Camptothecin Transformative Nanotubes as Effective Drug Carriers

喜树碱转化纳米管作为有效的药物载体

• 批准号: 8959008
• 负责人: Honggang Cui
• 金额: $ 20.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959008
• 关键词: Adverse effects; Amino Acid Sequence; Antigen Targeting; Antineoplastic Agents; Biodistribution; Blood Circulation; Camptothecin; Cancer cell line; Cell Cycle; Cells; Cellular Membrane; Chemistry; Clinical; Data; Dendrimers; Development; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Encapsulated; Endocytosis; Engineering; Enzymes; Equilibrium; Evaluation; Feedback; Foundations; Funding; Future; Glutamate Carboxypeptidase II; Glycols; Goals; Hydrogen Bonding; In Vitro; Individual; Kinetics; Length; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Micelles; Modeling; Molecular; Nanostructures; Nanotubes; Paclitaxel; Pathway interactions; Peptides; Pharmaceutical Preparations; Property; Proteins; Reporting; Research; Reticuloendothelial System; Route; Shapes; Site; Sonication; Structure; Surface; System; Technology; Testing; Therapeutic Index; Translations; Treatment Efficacy; Tube; Tubular formation; Tumor Tissue; Vesicle; Work; base; cancer type; circumnuclear torus; design; docetaxel; dosage; high risk; improved; in vivo; mouse model; nanocarrier; nanoparticle; nanoscale; prostate cancer cell; prostate cancer cell line; prostate cancer model; protein aminoacid sequence; public health relevance; research study; small molecule; targeted delivery; tumor; uptake; vector

 DESCRIPTION (provided by applicant): Targeted delivery of anticancer drugs to tumor sites promises immense benefits to cancer sufferers through both the reduction of side-effects and a greater treatment efficacy. The use of nanoscale carriers to modify the drug's pharmacokinetic properties and biodistribution profiles has been the focus of research in drug delivery over the past two decades. Despite significant progress in the development of nanocarriers, such as vesicles, dendrimers, micelles, and polymeric nanoparticles, similar progress in the translation of these vectors to routine clinical usage has yet to be realized. Further improvement of these carrier-based delivery systems requires multiple functions be incorporated into one single nanocarrier to fulfill the requirements for overcoming all the barriers that nanocarriers encounter en route to their target tumor tissue. Unfortunately, contradictory properties are often required for each of these barriers. Therefore, multistage nanocarriers with transformative properties in shape and size are highly desirable, though they present a significant engineering challenge. Our recent results have shown that transformative nanotubes (TNTs) formed by an anticancer drug camptothecin (CPT) can act as an effective carrier for a second anticancer drug, paclitaxel (PTX). We found that these nanotubes could increase the in vitro efficacy of the encapsulated PTX more than ten-fold over free PTX in a number of cancer cell lines as a result of the breakdown of long nanotubes to shorter tubes and toroidal structures in dilute conditions. These exciting results form the basis of this exploratory study. In Aim 1, we propose to optimize the transformative and physicochemical properties of the camptothecin nanotubes. We hypothesize that the stability of an individual nanotube is determined by the strength of the associative interactions among the molecular building units. Therefore, we will first modify the molecular design to optimize the physicochemical and transformative ability of the nanotubes. Peptide sequences of varying propensity to form intermolecular hydrogen bonding, as well as hydrophilic headgroups such as oligoethylene glycol, zwitterionic peptide, and PSMA-targeting ligand, will be incorporated into the molecular design, with the goal of gaining control over the kinetic stability and surface chemistry of the TNTs. In Aim 2, we will evaluate the potential of th transformative nanotubes developed in Aim 1 to act as effective drug carriers. We will first examine the drug loading capacity and efficiency of the nanotubes to encapsulate hydrophobic anticancer drug paclitaxel and docetaxel, and determine the efficacy of the loaded nanocarrier against a number of prostate cancer cell lines. We will perform mechanistic studies to elucidate the cellular uptake pathways. In Aim 3, we will attempt to determine the potential of PTX-loaded TNTs for in vivo drug delivery using a prostate cancer mouse model. We will assess their pharmacokinetic properties, measuring their circulation half-lives and biodistribution profiles through both passive and active targeting strategies.

 描述（由申请人提供）：将抗癌药物靶向递送至肿瘤部位，通过减少副作用和提高治疗功效，有望为癌症患者带来巨大益处。使用纳米级载体来改变药物的药代动力学特性和生物分布特征。尽管囊泡、树枝状聚合物、胶束和聚合物等纳米载体的开发取得了重大进展，但药物递送一直是过去二十年中药物递送研究的焦点。纳米颗粒，将这些载体转化为常规临床应用的类似进展尚未实现，这些基于载体的系统的进一步改进需要将多种功能整合到一个纳米载体中，以满足克服纳米载体遇到的所有障碍的要求。 不幸的是，这些屏障中的每一个都需要相互矛盾的特性，因此，非常需要具有形状和尺寸转化特性的多级纳米载体，尽管它们提出了重大的工程挑战。由抗癌药物喜树碱（CPT）形成的转化纳米管（TNT）可以作为第二种抗癌药物紫杉醇（PTX）的有效载体，我们发现这些纳米管可以增加体外的活性。由于在稀释条件下长纳米管分解为较短的管和环形结构，封装的 PTX 在许多癌细胞系中的功效比游离 PTX 高出十倍以上。这些令人兴奋的结果构成了这项探索性研究的基础。在目标 1 中，我们建议优化喜树碱纳米管的转化和物理化学性质，我们发现单个纳米管的稳定性是由分子之间缔合相互作用的强度决定的。因此，我们将首先修改分子设计，以优化不同倾向形成分子间氢键的肽序列以及亲水头基，例如低聚乙二醇、两性离子肽和PSMA-。目标配体将被纳入分子设计中，目的是控制 TNT 的动力学稳定性和表面化学。在目标 2 中，我们将评估目标 1 中开发的转化纳米管作为有效药物载体的潜力，我们将首先检查纳米管封装疏水性抗癌药物紫杉醇和多西紫杉醇的药物负载能力和效率，并确定负载的纳米载体对多种药物的功效。我们将进行机制研究以阐明细胞摄取途径。在目标 3 中，我们将尝试确定负载 PTX 的 TNT 的潜力。我们将通过被动和主动靶向策略评估其药代动力学特性，测量其循环半衰期和生物分布曲线。