Michael Jay Lab
I joined the faculty at the UNC Eshelman School of Pharmacy in 2008 after a twenty-seven-year career at the University of Kentucky College of Pharmacy. Prior to that, I had been at the University of Connecticut for one and a half years in the Department of Nuclear Medicine.
Growing up at a time when there was great concern about nuclear weapons (fallout from bomb tests, the Berlin Wall, the Cuban missile crisis, etc.) I was fascinated by radioactivity. While attending Pharmacy School in Buffalo, NY, I wondered if I could combine my interests in pharmaceuticals with radioactivity. I took a newly designed course on radiopharmaceuticals and was hooked from that point on. In graduate school I was fortunate enough to travel to Oak Ridge National Laboratories, where I used the large cyclotron there to make positron-emitting radionuclides that I ultimately incorporated into biologically-interesting molecules. I have continued this theme of working at the interface between the pharmaceutical and nuclear sciences throughout my career. This includes the application of pharmaceutical approaches to solve problems related to nuclear imaging and therapy, and the use of radioanalytical approaches to solve problems encountered in the development of novel formulations and drug-delivery systems. My career has come full-circle back to my childhood as I am now working on drugs to treat victims of nuclear terrorism.
Another theme I have focused on is to do research that is fun. While there have been some challenging moments, I have enjoyed almost every minute of it. I have had the pleasure to have trained twenty-eight MS and PhD students and another thirty-five postdoctoral fellows, as well as numerous undergraduate students.
My scientific academic career has taken me around the world to places that, in my youth, I never thought I would have seen. It has been a great ride so far and I look forward to many more years of fun.
My research projects are centered on the interface between the pharmaceutical and nuclear sciences. Recent activities have been focused on radionuclide decorporation agents, i.e., drugs that can hasten the elimination of transuranic elements from contaminated individuals following accidental contamination or a deliberate act of nuclear terrorism, and radiotherapeutic nanoparticles produced by neutron activation.
The Fukushima Daiichi nuclear incident in March 2011 has attracted world attention to the currently available radiological countermeasures for such disasters. In addition, the threat of nuclear terrorism using such methods as detonation of a radiological dispersion device (RDD, “dirty bomb”) also calls for effective medical countermeasures designed for use in mass casualty scenarios. In both these events, significant release of transuranic radionuclides into the environment could result in human exposure via inhalation or by contact. The Ca and Zn complexes of Diethylenetriaminepenta-acetic acid (DTPA) have been shown to be effective in enhancing the elimination of transuranic elements such as americium (Am), plutonium (Pu) and curium (Cm) in individuals who have been contaminated with radioisotopes of these elements. Injectable formulations of Ca-DTPA and Zn-DTPA are currently stored in the Strategic National Stockpile for use in the event of accidental contamination or a nuclear terrorism event. DTPA is a chelating agent that increases the rates of elimination of these elements through the exchange of calcium or zinc ions. DTPA is very water-soluble but, unfortunately, its oral bioavailability is minimal (i.e., ~1%). Because these products must be administered by a skilled professional and, like all sterile, injectable pharmaceuticals, are expensive to manufacture, they do not lend themselves well for use in an emergency situation.
In order to achieve greater oral bioavailability, we prepared lipophilic prodrugs of DTPA that serve to enhance the absorption of the chelator through the intestinal mucosal membrane. These prodrugs were designed to be metabolized to DTPA during or after absorption from the GI tract. We have selected a lead compounds and are conducting extensive animal experiments to determine the pharmacokinetic and toxicokinetic parameters of the prodrug. We are also conducting studies to determine the mechanisms by which it is metabolized. We have demonstrated that our lead compound has excellent decorporation efficacy after oral administration to animals that have been contaminated with 241Am and are and establishing the optimum dose and dosing schedule. We are also working with the Lovelace Respiratory Research Institute to test the efficacy of the prodrug in large animals that have been contaminated by inhalation of Am and Pu radioisotopes.
Our goal is to develop this prodrug into a drug product that can be included in the Strategic National Stockpile for use by the general public in the case of a radiation emergency. This lead prodrug will be advanced through the regulatory-based product development pathway under the “Animal Rule” (because true efficacy studies cannot ethically be conducted in humans) for approval by the FDA. A pre-IND briefing document will soon be submitted to the FDA.
This project is supported by funding ($6.6 MM) from NIAID. Collaborators on this project include Dr. Russ Mumper who is providing expertise in formulation and product development, and Dr. Bill Zamboni who directs GLP labs will be used for the bioassay work and who is writing the clinical study design and conducting the pharmacokinetic-toxicokinetic analyses.
