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

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 inrecent 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 aspecific 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 variableresponse only in a subpopulation of patients and development resistance against therapy due to the posttranslational modifications or loss of antigen expression. To address these issues with targeted therapies in thisproposal we will utilize a novel peptide amphiphile (PA) platform that our lab recently developed. These PAsdynamically interact with two types of endogenous lipid-containing biomolecules lipoproteins and lipid rafts andexploit them to target a broad range of solid tumors. In the preliminary experiments we found that our PAsstrongly accumulated in ~15 xenografted syngeneic and transgenic tumor models in mice and rats includingtumors with sizes <1 mm. We have also shown that our PAs can deliver different small molecule drugs in cellsenabling 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 broadrange of drugs to human diseases without targeting a specific antigen. Another major goal of this proposal is toperform in-depth mechanistic studies to better understand the biodistribution of PAs and their trafficking in cancercells. To achieve these goals we will rationally design a library of PAs using different saturated and unsaturatedlipid modifications and evaluate their interactions with plasma components cell membranes and subcellularcomponents 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 usevarious genetically engineered mouse models to understand how aberrant lipoprotein metabolism such as highcholesterol 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 withvarying hydrophobicities and mechanisms of action in mouse models. At the conclusion of this project we willlearn 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 delivera broad range of drugs and contrast agents to detect and treat almost any type of cancer and potentially otherdiseases associated with increased lipid metabolism such as cardiovascular diseases and inflammation.