Rigid-rod Peptides as Nanocarriers for Delivery of Cancer Drugs

刚性棒肽作为纳米载体用于递送癌症药物

基本信息

批准号：
8635373
负责人：
Katarzyna Slowinska
金额：
$ 10.84万
依托单位：
CALIFORNIA STATE UNIVERSITY LONG BEACH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635373
关键词：
Academia Adverse effects Allergic Reaction Antineoplastic Agents Area Award Biodegradation Biological Biological Assay Biological Availability Biomedical Research Breast Cause of Death Cells Clinical Collagen Colon Combined Modality Therapy Development Dose Drug Delivery Systems Drug Formulations Drug Targeting Exclusion Funding Future Goals Grant Head and neck structure Health Heating Human Immobilization In Vitro Industry Inhibitory Concentration 50 Interdisciplinary Study Laboratories Learning Length Link Lysine Malignant Neoplasms Measures Methodology Methods Modeling Molecular Conformation Non-Small-Cell Lung Carcinoma Organism Output Ovarian Paclitaxel Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Polymers Positioning Attribute Preparation Prodrugs Productivity Protocols documentation Radiosurgery Research Research Infrastructure Resistance Shapes Solubility Structure Students Sugar Acids Survival Rate Taxoids Testing Therapeutic Trypan Blue United States United States National Institutes of Health Water aqueous base cancer cell cancer therapy chemotherapy cytotoxicity graduate student improved in vivo interest local drug delivery mimetics monomer nanocarrier nanomedicine novel peptide structure polyarginine programs protein aminoacid sequence retinal rods skills triple helix undergraduate student uptake vector

项目摘要

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States. Next to surgery and radiation treatments, chemotherapy and combination therapies involving drugs are among the most successful in increasing patient survival rates. Paclitaxel (PTX) is one of the most successful taxoids in clinical use today. PTX is very effective in treatment of several cancers including: ovarian, breast, colon, head and neck, and non small cell lung cancer. Unfortunately, the currently used formulations which are intended to increase the solubility and thus bioavailability of PTX, are linked to adverse allergic reactions. Therefore several prodrugs, typically containing PTX conjugated with the hydrophilic and hydrolyzable groups such as polycarboxylic acids, sugars, polymers and peptides, were synthesized and tested. Despite these efforts there is a considerable interest in developing novel prodrugs for targeted drug delivery of PTX and other weakly soluble drugs to increase their therapeutic efficiency. The goal of this proposal is to develop a novel class of local drug delivery systems (nanocarriers) for low solubility drugs (such as PTX) based on collagen mimetic peptides assembled into triple helical peptide (THP) The conjugation of PTX with THP affords numerous potential advantages over currently used prodrugs: (1) it improves prodrug solubility, (2) it increases protease resistance due to rigid rod conformation (3) it allows incorporation of drug targeting sequence or cell penetrating vector, (4) it allows immobilization of the prodrug within a collagen matrix . Additionally, the THP nanocarrier unlike metallic nanocarriers biodegrades to biologically safe products. The proposal aims at developing peptide sequences to form water soluble model prodrugs based on PTX attached to the peptide's lysine group via succinylic link at C2'-OH position. By varying the peptide length and sequence the solubility of the prodrug will be adjusted. The proposed peptide sequences will form THP rigid-rod nanocarrier providing increased stability against in vivo biodegradation. Moreover, the THP carrier will open the possibility of delivering the hydrophobic drugs from hydrophilic collagen matrix. The release profile of a prodrug will be measured as a function of the nanocarrier structure. By synthesizing different length of THP and incorporating pre-heated (self-assembled) or non-preheated (blended) nanocarrier within collagen matrix we hope to effectively control the rates of the prodrug release. The feasibility of incorporating the cell-penetrating vectors into the prodrug wil be investigated. The incorporation of the polyarginine sequences into the prodrug sequence to study preferential nanocarrier cell uptake is also proposed. The cytotoxicity of the proposed Paclitaxel prodrug will also be studied. The developmental objective is to increase the PI's involvement in interdisciplinary research directly related to human health and to increase the productivity of the PI laboratory. The requested support will result in the development of new methodologies and protocols in the PI's laboratory and increased participation of graduate and undergraduate students, including students from traditionally underrepresented backgrounds. This SC-3 support, if awarded, will increase the PI's research output and improve competitiveness for major grant support such as NSF and NIH-RO1 type grants.

描述（由申请人提供）：癌症是美国第二大死因。除了手术和放射治疗之外，化疗和药物联合治疗是提高患者生存率最成功的方法之一。紫杉醇 (PTX) 是当今临床使用最成功的紫杉醇之一。 PTX非常有效用于治疗多种癌症，包括：卵巢癌、乳腺癌、结肠癌、头颈癌和非小细胞肺癌。不幸的是，目前使用的旨在增加PTX的溶解度并因此增加生物利用度的制剂与不良过敏反应有关。所以合成并测试了几种前药，通常含有与亲水性和可水解基团（例如聚羧酸、糖、聚合物和肽）缀合的 PTX。尽管做出了这些努力，但人们对开发用于 PTX 和其他弱溶性药物的靶向药物递送以提高其治疗效率的新型前药仍有相当大的兴趣。该提案的目标是开发一类新型的局部药物递送系统（纳米载体），用于基于组装成三螺旋肽（THP）的胶原模拟肽的低溶解度药物（例如 PTX）。PTX 与 THP 的缀合提供了巨大的潜力与目前使用的前药相比的优点：（1）它提高了前药的溶解度，（2）由于刚性杆构象，它增加了蛋白酶抗性（3）它允许掺入药物靶向序列或细胞穿透载体，（4）它允许将前药固定在胶原蛋白基质。此外，与金属纳米载体不同，THP 纳米载体可生物降解为生物安全产品。该提案旨在开发肽序列，以形成基于 PTX 的水溶性模型前药，PTX 通过 C2'-OH 位置的琥珀酰连接连接到肽的赖氨酸基团上。通过改变肽长度和序列，将调节前药的溶解度。所提出的肽序列将形成THP刚性棒纳米载体，提供更高的体内生物降解稳定性。此外，THP载体将开启从亲水性胶原基质递送疏水性药物的可能性。前药的释放曲线将作为纳米载体结构的函数来测量。通过合成不同长度的 THP 并将预热（自组装）或非预热（混合）纳米载体掺入胶原蛋白基质中，我们希望有效控制前药释放速率。将研究将细胞穿透载体掺入前药的可行性。还提出将聚精氨酸序列掺入前药序列以研究纳米载体细胞的优先摄取。还将研究所提出的紫杉醇前药的细胞毒性。发展目标是增加PI对与人类健康直接相关的跨学科研究的参与，并提高PI实验室的生产力。所请求的支持将导致 PI 实验室开发新的方法和协议，并增加研究生和本科生的参与，包括来自传统上代表性不足背景的学生。如果获得 SC-3 的支持，将增加 PI 的研究成果，并提高 NSF 和 NIH-RO1 类型赠款等主要赠款支持的竞争力。