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.

项目摘要 前列腺癌（PC）是男性人群中癌症死亡的主要原因。虽然治疗早期 PC期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， 化疗越来越多的人对采用靶向治疗来克服糖尿病有兴趣。 CRPC的化疗耐药性。两亲性尾锚定肽（ATAP）靶向线粒体以诱导 凋亡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。 凋亡因子通过将ATAP连接到内化RGD肽（iRGD），ATAP可以用于选择性地调节细胞内的细胞因子。 靶向癌细胞以抑制前列腺肿瘤生长。同时，高度期望的是， 药物可以共同递送，从而可以实现协同的双重药物作用。不幸的是，没有送货 在PC治疗中用于双重药物递送的载体在市场上可获得。自组装肽 纳米颗粒具有很好的生物相容性，因此有望用于靶向药物输送和成像 并且可以容易地被改性以与生物分子接合。研究人员小组的研究表明， 由二-或八-氨基酸组成的环肽可以自组装成纳米颗粒， 在可见光和近红外范围内的荧光，适用于细胞和深层组织 显像环肽纳米颗粒（cPNP）可以与肿瘤归巢部分拴系并用作肿瘤靶向分子。 用于治疗试剂的靶向共递送的载体。该项目旨在开发一种基于CPNP的 平台，以共同提供ATAP-iRGD和紫杉醇用于PC治疗，因此线粒体- 可实现依赖性凋亡和化疗。该平台还提供荧光跟踪 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 体内策略ATAP-iRGD通过羧基-胺交联与cPNP连接，紫杉醇通过羧基-胺交联与cPNP连接。 通过π-π堆积和静电相互作用缀合到cPNP上。这里，迭代方法是 提出设计和优化各种氨基酸组合的生物物理和生物化学性质， 获得生物相容性的并且适合于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。其功效在于 诱导PC细胞死亡的纳米颗粒将通过利用纳米颗粒的固有荧光来获得。的 将使用cPNP-ATAP/紫杉醇进行CRPC小鼠模型治疗的体内研究。在 此外，还将进行药代动力学和生物分布分析，以评价 双重药物输送平台。这项应用所开发的技术将奠定基础， 为CRPC的治疗建立一种高效和选择性的方法。