Targeted Combination Therapy for Breast Cancer

简介（申请人提供）：紫杉醇（PTX）是治疗乳腺癌（BCa）、前列腺癌（PCa）、肺癌等多种癌症的一线化疗药物。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（如果不是全部的话）癌细胞的药物量。这将有助于新获得耐药性的肿瘤亚群的选择性生存。开发有效的给药系统是提高化疗药物治疗指标的重要策略。Abraxane(R)是一种人类白蛋白稳定的PTX纳米制剂，已被批准用于临床应用，并证明了PTX治疗的毒性和疗效的改善。然而，这些颗粒的大小（~130 nm）不足以有效渗透到血管化不良的肿瘤组织中。基于胶束的制剂由于其体积小，可以有效地将药物输送到肿瘤中，并且各种类型的聚合物系统已经开发出来。大多数聚合物系统使用“惰性”赋形剂，缺乏治疗活性。大量载体材料的存在不仅增加了成本，而且带来了额外的安全问题。我们开发了一种peg衍生的基于栓塞的递送系统，该系统通过靶向X-linked inhibitor of apoptosis protein (XIAP)，同时增强靶向递送和使癌细胞对PTX敏感。与临床使用的PTX制剂紫杉醇相比，我们新系统中配制的PTX具有更高的最大耐受剂量（MTD, 100~120 PTX mg/kg）和抗肿瘤活性。本应用的重点是通过对构效关系（SAR）的系统研究来改进给药体系。然后在体外和体内检查它们与PTX协同作用的效率。最后，对其作用机理进行了探讨。BCa将被用作解决这些问题的模型系统。为了实现我们的目标，我们将追求四个具体目标：目标1将通过系统的SAR研究确定PEG-embelin偶联物的最佳结构；目的2：研究聚乙二醇-栓塞素与共给药协同抗肿瘤作用的机制；目的3将确定人BCa小鼠模型的体内肿瘤靶向效率和药代动力学；目的4将在人BCa异种移植小鼠模型中评估peg -embelin靶向PTX的协同抗肿瘤活性。本提案中提出的研究的完成可能会导致针对包括BCa在内的各种类型癌症的靶向联合治疗的新策略的发展。

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.