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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 18; pp. 4761 - 4766
• Main Authors: Gray, Bethany Powell, Kelly, Linsley, Ahrens, Douglas P., Barry, Ashley P., Kratschmer, Christina, Levy, Matthew, Sullenger, Bruce A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.05.2018
• Subjects: Aminobenzoates - chemistry; Aminobenzoates - pharmacology; Animals; Antidotes; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aptamers; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - pharmacology; Biocompatibility; Biological Sciences; Cancer; Cancer therapies; Conjugates; Conjugation; Cytotoxicity; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - pharmacology; Epithelial cells; Humans; Lesions; Male; Metastases; Mice; Mice, Nude; Oligopeptides - chemistry; Oligopeptides - pharmacology; Organic chemistry; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Studies; Toxicity; Tumors; Xenograft Model Antitumor Assays; antidote control; drug targeting; prostate cancer; aptamer; aptamer–drug conjugate
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1717705115

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.