Contamination by radioactive Am, Pu and Cm can occur by inhalation, skin adsorption, or by entrance through a wound. The transfer of these radioactive elements from experimental deep puncture wounds to the systemic circulation is generally a slow, steady process and rates of ranging from 0.052 to 6.3% of the injected dose per day, depending on the contaminants and the animal species. The total body clearance of 14C-labeled DTPA in rats 24 h after i.v. administration has been reported to range from 94-100% with half-lives ranging from 18.5 to 31.8 min. Comparison of the short half-life and rapid elimination of DTPA after i.v. injection to the slow introduction of radioactive actinide species into the bloodstream reveals a mismatch between the pharmacokinetics of DTPA and the biokinetic profile of actinides, which limits the effectiveness of the currently available DTPA treatments. Transdermal delivery of therapeutic agents provides many advantages over parenteral and oral routes such as a more uniform plasma drug levels, longer duration of action with reduced dosing frequency, and improved patient compliance and comfort with the ease of self-administration. It is highly desirable to deliver DTPA to the circulation at a zero-order rate to better match actinide biokinetic profiles and thus achieve optimal decorporation over an extended duration. Due to its low partition coefficient (log P = -4.90) and high melting point (219-220ºC), DTPA is not a good candidate for transdermal delivery. The penta-ethyl ester of DTPA, designated as C2E5, was designed and synthesized as a new radionuclide decorporation agent to overcome the limitations of current DTPA treatments. C2E5 possesses physicochemical properties suitable for transdermal delivery; it has a log P value of 3.3 and is a Newtonian liquid with a viscosity of 175 cP at 25ºC.
The aim of this study is to develop C2E5 transdermal formulations and evaluate the candidate formulations for sustained delivery of DPTA and other metabolites in vivo. Cream and ointment formulations were screened initially as C2E5 delivery vehicles, but the screening results showed that either C2E5 proved to be unstable in the matrices due to degradation or the C2E5 formulations underwent phase separation. C2E5 degradation in buffered aqueous solution follows pseudo-first order kinetics and C2E5 is most stable at a pH of approximately 4.2. Due to the high hydrolytic tendency of the C2E5 ester bonds in aqueous media, non-aqueous gel formulations were pursued to stabilize the moisture-labile C2E5 in the delivery vehicles. After application to the skin, esterases present in skin are expected to convert C2E5 to it various metabolites, including the fully de-esterified metabolite, DTPA.
When a C2E5 non-aqueous gel was applied to the skin of rats that had been contaminated with 241Am, enhanced decorporation of the radionuclide was observed that rivaled the results obtained with i.v. DTPA. Furthermore, a single doe has a peak effect 2-3 days after administration, indicating that zero-order delivery of chelators had been achieved.
The goal of this project is to develop a neutron-activatable radiotherapeutic nanoparticle (NP) for the treatment of cancer by intra-catheter administration. We hypothesize that administering these NPs directly to tumors can deliver efficacious radiation doses. The novelty of this agent is that it is produced by the neutron activation of stable isotopes in the NP matrix. Radionuclides produced by neutron irradiation of these NPs will decay by the emission of beta particles capable of delivering sufficient absorbed radiation doses to targeted cells. The surface of the NPs can be functionalized with a targeting ligand directed against ovarian tumors. Retention of the NPs in the tumor can be determined using SPECT/CT for radionuclides that also emit gamma photons. The process of rendering the NPs radioactive after they have been prepared allows their preparation in compliance with FDA current Good Manufacturing Practices without having to handle hazardous quantities of radioactivity, and permits flexibility in terms of adding different targeting ligands.
Mike Jay, Ph.D., received his B.S. in pharmacy from the State University of New York at Buffalo in 1976 and his Ph.D. in pharmaceutical sciences from the University of Kentucky in 1980. He was an assistant professor of nuclear medicine at the University of Connecticut Health Center from 1980 to 1981 and then returned to the University of Kentucky as an assistant professor of medicinal chemistry in 1981 and rose through the academic ranks. By the end of his twenty-seven years at the University of Kentucky, he was professor of pharmaceutics and professor of radiology.
Pharmaceutical scientist who received a PhD from Taipei Medical University and who is providing expertise in formulation development
Visiting scholar from the Institute of Molecular Medicine, Huaqiao University, Quanzhou, China with expertise on drug delivery systems
Katsuhuki (“K”) Sueda
Fifth-year graduate student as well as a full-time employee at GlaxoSmithKline. K earned an M.S. in pharmaceutical engineering from the University of Michigan and brings extensive experience in formulation and product development
Fifth-year graduate student who earned an M.S. in organic chemistry from the University of South Carolina and worked at GlaxoSmithKline for five years prior to starting his graduate studies. He completed an industrial internship at MedImmune in Rockville, MD. Yong is also the past Chair of the UNC Graduate AAPS Chapter.