Therapeutic Targeting Agents for Ovarian Cancer

 描述(申请人提供)：这是R01 CA115483资助金9年后的竞争性续期建议书。在4年前的上一次竞争更新中，我们建议开发一种新型的基于低聚胆酸/聚乙二醇基的纳米平台来负载紫杉醇(PTX)和SN-38，通过静脉注射进行靶向递送。和IP。接受卵泡刺激术治疗。我们还建议使用[14C]标记的紫杉醇来确定PTX负载的纳米载体在皮下和腹膜内OvCa异种移植模型中的体内生物分布和OvCa靶向特性。过去4年的拨款支持产生了24份出版物和3项专利申请。在第二次竞争更新中，我们建议通过(I)采用有效展示靶向配体的新策略，以及(Ii)化学调谐两亲性端突二聚体(单体单元)的胆酸核心，用于高容量负载多种抗癌药物，从而进一步开发基于寡胆酸/聚乙二醇基的纳米平台。这些新的概念将被系统地应用于基本的纳米平台，所产生的纳米颗粒将被充分表征它们的物理化学性质和它们在体内的肿瘤靶向性。然后，这些优越的特征将被结合并应用于开发新型的第三代靶向纳米载体，该载体具有高度的通用性、多功能、易于在临床上配制，并可作为有效的癌症治疗药物输送系统。我们将继续使用OvCa异种移植、皮下和腹膜内模型来评估这些新的纳米结构。我们之前已经证明，我们实验室开发的端树突体胶束纳米粒的治疗效果可以通过(I)引入端树突体间共价但可逆的交联键来提高纳米载体的体内稳定性，以及(Ii)通过在纳米载体表面修饰肿瘤靶向配体，如针对31整合素的OA02(环肽)。新一代基于端突二聚体的胶束纳米颗粒将(I)改善靶向配基显示，(Ii)增加适合纳米平台的治疗有效载荷范围。我们相信，这些改进将极大地提高这些纳米药物的通用性和体内疗效，不仅是在异种移植或转基因小鼠肿瘤模型中，而且在临床Ovca中也是如此。在这项竞争性的更新提案中，我们计划追求以下具体目标：1.改善我们胶束纳米载体上的配体展示2.开发新的杂化末端树突体，可以纳米制剂药物，否则不能用我们现有的末端树突体纳米制剂药物。3.从Aim 1和Aim 2中筛选出有希望的纳米载体，并在裸鼠皮下和腹膜内OvCa异种移植模型中进行生物分布和治疗效果的评估。

 DESCRIPTION (provided by applicant): This is a competitive renewal proposal of the R01 CA115483 grant after 9 years. In our last competitive renewal 4 years ago, we proposed to develop a novel oligocholic acid/PEG based nanoplatform to load paclitaxel (PTX) and SN-38 for targeted delivery via i.v. and i.p. for OvCa therapy. We also proposed to use [14C]-labeled paclitaxel to determine the in vivo biodistribution and OvCa targeting properties of PTX-loaded nanocarriers, in both subcutaneous and intraperitoneal OvCa xenograft models. This last 4 year grant support resulted in 24 publications and 3 patent applications. In this second competitive renewal, we propose to further develop our oligocholic acid/PEG based nanoplatform by (i) incorporating novel strategies for efficient display of targeting ligands, and (ii) chemical tuningof the cholic acid core of the amphiphilic telodendrimer (monomer unit) for high capacity loading of a wide range of anti-cancer drugs. These novel concepts will be systematically applied to the basic nanoplatform one at a time and the resulting nanoparticles will be fully characterized for their physicochemical properties and their in vivo tumor targeting properties. Those superior features will then be combined and adopted to the development of a novel third generation targeting nanocarrier that is highly versatile, multifunctional, easy to formulate in the clinics, nd can function as an efficacious drug delivery system for cancer therapy. We will continue to use OvCa xenograft, subcutaneous and intraperitoneal models, to evaluate these novel nanoconstructs. We have previously demonstrated that therapeutic efficacy of telodendrimer-based micellar nanoparticles developed in our laboratory can be enhanced by (i) introducing inter- telodendrimer covalent but reversible crosslinkages to improve the in vivo stability of the nanocarrier, and (ii) by decorating the surface of the nanocarrier with tumor targeting ligands such as OA02 (a cyclic peptide) against 31 integrin. The next generation telodendrimer- based micellar nanoparticle will (i) enable improvement of targeting ligand display, and (ii) increase the range of therapeutic pay-loads suitable for the nanoplatform. We believe these improvements will greatly enhance the versatility and in vivo efficacy of these nanoparticle drugs, not only in xenograft or transgenic murine tumor models, but also in clinical OvCa. In this Competitive Renewal Proposal, we plan to pursue the following specific aims: 1. To improve the ligand display on our micellar nanocarrier 2. To develop new hybrid telodendrimers that can nanoformulate drugs that otherwise cannot be nanoformulated with our existing telodendrimers. 3. Promising nanocarriers from aim 1 and 2 will be selected and evaluated in subcutaneous and intraperitoneal OvCa xenograft models in nude mice for biodistribution and therapeutic efficacies.