The process of angiogenesis directly influences the growth and metastatic properties of solid tumors. Clinically useful, innovative imaging technologies for detecting angiogenic activity are urgently needed. Recent discoveries of novel peptides that selectively home to tumor vasculature through their interaction with gelatinases in proliferating blood vessels support the development of new radiopharmaceuticals and radiological contrast materials for functional imaging by gamma scintigraphy and magnetic resonance imaging (MRI). One such peptide, a cyclic decapeptide, CTTHWGFTLC, binds with MMP-2 (gelatinase A) and MMP-9 (gelatinase B) selectively with high affinity. We propose to synthesize two series of peptide conjugates as targeted in vivo imaging agents using water-soluble polymers as carriers for either radioisotope or for paramagnetic metal ions to optimize the pharmacological properties and metal loading capacity of this peptide. Specifically, we will: (1) synthesize peptide-polyethylene glycol (PEG) conjugate with 111In-DTPA attached to one end of the PEG chains, and (2) synthesize conjugate of peptide and Gd-DTPA linked through a block copolymer linker. The copolymer, PEG-poly(L-glutamic acid) (PEG-PG), will allow coupling of multiple Gd-DTPA molecules to the side chain of PG block. The biodistribution and imaging properties of these agents will be evaluated in nude mice bearing human MDA-MB435 tumor. Finally, we will (3) validate the selective imaging of tumor vasculature with 111In- and Gd-labeled peptide- polymer conjugates by co-injecting unmodified/cold peptide with labeled peptides in our imaging studies. If successful, this developmental project will be expanded to assess the effect of various anti angiogenic agents on the early changes of the molecular target of this novel tumor vascular-specific peptide.
Showing the most recent 10 out of 84 publications
