(291a) (Invited Talk) Exploiting Barriers of the Body for Targeted Nanomedicine

Peptide-based, amphiphilic micelles are small, organic nanoparticles that can provide a tool for the detection and targeted delivery of therapeutics to diseases including cardiovascular and chronic kidney disease. Through rational design and molecular engineering of their physicochemical and biological properties, these nanoparticles can uniquely harness physiological and cellular barriers for diagnostic and therapeutic strategies. Herein, we discuss the development of multimodal, peptide micelles that can exploit clearance mechanisms and bind to specific markers for enhanced drug delivery.

For chronic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD), while small molecule drugs have been proposed as a therapy to manage disease progression, high dosages are often required to achieve therapeutic efficacy, generating off-target side effects, some of which are lethal. To address these limitations, our lab has designed kidney-targeting peptide micelles (KM) within a range of surface properties and sizes, and found KMs can cross the glomerular filtration barrier and bind to megalin, a multiligand cell surface receptor present on renal tubule cells. When incubated with human kidney proximal tubule cells, KMs were found to be biocompatible in vitro and showed higher accumulation in kidneys compared to nontargeted controls in vivo. Moreover, upon incorporation of a library of ADPKD drug candidates, KMs efficiency decreased cyst burden compared to free drugs using several routes of administration favorable for chronic diseases.

In addition, due to the modularity of micelles and their potential for theranostic applications, we will also discuss the development of nanoparticles delivering novel microRNAs as well as clinically relevant imaging agents to inhibit calcification and several pathological cell types in atherosclerosis. Throughout this presentation, we will discuss the potential of nanoparticles to harness barriers found in vivo to generate nanomedicine strategies with capabilities to bind to specific disease markers of interest, deliver a therapeutic, and monitor the progression and regression of the disease in real-time.