Targeted Combination Therapy for Breast Cancer

描述（由申请人提供）：紫杉醇（PTX）是用于各种类型癌症的一线化疗剂，包括乳腺癌（BCa）、前列腺癌（PCa）、肺癌等。然而，PTX的有效性受到不可耐受的全身毒性的限制，这限制了可以杀死大多数（如果不是所有）癌细胞的药物量。这将导致具有新获得的耐药性的肿瘤亚群的选择性存活。开发有效的给药系统是提高化疗药物治疗指数的重要策略。Abraxane（R）是一种人白蛋白稳定的PTX纳米制剂，已被批准用于临床使用，并证明PTX治疗的毒性和疗效均有改善。然而，这些颗粒的尺寸（~130 nm）不够小，无法有效穿透血管化不良的肿瘤组织。基于胶束的制剂可以有效地将药物递送到肿瘤，这是由于它们的小尺寸和各种类型的聚合物系统已经被开发。大多数聚合物系统使用缺乏治疗活性的“惰性”赋形剂。大量载体材料的存在不仅增加了成本，而且还带来了额外的安全问题。我们已经开发了一种基于PEG衍生的恩贝林的递送系统，其同时增强靶向递送并通过靶向X连锁凋亡抑制蛋白（XIAP）使癌细胞对PTX敏感。紫杉醇的最大耐受剂量（MTD，100~120 mg/kg）和抗肿瘤活性均优于紫杉醇。本申请的重点是通过对构效关系（SAR）的系统研究来改进递送系统。然后在体外和体内检查它们与PTX的协同作用的效率。最后，将研究其作用机制。BCa将被用作解决这些问题的示范系统。本论文的主要目的是：通过系统的构效关系研究，确定PEG-Embelin偶联物的最佳结构;研究PEG-Embelin与共递送药物协同抗肿瘤活性的机制;研究PEG-Embelin在人BCa小鼠模型中的体内靶向性和药代动力学;目的4将在人BCa异种移植的小鼠模型中评价PEG-恩贝林靶向PTX的协同抗肿瘤活性。完成本提案中的拟议研究可能会导致开发一种新的靶向联合治疗策略，用于治疗包括BCa在内的各种类型的癌症。

DESCRIPTION (provided by applicant): Paclitaxel (PTX) is the first-line chemotherapeutic agent for various types of cancers including breast cancer (BCa), prostate cancer (PCa), lung cancer and others. However, the effectiveness of PTX is limited by untolerated systemic toxicity, which limits the amount of drug that can be given to kill most if not all cancer cells. This will lad to selective survival of tumor subpopulations with newly acquired drug-resistance. Development of effective delivery systems represents an important strategy to improve the therapeutic index of chemotherapeutic drugs. Abraxane(R) is a human albumin-stabilized nanoformulation of PTX that has been approved for clinical use and demonstrated improvements in both toxicity and efficacy of PTX therapy. However, the size of these particles (~130 nm) is not sufficiently small to achieve effective penetration into poorly vascularized tumor tissues. Micelles-based formulations can effectively deliver drugs to tumors due to their small sizes and various types of polymeric systems have been developed. Most of the polymeric systems use "inert" excipients that lack therapeutic activity. The presence of large amounts of carrier materials not only adds to the cost but also imposes additional safety issue. We have developed a PEG-derivatized embelin- based delivery system that simultaneously enhances targeted delivery and sensitizes the cancer cells to PTX via targeting X-linked inhibitor of apoptosis protein (XIAP). PTX formulated in our novel system shows superior maximal tolerated dose (MTD, 100~120 PTX mg/kg) and antitumor activity over Taxol, a clinically used PTX formulation. This application is focused on improving the delivery system through systematic study on structure-activity relationship (SAR). Their efficiency in synergistic action with PTX is then examined both in vitro and in vivo. Finally, the mechanism of action will be investigated. BCa will be used as a model system to address these issues. Four specific aims will be pursued to achieve our goals: Aim 1 will define the optimal structure of PEG-embelin conjugates through systematic SAR study; Aim 2 will study the mechanism by which PEG-embelin synergizes with co-delivered drug in antitumor activity; Aim 3 will define the efficiency of in vivo tumor targeting and pharmacokinetics in a mouse model of human BCa; Aim 4 will evaluate the synergistic antitumor activity of PEG-embelin-targeted PTX in a mouse model of human BCa xenograft. Completion of the proposed studies in this proposal is likely to lead to the development of a new strategy of targeted combination therapy for the treatment of various types of cancers including BCa.