Targeted Combination Therapy for Breast Cancer

说明(申请人提供)：紫杉醇(PTX)是治疗各种癌症的一线化疗药物，包括乳腺癌(BCA)、前列腺癌(PCA)、肺癌和其他癌症。然而，PTX的有效性受到不可耐受的全身毒性的限制，这限制了可以给出的杀死大部分(如果不是全部)癌细胞的药物数量。这将有助于新获得耐药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数的重要策略。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，并证明PTX疗法的毒性和有效性都有所改善。然而，这些颗粒(~130 nm)的尺寸还不够小，不足以有效地渗透到血运不良的肿瘤组织中。基于胶束的制剂由于其尺寸小，可以有效地将药物输送到肿瘤中，各种类型的聚合物系统已经被开发出来。大多数聚合物系统使用的是缺乏治疗活性的“惰性”辅料。大量载体材料的存在不仅增加了成本，还带来了额外的安全问题。我们开发了一种基于聚乙二醇衍生物的Embelin递送系统，通过靶向X连锁的凋亡抑制蛋白(XIAP)，同时增强靶向递送，并使癌细胞对PTX敏感。在我们的新系统中配制的PTX显示出比临床使用的PTX制剂紫杉醇更好的最大耐受量(MTD，100~120 PTX mg/kg)和抗肿瘤活性。这一应用的重点是通过对构效关系(SAR)的系统研究来改进给药系统。然后在体外和体内检测它们与PTX的协同作用的效率。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示范系统。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研究确定聚乙二醇-恩贝林偶合物的最佳结构；目标2将研究聚乙二醇-恩贝林与共递送药物在抗肿瘤活性中的协同作用机制；目的3将定义在人BCA小鼠模型中的体内肿瘤靶向效率和药代动力学；目的4将在人BCA异种移植的小鼠模型中评估聚乙二醇靶向PTX的协同抗肿瘤活性。这项建议中拟议的研究的完成可能会导致开发一种新的靶向联合治疗策略，用于治疗包括胆囊癌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.