Jonathan C. Barnes, PhD

2017

Assistant Professor, Department of Chemistry, Washington University in St. Louis

A Novel Supramacromolecular Approach to Non-toxic Combination Anti-cancer Therapeutics

designing a better molecule to target and deliver treatments

Treatments for aggressive and metastatic types of cancer often come in the form of “cocktails” that consist of multiple small-molecule anti-cancer drugs that are typically administered several times intravenously during the course of a treatment regimen. Although this approach has proven to be effective in some cases, it is also incredibly toxic and debilitating for the patient.

To mitigate this toxicity, the drug delivery community has worked to develop systems capable of delivering anti-cancer drugs with improved pharmacokinetics/biodistributions and dramatically reduced toxicities; however, it is very challenging to construct platforms that can support the precise loading of three or more drugs that are required for treatment.

The Barnes group is developing a universal ‘plug-and-play’ type of drug delivery system…

Even more troubling, there are now concerns emerging over how drugs that are conjugated directly to the delivery platform are not released completely and efficiently once localized inside a tumor, and even when they are released in vitro/vivo, their modes of action may be different than those of the individual ‘free’ drugs.

These major delivery issues can often perturb or completely derail clinical trials that investigate efficacy using modern drug delivery systems. There is a pressing need for a better multi-drug delivery system that would provide complete and efficient release of drugs, while also preserving their desired modes of action.

To overcome these major challenges, the Barnes group is developing a universal ‘plug-and-play’ type of drug delivery system composed of chemically linked supramolecular monomers that act as ‘smart’ receptors, or docking stations, for a wide variety and combination of small-molecule anti-cancer drugs.

This ‘supramacromolecular’ approach is advantageous because it will allow for loading the unmodified drugs onto the polymer, without chemical modification of the drug, thus maintaining the expected mechanism of action of each drug. Additionally, we plan to incorporate water soluble monomers that possess targeting groups and imaging agents, which will allow for greater recognition of cancer cells and to track localization of the proposed delivery system in tumors, respectively.

The results of this research will ultimately lead to a general platform for personalized medicine since the desired combination of anti-cancer drugs required to treat a certain type of cancer can be loaded as needed for treatment.

2020 Final Report

Fighting Cancer Podcast

Episode 001

2018 Interim Report

Combination therapies – or drug ‘cocktails’ – are often employed to combat diseases such as cancer, and although effective, the drug combinations can be incredibly invasive due to off- target toxicity issues. Nano-based drug delivery systems can be advantageous in this regard since the toxic drugs can be shielded inside the nanomaterial and these non-specific issues can be reduced. However, it is still a major challenge to find a one-size-fits-all drug delivery vehicle that can be loaded and unloaded with any combination of small-molecule drugs without having to change the chemistry significantly each time a new clinically relevant combination is needed. The research in the Barnes group employs functional monomers that possess selective drug binding sites that can encapsulate a wide range of anti-cancer drugs through specific interactions, as well as monomers that serve as imaging agents that allow the nanomaterial to be tracked in vivo. These monomers can be polymerized and cross-linked to generate nanoparticles, resulting in a water-stable delivery vehicle that represents a non-toxic universal platform for combination anti-cancer therapeutics.

During the first year of support from the Cancer Research Foundation, the Barnes group has been able to (i) complete the synthesis of several functional monomers, (ii) optimize the chemistry to convert them into a multi-functional copolymer on which (iii) drug binding was investigated for multiple anti-cancer drugs. Additionally, we have developed (iv) a novel drug loading and cross-linking protocol, as well as building in (v) a near-IR imaging agent, ultimately resulting in narrowly dispersed nanoparticles that can encapsulate different drugs. In the second phase of this research, we will investigate the in vitro efficacy against several cancer cell lines, study the in vitro properties of the nanoparticles in mice (e.g., blood circulation lifetimes, biocompatibility, etc.), and develop nanoparticles that can disassemble on command in response to near-IR light, which will aid drug release and imaging in tumor tissues.