Image-guided Prodrug and siRNA Targeting of Cancer

描述（由申请人提供）：肿瘤学的两个至关重要的领域是（i）开发有效的治疗方法，最大限度地减少对正常组织的损伤，以及（ii）开发成功减少或消除转移性疾病的治疗策略。癌症化疗会对正常组织造成严重损伤，导致毁灭性的副作用。转移性疾病通常难以治疗，并且是患者死于癌症的主要原因。使用小干扰RNA（siRNA）技术下调过表达且对癌细胞至关重要的特定途径的能力为开发靶向原发性和转移性肿瘤的新型癌细胞特异性治疗提供了前所未有的机会。检测siRNA的递送并将其与主要定位在肿瘤内的化疗剂的递送联合收割机组合的能力在该探索中具有显著的优势。我们最近开发了一种原型药物，使我们能够通过MRI和光学成像非侵入性地观察前药酶（细菌胞嘧啶脱氨酶）的递送。有了这种能力，就有可能在肿瘤中存在高浓度的酶和正常组织中存在低浓度的酶的同时，给药无毒的前药5-氟胞嘧啶（其被酶转化为细胞毒性5-氟尿嘧啶），以使全身毒性最小化。我们打算通过结合靶向胆碱激酶和环氧合酶-2这两种在乳腺癌中至关重要的酶的siRNA来提高这一策略的有效性。本申请的目的是双重的。第一个是使用乳腺癌的临床前模型，利用成像引导的前药酶-siRNA治疗来开发有效的癌症治疗策略，以最大限度地减少对正常组织的损伤。第二种是在临床前使用这些策略来靶向转移性病变。MR和光学报告系统都包括在这些原型试剂中，因为MR用于临床翻译，而光学报告系统可用于用高分辨率显微镜观察酶-siRNA缀合物的掺入。本申请中提出的研究在未来还可以扩展到与前药酶治疗和放射疗法组合的放射或化疗修复酶的图像引导靶向。公共卫生相关性：我们在此应用程序中的目的有两个方面。首先是开发有效的治疗策略，利用成像引导的前药酶-siRNA治疗，将对正常组织的损伤最小化，从而减少或消除癌症治疗的破坏性副作用。第二是使用这些策略来靶向转移性病变，因为乳腺癌转移是治疗难治性的，并且是死亡的主要原因，并且迫切需要确定有效减少或消除转移的新治疗方法。

DESCRIPTION (provided by applicant): Two critically important areas in oncology are (i) the development of effective treatments that minimize damage to normal tissue, and (ii) the development of treatment strategies that are successful in reducing or eliminating metastatic disease. Cancer chemotherapy can inflict severe damage to normal tissue resulting in devastating side-effects. Metastatic disease is usually refractory to treatment and is a major cause of patients succumbing to cancer. The ability to downregulate specific pathways that are overexpressed and critically important to cancer cells using small interfering RNA (siRNA) technology provides unprecedented opportunities to develop novel cancer-cell specific treatments to target primary and metastatic tumors. The ability to detect the delivery of the siRNA and combine it with the delivery of a chemotherapeutic agent primarily localized within the tumor would be of significant advantage in this quest. We recently developed a prototype agent that allows us to visualize the delivery of a prodrug enzyme, bacterial cytosine deaminase, noninvasively with MRI and optical imaging. With this ability it is possible to time the administration of the nontoxic prodrug 5-fluorocytosine, that is converted by the enzyme to cytotoxic 5-fluorouracil, to coincide with the presence of high concentrations of the enzyme in the tumor and low concentrations in normal tissue, to minimize systemic toxicity. We intend to advance the effectiveness of this strategy by incorporating siRNA targeting of two enzymes, choline kinase and cyclooxygenase-2, that are critically important in breast cancer. The purpose of this application is two-fold. The first is to develop effective cancer treatment strategies utilizing imaged guided prodrug enzyme-siRNA treatment to minimize damage to normal tissue, using preclinical models of breast cancer. The second is to use these strategies, preclinically, to target metastatic lesions. Both MR and optical reporter systems are included in these prototype agents since MR is for clinical translation, whereas the optical reporter is useful for visualizing the incorporation of the enzyme-siRNA conjugate with high-resolution microscopy. The studies proposed in this application can also, in the future, be extended to image-guided targeting of radiation or chemotherapy repair enzymes in combination with prodrug enzyme treatment and radiation therapy. PUBLIC HEALTH RELEVANCE: Our purpose in this application is two-fold. The first is to develop effective treatment strategies utilizing imaged guided prodrug enzyme-siRNA treatment that will minimize damage to normal tissue, thereby reducing or eliminating the damaging side-effects of cancer treatment. The second is to use these strategies to target metastatic lesions, as breast cancer metastasis is refractory to treatment and a major cause of mortality, and there is an urgent need to identify new treatments that are effective at reducing or eliminating metastasis.