Medical Physics/ Nanotechnology: New nanotechnology platform for the targeting of diseased tissue

(in collaboration with Prof. Oleg Andreev, URI and Donald Engelman, Yale University)

 

The major questions in biomedical sciences are how to find disease with high accuracy and how to treat it effectively not affecting normal tissue. There are several approaches, which can help to achieve desirable results:

Targeted therapy: selective delivery of therapeutic and imaging agents to diseased tissue thereby increasing the effective concentration of these agents and reducing their accumulation in healthy tissue.

Improved route of drug administration: encapsulation of therapeutic agents into nano-sized vectors (such as liposomes or polymers) to improve pharmacokinetic properties of a drug.

Locally activated therapy: activation of a targeted therapeutic agent by external effectors, such as an electro-magnetic radiation, neutron beam irradiation, or ultrasound.

Multifunctionality: simultaneous targeted delivery of a therapeutic agent and an imaging probe to monitor drug distribution.

New approach to drug design: use of a new class of therapeutic agents: cell-impermeable molecules that would be translocated into cells only in diseased tissue while not affecting healthy cells.

 

Our research is based on use of a water-soluble membrane peptide, pHLIP, which we have shown to selectively target acidic solid tumors in vivo and to translocate cargo molecules into the cytoplasms of cultured cancer cells. The selectivity is based on the capability of pHLIP to insert across the lipid bilayer of a cell membrane and form a transmembrane alpha helix. Insertion is driven by the mildly acidic environment of tumors, whereas there is little insertion across the membranes of cells with the normal extracellular pH of healthy tissue.

 

The major goal is to develop a nanotechnology platform for selective delivery of imaging and therapeutic agents to tumors based on use of the pHLIP. We believe that pHLIP delivery platform could target more polar molecules to enter cancer cells, which might open a desirable area for therapeutic design. Such molecules would not cross the membranes of cells unless the delivery system was active, significantly reducing side effects. They would be less likely to be substrates for efflux pumps, and would be trapped in a cell once released from pHLIP. And, the chemical space for molecular design would be greatly expanded. Additionally, pHLIP is proposed to be adapted to facilitate the selective delivery of nano-vectors to cancer cells and promote the release of encapsulated therapeutics and imaging agents into the cytoplasm of cancer cells.

 

Representative Publications:

O. A. Andreev, A. D. Dupuy, M. Segala, S. Sandugu, D. A. Serra, C. O. Chichester, D. M. Engelman, Y. K. Reshetnyak. (2007) Mechanism and Uses of a Peptide that Targets Tumors and other Acidic Tissue In vivo, Proced. Natl. Acad. Sci U.S.A. 104 (19) 7893-7898.

 

Reshetnyak, Y. K., Andreev, O.A., Lehnert, U., & Engelman, D.M. (2006) Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proced. Natl. Acad. Sci U.S.A. 103(17) 6460-6465

Reshetnyak, Y. K., Andreev, O.A., Lehnert, U., & Engelman, D.M. (2006) Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proced. Natl. Acad. Sci U.S.A. 103(17) 6460-6465.