J. Andrew MacKay

PIBBS MENTOR

Assistant Professor

Pharmacology and Pharmaceutical Sciences
USC School of Pharmacy

Biomedical Engineering
Viterbi School of Engineering

Research Topics

  • Drug delivery
  • Biomolecular engineering
  • Liposomes
  • Elastin like polypeptides
  • Protein polymers,
  • Nanomedicine

Research Overview

OVERVIEW
Our lab engineers a new generation of polypeptide-based drug carriers that change physical properties in response to disease microenvironments. Cancer and ocular diseases are our primary focus. The delivery of drugs, both in the eye and throughout the body, is hindered by access and retention at the target site. Many drugs are dose-limited by toxicity at peripheral sites in the body. Our goal is to repackage these drugs into bioresponsive nanocarriers (10-200 nm in diameter), composed from lipids and/or peptides, which activate site-specific drug release and reduce toxicity. Successful carrier strategies are being formulated and evaluated for translation to the clinic.

PROTEIN POLYMERS
Protein polymers are a powerful technology exploited by our group. Some conformations/behaviors found in natural proteins can be recapitulated in repetitive genetically engineered peptides, such as leucine zippers, the collagen triple helix, or silkworm silk. A related example from human tropoelastin, the elastin-like-polypeptides (ELPs) are repeats of (Val-Pro-Gly-Xaa-Gly)n. ELPs have characteristic inverse phase transition temperatures above which they rapidly phase separate from bulk solution. A function of peptide sequence and environment, this reversible transition can cycle between soluble and insoluble states, equivalent to an on/off switch. Under isothermal conditions, ELP switches can be engineered for sensitivity to other specific environmental variables, such as pH, ionic strength, and conformation of adjacent proteins. As a pharmacological platform, genetically engineered ELPs are monodisperse, biodegradable, encoded from human self-antigens, and can incorporate specific residues for biological (protein) or chemical (drug) payloads. Our group actively explores design parameters that link environmental cues to peptide phase transitions and applications for these switches in disease microenvironments.

LIPOSOMES
Lipid-based drug carriers are another powerful technology used by our group. Composed of phospholipids similar to those found in cell membranes, liposomes are vesicles with aqueous interiors that can carry a variety of therapeutic cargo. The most prominent liposome-based chemotherapeutic, Doxil TM, consists of doxorubicin within a sterically shielded lipid bilayer. Liposome technology is mature, meaning that a wide platform of compositions, sizes and drug encapsulation methods are achievable. Building on this broad platform, our group explores liposomes coated with bioresponsive peptides that mediate rapid drug accumulation and release in the tumor microenvironment.

FUNDING
Within the past four years, we have been funded by the NIH National Eye Institute, the NIH National Institute of Biomedical Imaging and Bioengineering, the US Army TATRC, the Stop Cancer Foundation, the American Cancer Society, the USC Research Center for Liver Disease, the USC Ming Hsieh Institute, the Whittier Foundation, the Wright Foundation, the SC-CTSI, and the USC School of Pharmacy.