Camptothecin Transformative Nanotubes as Effective Drug Carriers

 描述(申请人提供)：通过减少副作用和更大的治疗效果，将抗癌药物定向递送到肿瘤部位，有望为癌症患者带来巨大的好处。利用纳米载体来修饰药物的药代动力学性质和生物分布特征一直是过去二十年来药物释放研究的重点。尽管纳米载体的发展取得了重大进展，如囊泡、树枝状大分子、胶束和聚合物纳米粒子，但这些载体转化为常规临床应用的类似进展尚未实现。这些基于载体的输送系统的进一步改进需要将多种功能结合到单个纳米载体中，以满足克服纳米载体遇到的所有障碍的要求 在前往目标肿瘤组织的途中。不幸的是，这些障碍中的每一个通常都需要矛盾的属性。因此，在形状和大小上具有转化特性的多级纳米载体是非常可取的，尽管它们构成了一个重大的工程挑战。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(TNTs)可以作为第二种抗癌药物紫杉醇(PTX)的有效载体。我们发现，由于长纳米管在稀释条件下分解成较短的管和环状结构，这些纳米管可以将包裹的PTX在许多癌细胞系中的体外效率提高十倍以上。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。我们假设，单个纳米管的稳定性取决于分子构建单元之间缔合相互作用的强度。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。不同倾向于形成分子间氢键的多肽序列以及低聚乙二醇、两性离子多肽和PSMA靶向配体等亲水性头基将被纳入分子设计，目的是控制TNTs的动力学稳定性和表面化学。在目标2中，我们将评估在目标1中开发的转化纳米管作为有效药物载体的潜力。我们将首先检测纳米管包裹疏水性抗癌药物紫杉醇和多西紫杉醇的载药量和效率，并测定负载的纳米载体对一些前列腺癌细胞株的疗效。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来确定PTX负载的TNTs在体内给药的潜力。我们将评估它们的药代动力学特性，通过被动和主动靶向策略测量它们的循环半衰期和生物分布情况。

 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.