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

• 批准号: 8214118
• 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
• 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/8214118
• 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; 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

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. PUBLIC HEALTH RELEVANCE: This proposal describes a novel class of local drug delivery nanocarriers for low solubility anti-cancer drugs, such as Paclitaxel, based on collagen mimetic peptides assembled into triple helical peptide (THP). Conjugation of Paclitaxel with THP, a rigid- rod nanocarrier, offers numerous potential advantages over currently used prodrugs by increasing solubility in water, improving stability, allowing incorporation of drug targeting sequence or cell penetrating vector, and allowing local delivery of hydrophobic drugs from hydrophilic collagen matrix.

描述（由申请人提供）：癌症是美国第二大死亡原因。除了手术和放射疗法之外，涉及药物的化学疗法和联合疗法是提高患者生存率的最成功的疗法。紫杉醇（PTX）是当今临床用途中最成功的类似类型之一。 PTX非常有效 在几种癌症的治疗中，包括：卵巢，乳房，结肠，头颈和非小细胞肺癌。不幸的是，目前使用的制剂旨在增加溶解度并因此PTX的生物利用度与不良过敏反应有关。所以 合成并测试了几种原生，通常包含与亲水性和可水解基团结合的PTX，例如聚羧酸，糖，聚合物和肽。尽管做出了这些努力，但仍有很大的兴趣开发用于靶向PTX和其他弱溶性药物的新型前药，以提高其治疗效率。 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杆构象（3）它允许掺入药物靶向序列或细胞穿透载体，（4）它允许该前药固定在A内 胶原蛋白矩阵。此外，THP纳米载体与金属纳米载体不同，生物降解对生物学安全产品。该提案旨在开发肽序列，以通过C2'-OH位置的Succinylic Link在肽赖氨酸基团附加到肽赖氨酸基团的PTX形成水溶性模型前药。通过改变肽长度和序列，将调整前药的溶解度。所提出的肽序列将形成THP刚性纳米载体，从而为体内生物降解提供了提高的稳定性。此外，THP载体将开放从亲水性胶原基质中输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进行测量。通过合成不同的THP长度并结合了预热（自组装）或在胶原矩阵中的未删除（混合）纳米载体，我们希望能有效地控制Proprug释放的速率。将研究将细胞穿透载体掺入前药的可行性。还提出了将聚精氨酸序列掺入前药序列中，以研究优先纳米载体细胞摄取。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参与与人类健康直接相关的跨学科研究并提高PI实验室的生产率。所要求的支持将导致PI实验室的新方法和协议的发展，并增加研究生和本科生的参与，包括传统上代表性不足的背景的学生。如果获得了SC-3的支持，将增加PI的研究成果，并提高NSF和NIH-RO1型赠款等主要赠款支持的竞争力。 公共卫生相关性：该提案描述了一类新型的局部药物输送纳米载体，用于低溶解度抗癌药物，例如紫杉醇，基于组装成三重螺旋肽（THP）的胶原蛋白模拟肽。紫杉醇与刚性纳米载体THP的结合通过提高水的溶解度，提高稳定性，允许将药物靶向序列或细胞穿透性载体纳入当前使用的前药，从而提供了许多潜在的优势，并允许将疏水药物局部从水生生物胶原蛋白矩阵中递送。