Fibrin Targeted Cancer Therapy

描述（由申请人提供）：我们提出通过主动靶向肿瘤纤维蛋白沉积来提高脂质体药物的疗效，从而显著增加药物在肿瘤中的生物分布，从而诱导更有效的肿瘤细胞杀伤。脂质体包膜药物通过增强渗透和滞留效应，延长了血浆循环时间，并实现了对肿瘤的非特异性靶向。多柔比星脂质体制剂（Doxil(R)）被批准用于转移性乳腺癌和卵巢癌的治疗，并提高生存率。第二代脂质体试图改进这种被动靶向机制，用靶向肿瘤相关靶点的配体修饰脂质体，从而进一步提高局部肿瘤浓度。我们建议利用我们实验室开发的一种高度特异性的纤维蛋白结合肽Tn6-Fbn，将脂质体靶向大多数生长肿瘤中常见的突出的纤维蛋白沉积物。纤维蛋白是肿瘤靶向的极好靶标：它在宿主-肿瘤界面和整个肿瘤基质中高浓度存在，除了伤口愈合外，在正常组织中不混杂。它代表了一个高容量的脂质体化疗缓释储存库，它是有效的肿瘤选择性，适用于大多数（如果不是全部）实体肿瘤类型，并存在于整个肿瘤发展过程中。我们已经对这一概念进行了早期验证，证明了基于Tn6-Fbn的磁共振成像探针EP-2104R对小鼠乳腺癌异种移植瘤基质中的纤维蛋白的靶向性和保留性。本课题涉及纤维蛋白靶向脂质体的合成和表征，以及优化关键的理化生化特性，包括脂质体稳定性和纤维蛋白结合。将在原位乳腺癌模型中评估脂质体在肿瘤中的生物分布，并结合体内分子成像和肿瘤组织学与非靶向对照进行比较。最后，我们将评估纤维蛋白靶向脂质体阻止原发肿瘤生长的能力

DESCRIPTION (provided by applicant): We propose to improve efficacy of liposomal drugs by active targeting to tumoral fibrin deposits so as to significantly increase biodistribution of drugto the tumor, thus inducing more effective tumor cell killing. Liposomal encapsulated drugs achieve extended circulation times in plasma and some non-specific targeting to tumors via an enhanced permeation and retention effect. Liposomal doxorubicin formulation (Doxil(R)) is approved as a treatment for metastatic breast and ovarian cancer, and improves survival. Second-generation liposomes seek to improve upon this passive targeting mechanism by decorating liposomes with ligands directed to tumor-associated targets, thus further enhancing the local tumor concentration. We propose to exploit a highly specific fibrin binding peptide, Tn6-Fbn, developed in our lab to target liposomes to the prominent fibrin deposits that are common to most growing tumors. Fibrin is an excellent target for tumor targeting: it is present at high concentration at the host-tumor interface and throughout the tumor stroma, and apart from wound healing, is not otherwise promiscuous in normal tissue. It represents a high capacity storage depot for sustained release of liposomal chemotherapy that is effectively tumor selective, general to most (if not all) solid tumor types, and present throughout tumor development. We have performed early validation of this concept demonstrating targeting and retention of a Tn6-Fbn based magnetic resonance imaging probe, EP-2104R, to fibrin in the tumor stroma of a murine breast cancer xenograft. This proposal involves synthesizing and characterizing fibrin targeted liposomes, as well as optimizing key physicochemical and biochemical properties, including liposome stability and fibrin binding. Biodistribution of liposomes to tumors will be evaluated in an orthotopic breast cancer model and compared to non-targeted controls using a combination of in vivo molecular imaging and tumor histology. Finally, the ability of fibrin targeted liposomes to prevent primary tumor growth will be evaluated and compared to non-targeted liposomes and the gold standard Doxil.