Camptothecin Transformative Nanotubes as Effective Drug Carriers

 描述（由申请人提供）：将抗癌药物靶向递送至肿瘤部位，通过减少副作用和更大的治疗效果，有望为癌症患者带来巨大益处。在过去的二十年里，使用纳米载体来改变药物的药代动力学性质和生物分布概况一直是药物递送研究的焦点。尽管在纳米载体如囊泡、树枝状聚合物、胶束和聚合物纳米颗粒的开发方面取得了重大进展，但在将这些载体转化为常规临床用途方面的类似进展尚未实现。这些基于载体的递送系统的进一步改进需要将多种功能并入单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 在到达目标肿瘤组织的途中不幸的是，这些障碍中的每一个往往需要矛盾的属性。因此，具有形状和大小的转变性质的多级纳米载体是非常期望的，尽管它们提出了重大的工程挑战。我们最近的研究结果表明，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封装的PTX的体外疗效超过10倍以上的游离PTX在一些癌细胞系的结果，在稀释条件下的长纳米管的分解为较短的管和环形结构。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。我们假设单个纳米管的稳定性是由分子构建单元之间的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，以优化纳米管的物理化学和转化能力。不同倾向的肽序列形成分子间氢键，以及亲水性头基，如寡聚乙二醇，两性离子肽，和PSMA靶向配体，将被纳入分子设计中，与获得控制的动力学稳定性和表面化学的TNT的目标。在目标2中，我们将评估目标1中开发的变革性纳米管作为有效药物载体的潜力。我们将首先检查纳米管的载药能力和效率，以封装疏水性抗癌药物紫杉醇和多西他赛，并确定负载纳米载体对前列腺癌细胞系的疗效。我们将进行机制研究，以阐明细胞摄取途径。在目标3中，我们将尝试使用前列腺癌小鼠模型确定PTX负载的TNT用于体内药物递送的潜力。我们将评估其药代动力学特性，通过被动和主动靶向策略测量其循环半衰期和生物分布特征。

 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.