Tumor imaging using technetium-99m bound to pH-sensitive peptides.
Solid tumors often display metabolic abnormalities that consistently produce low pH in the extracellular space of poorly perfused tissue. These acidic regions may provide a mechanism for drug targeting. Peptides have been designed in such a manner that they exist in an anionic hydrophilic form at the pH of normal tissues, but then undergo a sharp transition to a non-ionic lipophilic form at reduced pH. Peptides were labeled with fluorescein or technetium-99m (99mTc) and evaluated in vitro and in two murine models of cancer. Our studies suggest that PAP-1, an 18 amino acid pH activated peptide with a pH of transition between hydrophilic and lipophilic forms (pT) of 6.4, will deliver fluorescein and 99mTc to tumors. Activation of PAP-1 by low pH and penetration into the plasma membrane of cells and tumors were confirmed using flow cytometry, fluorescence microscopy, and gamma scintigraphy. These results support our central hypothesis that PAP-1 may enable the selective delivery of macromolecules to tumors. This technology has potential for exploiting a common property of tumors to achieve highly specific medical intervention.
Mata
John E
JE
Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331, USA. john.mata@oregonstate.edu
Dyal
Leslie A
LA
Slauson
Margorie E
ME
Summerton
James E
JE
Loehr
Christiane
C
Tyson
Arhie Reid
AR
Rodriguez-Proteau
Rosita
R
Gustafson
Scott B
SB
D000818:Animals; D045744:Cell Line, Tumor; D006863:Hydrogen-Ion Concentration; D007089:Image Enhancement / Q000379:methods; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000493:pharmacokinetics*; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013667:Technetium / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; C000612141:REG3A protein, human; D019275:Radiopharmaceuticals; D013667:Technetium