Cyclic Peptide Nanoparticles Based Dual-drug Delivery to Treat Prostate Cancer

基于环肽纳米颗粒的双药递送治疗前列腺癌

• 批准号: 9498479
• 负责人: Mingjun Zhang
• 金额: $ 45.64万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9498479
• 关键词: Amines; Amino Acids; Androgens; Animal Cancer Model; Antiandrogen Therapy; Apoptosis; Apoptotic; Biochemical; Biodistribution; Biological; Biophysics; Cancer Etiology; Carbodiimides; Cell Death; Cells; Cessation of life; Complex; Cyclic Peptides; Development; Diagnosis; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Early treatment; Electrostatics; Excision; Exhibits; Face; Feedback; Fluorescence; Foundations; Goals; Homing; Human; Image; In Vitro; Lead; Link; Malignant neoplasm of prostate; Mediating; Methods; Mitochondria; Modeling; Molecular; Monitor; Mus; Neoplasms; Nuclear; Operative Surgical Procedures; Paclitaxel; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Population; Property; Prostate Cancer therapy; Prostatic Neoplasms; RGD (sequence); Radiation; Reaction; Reagent; Research; Research Personnel; Resistance; Safety; Tail; Technology; Therapeutic; Tissue imaging; Toxic effect; Toxicology; Xenograft procedure; anticancer activity; base; biomaterial compatibility; cancer cell; cancer therapy; castration resistant prostate cancer; catalyst; chemical property; chemotherapy; crosslink; cytotoxic; design; efficacy study; experimental study; improved; in vivo; interest; intravenous administration; live cell imaging; male; men; molecular imaging; mouse model; nanoparticle; neoplastic cell; novel; preference; pro-apoptotic protein; prostate cancer cell; prostate cancer cell line; targeted delivery; targeted treatment; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth; tumor xenograft; uptake

PROJECT SUMMARY Prostate cancer (PC) is a leading cause of cancer death among male population. While treatments for early stage PC often utilize anti-androgen therapy, most patients eventually develop androgen-independent castration-resistant prostate cancer (CRPC) that requires surgical resection followed by radiation and chemotherapy. There are increasing interests in employing mitochondria-targeting therapeutics to overcome chemo-resistance in treating CRPC. Amphipathic tail-anchoring peptide (ATAP) targets mitochondria to induce apoptosis. The cytotoxic effects of ATAP do not require pro-apoptotic proteins, nor they are influenced by anti- apoptotic factors. By linking ATAP to an internalizing RGD peptide (iRGD), ATAP can be used to selectively target cancer cells to suppress prostate tumor growth. Meanwhile, it is highly desired that a chemotherapeutic drug can be co-delivered, so that synergistic dual drug effects can be achieved. Unfortunately, no delivery vehicles are available in the market for dual drug delivery in PC treatments. Self-assembled peptide nanoparticles hold great promise for targeted drug delivery and imaging, as they are inherently biocompatible and can be easily modified to interface with biomolecules. Studies from the investigators' groups showed that cyclic peptides consisting of di- or octa-amino acids can self-assemble into nanoparticles exhibiting stable fluorescence in the range of visible and near infrared ranges, which are suitable for cell and deep tissue imaging. The cyclic peptide nanoparticles (cPNP) can be tethered with tumor homing moieties and serve as a vehicle for targeted co-delivery of therapeutic reagents. This project is aimed to develop a cPNP-based platform to co-deliver ATAP-iRGD and paclitaxel for PC treatments, so that synergetic effects of mitochondria- dependent apoptosis and chemotherapy can be achieved. The platform also provides fluorescent tracking capability for drug release, thus allows us to uncover the targeting mechanism and to optimize therapeutic strategies in vivo. ATAP-iRGD is linked to cPNPs via carboxyl-to-amine crosslinking, and paclitaxel is conjugated onto cPNPs through π-π stacking and electrostatic interactions. Here, an iterative approach is proposed to design and optimize biophysical and biochemical properties of various amino acid combinations in achieving a cPNP tumor-targeting vehicle that is biocompatible and suitable for dual drug loading and release. The pathways of iRGD-guided cPNP-ATAP/paclitaxel penetration and release will be studies. Its efficacy in inducing death of PC cells will be obtained by taking advantage of the nanoparticle's intrinsic fluorescence. The in vivo studies for treatments of mouse models of CRPC will be conducted using the cPNP-ATAP/paclitaxel. In addition, pharmacokinetic and bio-distribution analyses will be conducted to evaluate safety and toxicity of the dual drug delivery platform. The technology developed in this application will lay down the foundation of building a highly effective and selective method for CRPC treatment.

