Role of Telmisartan on Intra-Tumoral Distribution of Targeted Nanoparticles

描述（由申请人提供）：尽管癌症治疗取得了最新进展，但NSCLC患者的临床结局并不令人印象深刻。我们的实验室一直致力于使用吸入和口服抗癌药物治疗肺癌。含有纳米颗粒的化学治疗药物的主动靶向可以通过在靶位点实现更高的浓度来有效地治疗腺癌。EphA 2是一种Eph家族受体酪氨酸激酶，在90%的NSCLC肿瘤中过表达;高水平的EphA 2预测患者的总体生存率较差。在我们实验室进行的研究表明，H460和A549肿瘤表达EphA 2受体。最近，肽YSAYPDSVPMMS（YSA）已被证明选择性结合肺癌和前列腺癌细胞上的EphA 2受体。利用YSA肽选择性结合和肺癌细胞中EphA 2受体的过表达状态，我们提出了一种YSA肽缀合的NC系统，以同时选择性地将抗癌药物递送至肺癌肿瘤。然而，不管纳米颗粒的靶向性质如何，它们的肿瘤内分布实际上是由致密的胶原网络和高度纤维化的结缔组织引起的。据报道，使用抗纤维化剂可以减少肿瘤间质纤维化并促进纳米颗粒在肿瘤内的分布。最近的研究表明，氯沙坦通过抑制转化生长因子β 1（TGF- 1）提高载药纳米粒的渗透性和治疗效果。我们实验室的初步研究表明，替米沙坦（AT 1阻滞剂）产生的纤维溶解作用是氯沙坦的3倍。因此，预期预先使用替米沙坦治疗将使肿瘤失去其致密的胶原蛋白网络，并将促进纳米治疗剂更好地在肿瘤内分布。我们打算在向实体肺肿瘤施用NCS-Ds（含有多西他赛的纳米颗粒）之前通过吸入和口服途径用替米沙坦治疗肺肿瘤。我们假设YSA缀合的靶向纳米颗粒（NCs-D-Y）将选择性地分布、结合并主动内化到过表达EphA 2的肺癌和肿瘤新生血管细胞中。替米沙坦的抗纤维化作用将促进这种分布。我们的具体目标是：具体目标1：制备和评估各种NC-D-Y制剂。为此，我们将制备与YSA肽缀合的NCs-D（NCs-D-Y），其显示特异性靶向EphA 2受体并抑制体外肿瘤细胞生长的证据。具体目的2：原位和转移性肿瘤中NCs-F-Y和NCs-D-Y的体内药代动力学和药效学评价。为此，在替米沙坦治疗后，将NCs-D-Y静脉内施用至携带肺肿瘤的动物，用于EphA 2特异性靶向递送。这些研究的结果将使我们能够评估替米沙坦在增强靶向纳米颗粒与其各种化疗药物有效载荷的肿瘤内递送中的作用。该提案的长期目标是将目前的方法用于其他纤维化肿瘤以及其他纳米颗粒有效载荷，如siRNA，shRNA或小分子抗癌药物。

DESCRIPTION (provided by applicant): Despite recent advances in cancer treatment, the clinical outcome among NSCLC patients is not impressive. Our laboratory has been working with the use of inhalation and oral delivery of anticancer agents for treatment of lung cancer. Active targeting of chemotherapeutic drugs containing nanoparticles may effectively treat adenocarcinomas by achieving higher concentration at target sites. EphA2, an Eph family receptor tyrosine kinase is overexpressed in 90% of NSCLC tumors; high levels of EphA2 predicted poorer overall patient survival. Studies conducted in our laboratory have shown that H460 and A549 tumors express EphA2 receptors. Recently, the peptide, YSAYPDSVPMMS (YSA) has demonstrated to selectively bind to EphA2 receptors on lung and prostate cancer cells. Taking advantage of YSA peptide selective binding and overexpressed status of EphA2 receptors in lung cancer cells, we propose an YSA peptide conjugated NCs system to simultaneously and selectively deliver anticancer drugs to lung cancer tumors. However, irrespective of the targeting nature of the nanoparticles, their intratumoral distribution is hindeed by dense collagen network and highly fibrous interstitium. Use of antifibrotic agents has reported to decrease tumor interstitial fibrosis and promote nanoparticle intratumoral distribution. Recent studies have demonstrated that Losartan through transforming growth factor beta 1 (TGF- 1) inhibition improved the penetration and therapeutic efficacy of drug loaded nanoparticles. Preliminary studies from our laboratory suggest that Telmisartan (AT1 blocker) produced 3 fold higher fibrolysis than Losartan. Therefore, it is expected that prior treatment with Telmisartan will make tumors lose their dense collagen network and will promote better intratumoral distribution of nanotherapeutics. We intend to treat the lung tumors with Telmisartan by inhalation and oral route prior to administering the NCs- Ds (Docetaxel containing nanoparticles) to solid lung tumors. We hypothesize that YSA conjugated targeted nanoparticles (NCs-D-Y) will selectively distribute, bind and actively internalize into the EphA2 over expressing lung cancer and tumor neovascular cells. This distribution will be facilitated by Telmisartan by its antifibrotc effects. Our specific Aims are: Specific Aim 1: To prepare and evaluate various NC-D-Y formulations. In this aim we will prepare NCs-D conjugated with YSA peptide (NCs-D-Y) which shows evidence of specific targeting to the EphA2 receptors and inhibiting the growth of tumor cells in vitro. Specific Aim 2: In vivo Pharmacokinetic and Pharmacodynamic evaluation of NCs-F-Y and NCs-D-Y in orthotopic and metastatic tumors. In this aim, following Telmisartan treatment, the NCs-D-Y will be administered intravenously to lung tumor bearing animals for EphA2 specific targeted delivery. Telmisartan will make difficulty penetrable solid tumors into easily nanoparticle penetrable loose interstitial networks The results emanating from these studies will allow us to assess the role of Telmisartan in enhancing intratumoral delivery of targeted nanoparticles with their payloads of various chemotherapeutic drugs. The long term objectives of this proposal are to use the current approach to other fibrotic tumors and also with other nanoparticle payloads like siRNA, shRNA or small molecule anticancer drugs.