotherapy but it could also obviate the need for surgical tumor removal in some cases. However, before such an approach can be implemented, the key question that must be addressed is: At what depths can light activation (via two-photon excitation, 2PE) produce biologically useful levels of drugs? That question, in the context of application to Ras-driven cancers, is the focus of the research proposed here. Thus, in Aim 1, we will synthesize and study the properties of a caged fluorophore model and caged inhibitors of protein prenyltransferases including a caged farnesyltransferase inhibitor (FTI), a caged geranylgeranyltransferase inhibitor (GGTI) and a caged dual prenylation inhibitor (DPI) in solution and in cell culture models. In Aim 2, a phantom tissue model will be used to evaluate the efficiency of uncaging of a fluorphore and caged inhibitors of protein prenyltransferases at different depths. Finally, in Aim 3 we will test the efficacy of site-specific uncaging of a caged FTI, a caged GGTI and a caged DPI for inhibiting H-Ras- and K-Ras-stimulated transformation and tumor formation in both a mouse skin cancer model and an in vivo xenograft model. If successful, this approach could be a revolutionary step in improving cancer therapy.