Light-targeted drug delivery

描述（由申请人提供）：许多类型的癌症化疗都有严重的副作用。需要用于将有效的细胞毒性剂选择性递送至癌细胞的新方法来解决这个问题。目前的方法包括使用抗体将药物靶向癌细胞，在癌细胞存在下从无活性的前药形式释放细胞毒性化合物，以及光动力疗法，其中光用于从固有无毒的光敏剂产生细胞毒性单线态氧。这种对光敏剂的依赖有缺点;特别是，这意味着所有的光动力疗法都依赖于氧气，这是缺氧肿瘤微环境中的一个问题。该提案的第一个目标是开发两种基于光致药物递送的多功能和氧独立的癌症治疗策略。第一种策略是通过一个易光裂的连接体将药物连接到一个细胞不可渗透的基团上。光照将释放游离药物，允许其进入细胞。第二种策略涉及使用构象可转换的肽，该肽在光照下变得可渗透细胞，允许其携带药物穿过细胞膜。虽然原则上这两种策略都可以用于递送许多类型的药物，但该提议将集中在抗癌化疗药物阿霉素上。对于两种策略，将使用流式细胞术和共聚焦显微镜监测缀合物进入食管腺癌细胞的增强。将测定多柔比星缀合物在存在和不存在光的情况下的IC 50值，并将建立光引起的细胞死亡的空间控制。缺氧环境中的细胞死亡也将是 验证最后，将使用心肌细胞、骨髓细胞和成纤维细胞分析多柔比星缀合物的脱靶毒性。光致药物递送的成功实施将为光靶向癌症治疗提供一种新的、强有力的方法。 公共卫生相关性：该提案旨在开发一种新的多功能方法，用于光治疗食管癌。光将用于将化学治疗剂递送到食管癌细胞中。

DESCRIPTION (provided by applicant): Many types of cancer chemotherapy suffer from severe side effects. New methods for selective delivery of potent cytotoxic agents to cancer cells are needed to solve this problem. Current approaches include targeting a drug to a cancer cell using an antibody, release of a cytotoxic compound from an inactive, prodrug form in the presence of the cancerous cell, and photodynamic therapy, where light is used to create cytotoxic singlet oxygen from an inherently non-toxic photosensitizer. This reliance on photosensitizers has drawbacks; in particular, it means that all photodynamic therapy is dependent on oxygen, a problem in hypoxic tumor microenvironments. The first objective of this proposal is the development of two versatile and oxygen independent strategies for cancer treatment based on light-enabled drug delivery. The first strategy involves attaching a drug to a cell impermeable group via a light-scissile linker. Illumination will release the free drug permitting its entry into the cell. A second strategy involves using a conformationally switchable peptide that becomes cell permeable upon illumination, allowing it to carry the drug across the cell membrane. Although in principle both of these strategies could be used to deliver many types of drugs, this proposal will focus on the anticancer chemotherapeutic doxorubicin. For both strategies, the enhancement in entry of the conjugates into esophageal adenocarcinoma cells will be monitored using flow cytometry and confocal microscopy. The IC50 values of the doxorubicin conjugates in the presence and absence of light will be determined, and spatial control of cell death by light will be established. Cell death in hypoxic environments will also be verified. Finally, the off target-toxicity of the doxorubicin conjugates will be analyzed using cardiomyocytes, bone marrow cells, and fibroblasts. Successful implementation of light-enabled drug delivery will provide a new, powerful approach for light-targeted cancer treatment. PUBLIC HEALTH RELEVANCE: This proposal aims to develop a new versatile method for the treatment of esophageal cancer with light. Light will be used to deliver a chemotherapeutic agent into esophageal cancer cells.