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

• 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
• 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

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）：尽管最近癌症治疗取得了进展，但非小细胞肺癌患者的临床结果并不令人印象深刻。我们的实验室一直在研究吸入和口服抗癌药物治疗肺癌的方法。含有纳米颗粒的化疗药物的主动靶向可以通过在靶部位达到更高的浓度来有效地治疗腺癌。EphA2， Eph家族受体酪氨酸激酶在90%的NSCLC肿瘤中过表达；高水平的EphA2预示着较差的患者总体生存。我们实验室的研究表明，H460和A549肿瘤表达EphA2受体。最近，一种名为YSAYPDSVPMMS （YSA）的肽被证明可以选择性地与肺和前列腺癌细胞上的EphA2受体结合。利用肺癌细胞中YSA肽的选择性结合和EphA2受体的过表达状态，我们提出了YSA肽偶联NCs系统，可同时选择性地向肺癌肿瘤输送抗癌药物。然而，不管纳米颗粒的靶向性如何，它们在肿瘤内的分布确实是由致密的胶原网络和高度纤维间质组成的。据报道，使用抗纤维化药物可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）提高了载药纳米颗粒的穿透性和治疗效果。我们实验室的初步研究表明替米沙坦（AT1阻滞剂）产生的纤维溶解比氯沙坦高3倍。因此，我们预计，预先使用替米沙坦治疗将使肿瘤失去其致密的胶原网络，并促进纳米治疗药物更好地在肿瘤内分布。我们打算在使用NCs- Ds（含纳米粒子的多西紫杉醇）治疗实体肺肿瘤之前，先用替米沙坦吸入和口服治疗肺肿瘤。我们假设YSA偶联靶向纳米颗粒（NCs-D-Y）将选择性地分布、结合并主动内化到EphA2过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。在体外实验中，我们将制备具有特异性靶向EphA2受体并抑制肿瘤细胞生长的YSA肽缀合物NCs-D （NCs-D- y）。特异性目的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价。为此，在替米沙坦治疗后，NCs-D-Y将静脉注射给肺肿瘤动物，用于EphA2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肿瘤内靶向纳米颗粒及其各种化疗药物的有效载荷的传递方面的作用。这项提议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。