Tunable cytotoxic aptamer-drug conjugates for the treatment of prostate cancer.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Powell Gray, B; Kelly, L; Ahrens, DP; Barry, AP; Kratschmer, C; Levy, M; Sullenger, BA
Published Date
- May 1, 2018
Published In
Volume / Issue
- 115 / 18
Start / End Page
- 4761 - 4766
PubMed ID
- 29666232
Pubmed Central ID
- PMC5939073
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1717705115
Language
- eng
Conference Location
- United States