Exploiting dynamic in vivo interactions of peptide amphiphiles with lipid-containing biomolecules to develop a universal drug delivery platform

Oregon Health & Science University, Portland OR

Investigators

Abstract

Abstract. Delivering therapeutic drugs specifically to target tissues with minimized off-target accumulation can improve the efficacy and safety of therapies. With this overall motivation, various delivery platforms have been developed in recent years for targeted drug delivery, including antibody-drug conjugates (ADCs) and nanomedicines. These drug delivery platforms typically target an antigen to deliver toxins into diseased cells. However, targeting a specific antigen brings several important limitations such as antigen expression in healthy tissues often causing a narrow therapeutic window, inter- and intra-patient heterogeneity in antigen expression yielding highly variable response only in a subpopulation of patients, and development resistance against therapy due to the post translational modifications or loss of antigen expression. To address these issues with targeted therapies, in this proposal, we will utilize a novel peptide amphiphile (PA) platform that our lab recently developed. These PAs dynamically interact with two types of endogenous lipid-containing biomolecules, lipoproteins and lipid rafts, and exploit them to target a broad range of solid tumors. In the preliminary experiments, we found that our PAs strongly accumulated in ~15 xenografted, syngeneic, and transgenic tumor models in mice and rats, including tumors with sizes <1 mm. We have also shown that our PAs can deliver different small molecule drugs in cells, enabling improved anti-tumor efficacy in mouse models with reduced side effects compared to free drugs. Building upon these results, our goal in this proposal is to develop a platform that can universally deliver a broad range of drugs to human diseases without targeting a specific antigen. Another major goal of this proposal is to perform in-depth mechanistic studies to better understand the biodistribution of PAs and their trafficking in cancer cells. To achieve these goals, we will rationally design a library of PAs using different saturated and unsaturated lipid modifications and evaluate their interactions with plasma components, cell membranes, and subcellular components using in vitro experiments and molecular dynamics simulations in the first Aim. The second Aim will evaluate the effects of PA structure on their biodistribution in wild-type and tumor-bearing mice. We will also use various genetically engineered mouse models to understand how aberrant lipoprotein metabolism, such as high cholesterol and cholesterol medicines, affects the biodistribution of PAs as they are trafficked in vivo on lipid- containing biomolecules. In the final Aim, we will evaluate this platform to deliver a broad range of drugs with varying hydrophobicities and mechanisms of action in mouse models. At the conclusion of this project, we will learn more about the universal cancer-targeting mechanism of our PA platform. In addition, we will optimize its structure further for the precise delivery of various drugs. If successful, our technology will be available to deliver a broad range of drugs and contrast agents to detect and treat almost any type of cancer and potentially other diseases associated with increased lipid metabolism, such as cardiovascular diseases and inflammation.