J. Andrew MacKay, Ph.D.

Assistant Professor
Pharmacology and Pharmaceutical Sciences
Biomedical Engineering

Phone: (323) 442-4118
Fax: (323) 442-1390
Email: jamackay@usc.edu

Research Interest
Our lab is engineering a new generation of drug carriers that change physical properties in response to diseased microenvironment. Cancer is our primary focus, with special consideration given to diseases of the central nervous system. Many chemotherapeutics are dosage-limited by toxicity at peripheral sites in the body. To address this limitation, we explore approaches to repackage these drugs into bioresponsive nanocarriers (10-200 nm in diameter). Composed from lipids and/or peptides, these particles are designed to reduce drug exposure at sites of toxicity and to activate drug release in the tumor. Successful carrier strategies will be formulated and evaluated for translation to the clinic.

Phase transitioning peptides 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 has been derived from human tropoelastin, the elastin-like-polypeptides (ELPs), which are repeats of the amino acid sequence (Val-Pro-Gly-Xaa-Gly)n. ELPs display characteristic inverse phase transition temperatures above which they rapidly phase separate from aqueous 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 with sensitivity to other specific environmental variables, such as pH, ionic strength, and conformation of adjacent proteins. As a pharmaceutical platform, genetically engineered ELPs are monodisperse, biodegradable, encoded from human self-antigens, and can incorporate biological (protein) or chemical (drug) payloads. Our group actively explores design parameters that link environmental cues to peptide phase behavior and applies these switches to react to microenvironment of tumors and other pathology.

Liposomes are another powerful technology used by our group. Composed of phospholipids similar to those found in cell membranes, liposomes are vesicles with aqueous interiors, which can carry a variety of therapeutic cargo. The maturity of liposome technology provides a wealth of possible compositions, nanoparticle sizes, and drug encapsulation methods. Building on this broad platform, our group explores liposomes modified with bioresponsive peptides that mediate accumulation and release in disease microenvironments.

Biography
Dr. MacKay received his S.B. in chemical engineering and biology from the Massachusetts Institute of Technology in 1999. After working for a Boston area biotechnology company, he entered the Joint Graduate Group in Bioengineering at the University of California at San Francisco and Berkeley. At UCSF-Berkeley, he earned a Howard Hughes Medical Institute Predoctoral Fellowship. Upon completing his Ph.D. in 2005, Dr. Mackay joined the Department of Biomedical Engineering at Duke University, where he earned a Kirschstein National Research Service Award Postdoctoral Fellowship. Dr. MacKay joined the faculty in the Department of Pharmaceutical Sciences at the University of Southern California as an Assistant Professor in December 2008.

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Research Support
Ad5 Fiber Entry and Trafficking in Lacrimal Acini
NIH/NEI 3 RO1
Co-Investigator
$250,000 in direct costs

Positron Emission Tomography of Peptide-drug Nanoparticles Targeted to Tumor Blood Supply
American Cancer Society Pilot Project
6/1/09-5/31/10
Principal Investigator
$20,000

Hepatic Trafficking and Anti-tumor Activity of Genetically Engineered Glyco-celles
NIH/NIDDK Pilot Project
3/1/09-2/28/10
Principal Investigator
$37,500

University of Southern California Seed Funding
12/1/08 - 12/1/11
Principal Investigator
$500,000