Role of Telmisartan on Intra-Tumoral Distribution of Targeted Nanoparticles

替米沙坦对靶向纳米颗粒肿瘤内分布的作用

基本信息

批准号：
8637758
负责人：
Mandip Singh Sachdeva
金额：
$ 18.21万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637758
关键词：
A549 Abraxane Adenocarcinoma Adverse effects Albumin-Stabilized Nanoparticle Paclitaxel Angiotensin Receptor Animals Antihypertensive Agents Antineoplastic Agents Apoptosis Binding Biodistribution Breathing Cancer Model Cancer Patient Cell Survival Cells Cleaved cell Clinical Collagen Complex Deposition Development Diagnosis Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Formulations Drug Kinetics E-Cadherin Eph Family Receptors EphA2 Receptor Evaluation Fibroblasts Fibrosis Gelatinase A Growth Healthcare Systems Homing In Situ Nick-End Labeling In Vitro Investigation Laboratories Link Losartan Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Manuscripts Modeling Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal Cell Oral Outcome PECAM1 gene Patients Penetration Peptides Permeability Pharmaceutical Preparations Pharmacodynamics Preparation Process Protein Tyrosine Kinase Reporting Research Research Design Role Route Site Small Interfering RNA Solid Solid Neoplasm Structure of parenchyma of lung Survival Rate System Testing Therapeutic Tissues Toxic effect Treatment Efficacy Vimentin Work angiogenesis anticancer activity cancer cell cancer therapy caspase-3 combinatorial controlled release design docetaxel drug efficacy global health human TGFB1 protein improved in vivo interstitial nanoparticle nanotherapeutic neoplastic cell neovascular novel strategies overexpression pancreatic neoplasm prostate cancer cell public health relevance receptor mediated endocytosis small hairpin RNA small molecule success survivin targeted delivery telmisartan tumor uptake

项目摘要

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.

描述（由申请人提供）：尽管癌症治疗最近取得了进展，但 NSCLC 患者的临床结果并不令人印象深刻。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。含有纳米粒子的化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治疗腺癌。 EphA2 是一种 Eph 家族受体酪氨酸激酶，在 90% 的 NSCLC 肿瘤中过度表达； EphA2 水平高预示患者总体生存率较差。我们实验室进行的研究表明，H460 和 A549 肿瘤表达 EphA2 受体。最近，YSAYPDSVPMMS (YSA) 肽已被证明能够选择性地结合肺癌和前列腺癌细胞上的 EphA2 受体。利用 YSA 肽选择性结合和肺癌细胞中 EphA2 受体的过表达状态，我们提出了一种 YSA 肽缀合的 NCs 系统，可同时选择性地将抗癌药物递送至肺癌肿瘤。然而，无论纳米颗粒的靶向性质如何，它们的肿瘤内分布都受到致密的胶原网络和高度纤维化的间质的阻碍。据报道，使用抗纤维化药物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β1（TGF-1）提高了载药纳米颗粒的渗透和治疗效果。我们实验室的初步研究表明，替米沙坦（AT1 阻滞剂）产生的纤维溶解作用比氯沙坦高 3 倍。因此，预计预先用替米沙坦治疗将使肿瘤失去致密的胶原蛋白网络，并促进纳米治疗药物更好的肿瘤内分布。我们打算在对实体肺肿瘤施用 NCs-D（含有多西紫杉醇的纳米颗粒）之前，通过吸入和口服途径用替米沙坦治疗肺部肿瘤。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度表达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 配方。为此，我们将制备与 YSA 肽缀合的 NCs-D (NCs-D-Y)，其显示出特异性靶向 EphA2 受体并在体外抑制肿瘤细胞生长的证据。具体目标 2：NCs-F-Y 和 NCs-D-Y 在原位和转移性肿瘤中的体内药代动力学和药效学评估。为此，在替米沙坦治疗后，NCs-D-Y 将静脉注射至携带肺肿瘤的动物，以进行 EphA2 特异性靶向递送。替米沙坦将使难以穿透的实体瘤变成易于纳米粒子穿透的松散间质网络。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粒子及其各种化疗药物的有效负载的肿瘤内递送方面的作用。该提案的长期目标是将当前的方法用于其他纤维化肿瘤以及其他纳米颗粒有效负载，如 siRNA、shRNA 或小分子抗癌药物。