Oligonucleotide aptamer-drug conjugates for targeted therapy of acute myeloid leukemia.

TitleOligonucleotide aptamer-drug conjugates for targeted therapy of acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsZhao N, Pei S-N, Qi J, Zeng Z, Iyer SP, Lin P, Tung C-H, Zu Y
JournalBiomaterials
Volume67
Pagination42-51
Date Published2015 Oct
ISSN1878-5905
KeywordsAptamers, Nucleotide, Base Sequence, Bone Marrow, Cell Line, Tumor, Cell Proliferation, DNA, Single-Stranded, Humans, Leukemia, Myeloid, Acute, Methotrexate, Molecular Sequence Data, Molecular Targeted Therapy, Proto-Oncogene Proteins c-kit
Abstract

Oligonucleotide aptamers can specifically bind biomarkers on cancer cells and can be readily chemically modified with different functional molecules for personalized medicine. To target acute myeloid leukemia (AML) cells, we developed a single-strand DNA aptamer specific for the biomarker CD117, which is highly expressed on AML cells. Sequence alignment revealed that the aptamer contained a G-rich core region with a well-conserved functional G-quadruplex structure. Functional assays demonstrated that this synthetic aptamer was able to specifically precipitate CD117 proteins from cell lysates, selectively bound cultured and patient primary AML cells with high affinity (Kd < 5 nM), and was specifically internalized into CD117-expressing cells. For targeted AML treatment, aptamer-drug conjugates were fabricated by chemical synthesis of aptamer (Apt) with methotrexate (MTX), a central drug used in AML chemotherapy regimens. The formed Apt-MTX conjugates specifically inhibited AML cell growth, triggered cell apoptosis, and induced cell cycle arrest in G1 phase. Importantly, Apt-MTX had little effect on CD117-negative cells under the same treatment conditions. Moreover, exposure of patient marrow specimens to Apt-MTX resulted in selective growth inhibition of primary AML cells and had no toxicity to off-target background normal marrow cells within the same specimens. These findings indicate the potential clinical value of Apt-MTX for targeted AML therapy with minimal to no side effects in patients, and also open an avenue to chemical synthesis of new, targeted biotherapeutics.

DOI10.1016/j.biomaterials.2015.07.025
Alternate JournalBiomaterials
PubMed ID26204224
PubMed Central IDPMC4550516
Grant ListR01 CA151955 / CA / NCI NIH HHS / United States
R33 CA173382 / CA / NCI NIH HHS / United States
R01CA151955 / CA / NCI NIH HHS / United States
R33CA173382 / CA / NCI NIH HHS / United States
Related Institute: 
Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
525 East 68th Street New York, NY 10065