项目概要 前列腺癌（PC）是早期治疗期间男性癌症死亡的主要原因。 PC阶段经常采用抗雄激素治疗，大多数患者最终发展为雄激素非依赖性 去势抵抗性前列腺癌 (CRPC)，需要手术切除，然后进行放射治疗 人们越来越关注采用线粒体靶向疗法来克服这一问题。 两亲性尾锚肽（ATAP）靶向线粒体诱导化疗耐药。 ATAP 的细胞毒性作用不需要促凋亡蛋白，也不受抗凋亡蛋白的影响。 通过将 ATAP 连接到内化 RGD 肽 (iRGD)，ATAP 可用于选择性地抑制细胞凋亡。 同时，非常需要一种化疗药物。 药物可以共同递送，从而可以实现协同双重药物效应，但不幸的是，没有递送。 市场上有用于 PC 治疗中双重药物输送的车辆。 纳米粒子在靶向药物输送和成像方面具有巨大的前景，因为它们本质上具有生物相容性 并且可以很容易地进行修改以与生物分子相互作用。研究人员的研究表明， 由二或八氨基酸组成的环肽可以自组装成纳米颗粒，表现出稳定性 可见光和近红外范围内的荧光，适用于细胞和深层组织 环肽纳米粒子（cPNP）可以与肿瘤归巢部分连接并用作成像。 该项目旨在开发一种基于 cPNP 的治疗试剂靶向共同递送工具。 平台共同递送 ATAP-iRGD 和紫杉醇用于 PC 治疗，从而使线粒体- 该平台还可以实现依赖性细胞凋亡和化疗。 药物释放的能力，从而使我们能够揭示靶向机制并优化治疗 ATAP-iRGD 通过羧基到胺交联与 cPNP 连接，紫杉醇是 通过 π-π 堆积和静电相互作用共轭到 cPNP 上，这是一种迭代方法。 提出设计和优化各种氨基酸组合的生物物理和生化特性 实现具有生物相容性并适合双重药物装载和释放的 cPNP 肿瘤靶向载体。 将研究 iRGD 引导的 cPNP-ATAP/紫杉醇渗透和释放的途径及其功效。 利用纳米粒子的固有荧光来诱导 PC 细胞死亡。 将使用 cPNP-ATAP/紫杉醇 In 进行 CRPC 小鼠模型治疗的体内研究。 此外，还将进行药代动力学和生物分布分析，以评估该药物的安全性和毒性。 该应用开发的技术将为双药物递送平台奠定基础。 建立一种高效、选择性的 CRPC 治疗方法。

项目成果

Quantum confined peptide assemblies with tunable visible to near-infrared spectral range.

具有可调谐可见光到近红外光谱范围的量子限制肽组件。

• 发表时间: 2018-08-13
• 影响因子: 16.6
• 作者: Tao, Kai;Fan, Zhen;Sun, Leming;Makam, Pandeeswar;Tian, Zhen;Ruegsegger, Mark;Shaham;Hansford, Derek;Aizen, Ruth;Pan, Zui;Galster, Scott;Ma, Jianjie;Yuan, Fan;Si, Mingsu;Qu, Songnan;Zhang, Mingjun;Gazit, Ehud;Li, Junbai
• 通讯作者: Li, Junbai