Fibrin Targeted Cancer Therapy

纤维蛋白靶向癌症治疗

• 批准号: 8831965
• 负责人: Himashinie Diyabalanage
• 金额: $ 24.22万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2017-04-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831965
• 关键词: Affinity; Animals; Apoptosis; Binding; Biochemical; Biodistribution; Biological Assay; Blood Circulation; Breast Cancer Model; Breast Cancer cell line; Cancer cell line; Cell Adhesion; Chemotherapy-Oncologic Procedure; Clinical; Confocal Microscopy; Deposition; Development; Dose; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Formulations; Drug Kinetics; Encapsulated; Enzymes; Equilibrium; Fibrin; Fluorescence Polarization; Generations; Gold; Growth Factor; Histology; Immunohistochemistry; Implant; In Vitro; Injection of therapeutic agent; Kinetics; Label; Lead; Ligands; Liposomal Doxorubicin; Liposomes; Liver; Location; MDA MB 231; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Metastatic breast cancer; Modeling; Monitor; Mus; Near-infrared optical imaging; Normal tissue morphology; Peptides; Permeability; Pharmaceutical Preparations; Plasma; Preparation; Primary Neoplasm; Property; Reticuloendothelial System; Serum; Solid Neoplasm; Specificity; Staining method; Stains; Supporting Cell; Surface; Testing; Therapeutic Index; Time; Toxic effect; Treatment Efficacy; Validation; Wound Healing; Xenograft procedure; angiogenesis; base; bioluminescence imaging; cell killing; chemotherapy; cyanine dye 5; cytotoxicity; dosage; drug efficacy; imaging probe; improved; in vivo; killings; malignant breast neoplasm; migration; molecular imaging; nanobiology; nanoparticle; neoplastic cell; neovasculature; novel; optical imaging; peptide analog; prevent; public health relevance; stoichiometry; targeted cancer therapy; targeted delivery; theranostics; tumor; tumor growth; uptake

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.

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物以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来提高脂质体药物的功效。脂质体包封的药物通过增强的渗透和保留效应实现在血浆中的延长的循环时间和对肿瘤的一些非特异性靶向。脂质体阿霉素制剂（Doxil（R））被批准作为转移性乳腺癌和卵巢癌的治疗，并提高生存率。第二代脂质体试图通过用针对肿瘤相关靶标的配体修饰脂质体来改善这种被动靶向机制，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高度特异性的纤维蛋白结合肽Tn 6-Fbn，将脂质体靶向大多数生长肿瘤常见的突出纤维蛋白沉积物。FIGH 4是肿瘤靶向的极好靶标：它以高浓度存在于宿主-肿瘤界面和整个肿瘤基质中，并且除了伤口愈合之外，在正常组织中不是混杂的。它代表了脂质体化疗持续释放的高容量储存库，其具有有效的肿瘤选择性，对大多数（如果不是全部）实体瘤类型通用，并且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Tn 6-Fbn的磁共振成像探针EP-2104 R对鼠乳腺癌异种移植物的肿瘤基质中的纤维蛋白的靶向和保留。该提案涉及合成和表征纤维蛋白靶向脂质体，以及优化关键的物理化学和生物化学性质，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价脂质体在肿瘤中的生物分布，并使用体内分子成像和肿瘤组织学的组合与非靶向对照进行比较。最后，将评估纤维蛋白靶向脂质体预防原发性肿瘤生长的能力 并与非靶向脂质体和金标准Doxil进行比较。