The overall goal of this NCDDG is to develop high-affinity and high-specificity targeting agents for lymphoid malignancies. We hypothesize that (i) alpha4beta1 integrin (activated state) is an excellent therapeutic target for lymphoid malignancies, (ii) the peptidomimetic leads that have already been identified in our laboratory, after further optimization, will become effective therapeutic agent for human and canine lymphoid malignancies, (iii) by screening additional diverse peptide and peptidomimetic libraries, targeting leads against other cell surface receptors will be identified, and (iv) some of these peptidomimetic compounds, in oligomeric form (either homopolymer or heteropolymer) may be able to cross-link cell surface molecules resulting in higher avidity and possibly causing cell signaling and cellular responses. We believe these targeting agents, when radiolabeled (e.g. with 90Y) or conjugated to liposomes containing chemotherapeutic agents such as doxorubicin (e.g. Doxil(R)), can be used as highly specific therapeutic agents for lymphoid malignancies. In this program, we propose to use combinatorial chemistry, molecular modeling methods, and other biophysical techniques to further optimize our lead compounds, and to characterize the compounds with respect to binding specificity and affinity of, as well as their biochemical effects on normal and malignant lymphoid cells. Although our focus is to further optimize our targeting agents for activated alpha4beta1 integrin, we also plan to screen diverse peptide and peptidomimetic libraries for ligands that bind to other non-integrin receptors. These ligands could potentially be used either by themselves, or in conjunction with the alpha4beta1 integrin targeting compounds as therapeutic agents for lymphoid malignancies.
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