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.
Multiple functions must be incorporated into one single nanocarrier to fulfill the requirements for overcoming all the barriers that the carrier encounters en route to its target tumor tissue, however, contradictory properties are often required for each of these barriers. The goal of this project is to assess the use of campthothin (CPT) transformative nanotubes (TNTs) as effective drug carriers for paclitaxel and other small molecule hydrophobic anticancer drugs and to optimize the transformative and physicochemical properties of the CPT nanotubes for both in vitro and in vivo studies of aggressive prostate cancer. Notably, the transformative nanotubes themselves are also made of the anticancer drug CPT possessing a high and quantitative CPT loading (>35%CPT loading by mass).
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