Tunable cytotoxic aptamer–drug conjugates for the treatment of prostate cancer

Abstract

Therapies that can eliminate both local and metastatic prostate tumor lesions while sparing normal organ tissue are desperately needed. With the goal of developing an improved drug-targeting strategy, we turned to a new class of targeted anticancer therapeutics: aptamers conjugated to highly toxic chemotherapeutics. Cell selection for aptamers with prostate cancer specificity yielded the E3 aptamer, which internalizes into prostate cancer cells without targeting normal prostate cells. Chemical conjugation of E3 to the drugs monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) yields a potent cytotoxic agent that efficiently kills prostate cancer cells in vitro but does not affect normal prostate epithelial cells. Importantly, the E3 aptamer targets tumors in vivo and treatment with the MMAF-E3 conjugate significantly inhibits prostate cancer growth in mice, demonstrating the in vivo utility of aptamer-drug conjugates. Additionally, we report the use of antidotes to block E3 aptamer-drug conjugate cytotoxicity, providing a safety switch in the unexpected event of normal cell killing in vivo.

Modulating Aptamer Specificity with pH-Responsive DNA Bonds

“…Instead, they are expressed at lower levels, or even at similar levels, in certain healthy tissues. 11,12 It is therefore not surprising that toxicity toward healthy tissue cannot be avoided under these circumstances and that such toxicity has often been observed with targeted therapies. 7,13 While research to improve targeting specificity has mainly focused on combinatorial approaches that can recognize two or more cell surface markers, 14–17 smart aptamers capable of distinguishing a target cell receptor from the same receptor on the membranes of nontarget cells, but without the need to design a new recognition sequence, are in high demand.…”

Modified nucleic acids: replication, evolution, and next-generation therapeutics

“…In another recent report, Sullenger and colleagues modified RNA aptamers against prostate cancer cells with 2′F pyrimidines. Upon conjugation with small molecule drugs or therapeutic peptides, these aptamers displayed significant specificity and toxicity against cancerous but not normal cells [ 196 , 197 ]. We direct the reader to a recent review for a more detailed panorama of modified aptamer chemistry and related technologies [ 198 ].…”

<p>Aptamers as Versatile Ligands for Biomedical and Pharmaceutical Applications</p>

“…Powell et al synthesized tunable cytotoxic aptamer-drug conjugates for the treatment of prostate cancer. 55 A prostate cancer-specific aptamer (E3) was produced using cell SELEX selection. The aptamer was internalized into prostate cancer cells, but not into normal prostate cells.…”