Our lab has been funded by NIH to develop an orally bioavailable chelator that could be used to remove heavy radioactive metals like Americium (Am) and Plutonium (Pu) in people who have been accidentally (e.g., in a nuclear power facility) or deliberately (e.g., following an act of nuclear terrorism with a ‘dirty bomb’) contaminated with radioactive actinide elements like ²⁴¹Am. As part of this work, we developed an analog of the chelator DTPA that exhibited good oral bioavailability. Furthermore, we demonstrated that our novel orally bioavailable DTPA analog, designated as C2E2, was able to bind ²⁴¹Am with high affinity and that it was effective in vivo, i.e., it was able to reduce the total body burden of ²⁴¹Am in contaminated rats and beagle dogs after oral administration. We also conducted studies in GLP labs to assess the safety/and toxicity of C2E2. In addition to defining the No Observed Adverse Effect Level  (NOAEL) doses, we determined that no depletion of other essential metals occurred after oral C2E2 administration. An Investigational New Drug (IND) for a Phase 1 single ascending and multiple ascending dose first-in-human trial is now active; we aim to enroll human volunteers for these studies in the near future.

We also discovered that C2E2 was able to bind to other heavy metals of interest, including gadolinium (Gd) and lead (Pb). We are currently evaluating the ability of orally administered C2E2 to reduce the tissue burden of toxic Gd ions following administration of Gd-Based Contrast Agents (widely used in magnetic resonance imaging (MRI) procedures) as well the efficacy of C2E2 to reduce tissue Pb content in contaminated animals.

The Centers for Disease Control and Prevention (CDC) reported that in 2016 there were approximately 64,000 deaths resulting from drug overdoses, mostly driven by synthetic opioids, which represents an increase of greater than 17% from the previous year. Dentists are among the leading prescribers of opioid prescriptions; Opiates are regularly prescribed by oral surgeons, 85% of whom indicated they nearly always prescribe opiates, after wisdom teeth extraction (third molar extraction) to reduce acute/ extreme pain caused by dry sockets, which occur in 5-10% of patients following extraction. Approximately 21 million surgical tooth extractions are performed on ~10 million patients each year in the US. One of the key points of the American Dental Association’s ‘Statement on the Use of Opioids in the Treatment of Dental Pain’ is that dentists should recognize multimodal pain strategies for management for acute postoperative pain as a means for sparing the need for opioid analgesics.  The goal of this project is to develop a local treatment for pain associated with the extraction of teeth, such as third molars (‘wisdom teeth’) that does not involve an opiate. This involves the development of a formulation consisting of a resorbable matrix that can be placed in the tooth socket following extraction for delivery of an anesthetic agent in a sustained release manner over a period of 4-7 days. We expect that successful development of this product and its implementation in dentistry/oral surgery practice will lead to a significant reduction in the number of opiate prescriptions written for patients suffering from dry sockets or other painful sequelae resulting from dental procedures.