CAMP Professor Partch Pursues Research in Drug Overdose Remediation: A New Venue for Particles in Biotechnology

Nanoparticles for in vivo controlled and selective removal of overdosed drugs from blood are virtually unknown, yet hold great potential for saving lives. The drugs may be legal and administered by an MD, may be the illegal "street" type, or even agents of bioterrorism. The opposite technology, controlled time and targeted release of therapeutic agents, is mature and employed in the delivery of several common pharmaceuticals. This is a progress report on a pioneering interdisciplinary effort being carried out by
CAMP Professor Richard Partch,
CAMP graduate student
Evon Powell ( who received a poster session award on this topic), and several Co- Principal Investigators affiliated with the University of Florida including one of Partch's former Clarkson Ph.D. students, Visiting Professor Young-Hwan Lee from Kyungwon University in Seoul, Korea.

The goals of this research are to prepare, characterize and evaluate the in vitro and in vivo ability of several types of dispersed phases to absorb, bind and/or otherwise detoxify some of the most commonly overdosed chemicals that cause large numbers of deaths annually. Chemists like Partch play a pivotal role in the preparation and surface activation of particles that are undergoing evaluation by anesthesiologists on the team.

The dispersed phases under investigation include

1. Oil-in-water microemulsions designed to absorb lipophilic toxin molecules. The microemulsions may be stabilized by a monomeric or polymerizable surfactant. Data in Figure 10 shows that the microemulsion (ME-I; ME-II) approach has merit. Note the rapid lowering of the blood plasma concentration of a frequently overdosed prescribed antidepressant. On the same scale, 100% of cocaine is removed. The efficiency is limited by the composition and amount of microemulsion employed. For example, one composed of triglycerides and PEG removes 90% of 5 ÁM bupivacaine local anesthetic from saline and 80% from each blood plasma and blood.

2. Hydrophilic polymer microgels with pores filled with oil. In preliminary tests this type of dispersed phase shows less promise for drug removal than the microemulsion systems.

3. Hard or hard shell particles with high surface area having molecularly templated pores and/or with surfaces chemically modified, with binding sites that target a molecular feature unique to a toxin in question

4. Dispersed phases (1 - 3), but with an enzyme incorporated into the particle matrix capable of destroying an overdosed drug. Figure 11 shows that this option is viable. An "ideal" dispersed phase for use in detoxification might be some combination of the four types, as shown in Figure 12.





Figure 10

Figure 10.Percent efficiency of binding (removal) of a toxic antidepressant from blood plasma by ethyl butyrate microemulsions

Figure 11

Figure11. Kinetics of rapid destruction of toxic bupivacaine anesthetic by microemulsion containing P450 enzyme.

Figure 12

Figure 12. Structure of a proposed "ideal" nanoparticle for remediation of overdosed lipophilic chemicals from blood .

Professor Partch is focusing his organic chemical expertise on surface modification of particles to achieve the goals of this project. The cores of such particles include metal oxides as well as various organic biopolymers. Figure 13 shows one structural concept that successfully causes toxins to bind to carrier particles and thereby be deactivated. The fundamental basis for the binding is strong intermolecular interaction between electron deficient and electron enriched benzene rings.

His team has prepared 5-15nm silica particles having surface areas greater than 800 m2/g (which bind negligible toxin) and with 80-100 covalently attached p electron deficient acceptor benzene rings per particle. Particles with attached receptors have very high affinity for toxin molecules such as bupivacaine and cocaine, even when only 0.05% solids are administered. (See Figure 14.) They are also useful for removing overdosed polycyclic aromatic pharmaceuticals and carcinogens, all of which have electron rich rings.

Indeed the p-p binding concept is so successful that pi acceptors are not only being attached to inorganic and biopolymer latex particles, but are also being incorporated into the less efficient microemulsion and microgel dispersed phases discussed. All of the advances in the various approaches described have been made during 2001, and it is anticipated that in 2002 the dispersed phase giving the best in vitro result will be evaluated in vivo. Beyond restoring human health from an overdose of legally administered therapeutic agents, the research program has the potential of producing nanoparticles capable of detoxifying a wide variety of molecules used by addicts and terrorist groups.


Figure 13 Figure 14

Figure 13. Surface chemical features of a nanoparticle showing covalently attached p acceptor aromatic rings complexed in two possible ways to toxin pdonor aromatic rings


Figure 14. Life-saving percent efficiency of binding (removal) of toxic bupivacaine anesthetic by silica nanoparticles with (YL31-1, YL 35-1) attached p acceptors.




For more information about Professor Partch, you may call him at 315-268-2351 or send e-mail to partch@clarkson.edu.