This mini-review article is part of a special issue dedicated to Donald S. Coffey, a pioneer translational research scientist, exemplary mentor, and leader in urologic and urologic oncology research. This article first briefly reflects on life and scientific lessons from Don Coffey. It then reviews the development of two
prostate cancer targeting
RNA aptamers, xPSM-A9 and xPSM-A10, through in vitro selection for aptamers that bind to the extracellular domain of the Prostate Specific Membrane
Antigen (PSMA). These 2'-fluorpyrimidine
RNA aptamers selectively bind PSMA on the surface of
prostate cancer cells, inhibit PSMA
glutamate carboxypeptidase activity, and internalize into PSMA-expressing
cancer cells. The truncation of both aptamers, through experimentation as well as logical design, has produced smaller
isoforms including A10-3, A10-3.2, A9g and A9L. The larger aptamer
isoforms xPSM-A9 and xPSM-A10 are limited to production by in vitro transcription and
polyacrylamide gel purification, while smaller
isoforms can be generated by chemically synthesis. A series of aptamer conjugates have been developed through chemical crosslinking, complementary annealing strategies, or a combination of both, for the targeting of experimental
therapeutics to and into
prostate cancer cells. The resulting aptamer conjugates, including nanoparticles and
siRNA conjugates, selectively target PSMA-positive
prostate cancer cells and xenograft
tumors, and demonstrate potent cytotoxic and tumoricidal activity. These experimental therapeutic agents provide a platform for realizing and optimizing the potential of
tumor-selective targeting and
drug delivery.