LIGHT ACTIVATED ANTI-CANCER DRUGS

光激活抗癌药物

• 批准号: 8690531
• 负责人: MARK D DISTEFANO
• 金额: $ 17.46万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690531
• 关键词: Address; Adverse effects; Affect; Animals; Antibodies; Antineoplastic Agents; Area; Cancer Model; Cell Culture Techniques; Cells; Chemicals; Chemistry; Confocal Microscopy; Consult; Development; Dimethylallyltranstransferase; Disease; Dyes; Epithelial; Excision; Farnesyl Transferase Inhibitor; HRAS gene; Inhibition of Apoptosis; Institutes; Killer Cells; Light; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medicine; Modality; Modeling; Mus; Mutation; Normal tissue morphology; Operative Surgical Procedures; Organic Synthesis; Paper; Pharmaceutical Preparations; Photochemistry; Physics; Preparation; Process; Property; Protein Isoprenylation; Proteins; Research; Rhodamine; Signal Pathway; Site; Skin; Skin Cancer; Solutions; Surface; Tissue Embedding; Tissue Model; Tissues; Toxic effect; Xenograft Model; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; chromophore; contextual factors; design; efficacy testing; farnesylation; fluorophore; improved; in vivo; inhibitor/antagonist; innovation; mouse model; photoactivation; prenylation; prevent; public health relevance; research study; tissue phantom; tumor; two-photon

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.

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药物。虽然有用，但所有这些药物都表现出显着的副作用。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“笼中”（非活性）药物来解决上述问题，这些药物可以通过长波长光以特定位点的方式“释放”（激活）；此类药物可以专门针对肿瘤并保护正常组织。这一创新策略基于两个光子可去除保护基团（包括 Bhc、BHQ 和 NDBF）领域化学的最新发展。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。由于长波长光可以有效地穿透组织，因此这种解笼策略可用于选择性地释放皮肤下肿瘤内的抗癌药物，而不影响周围组织。这不仅可以减少化疗的副作用，而且在某些情况下还可以避免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：光激活（通过双光子激发，2PE）在什么深度可以产生生物有用水平的药物？在应用于 Ras 驱动的癌症的背景下，这个问题是本文提出的研究的重点。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烯基转移酶笼状抑制剂的特性，包括笼状法呢基转移酶抑制剂（FTI）、笼状香叶基香叶基转移酶抑制剂（GGTI）和笼状双异戊二烯基化抑制剂（DPI）。溶液和细胞培养模型中。在目标 2 中，将使用幻影组织模型来评估不同深度的荧光团和蛋白异戊二烯转移酶的笼蔽抑制剂的解笼效率。最后，在目标 3 中，我们将在小鼠皮肤癌模型中测试笼式 FTI、笼式 GGTI 和笼式 DPI 的位点特异性解笼对于抑制 H-Ras 和 K-Ras 刺激的转化和肿瘤形成的功效和体内异种移植模型。如果成功，这种方法可能是改善癌症治疗的革命性一步。