Treating Tumors at Low Drug Doses Using an Aptamer–Peptide Synergistic Drug Conjugate

Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non‐optimal drug ratios. A modular framewo...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-01, Vol.58 (5), p.1437-1441
Main Authors: Pusuluri, Anusha, Krishnan, Vinu, Lensch, Valerie, Sarode, Apoorva, Bunyan, Elaine, Vogus, Douglas R., Menegatti, Stefano, Soh, H. Tom, Mitragotri, Samir
Format: Article
Language:English
Subjects:
Aptamers
aptamer–drug conjugate
Biocompatibility
Breast cancer
Camptothecin
cancer
Chemotherapy
Doxorubicin
Drug delivery
Drug delivery systems
Drug dosages
Drugs
nucleolin
Oncology
peptide scaffolds
Peptides
synergy
targeted drug-delivery
Toxicity
Tumors
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Summary:Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non‐optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor‐targeting aptamers for effective low‐dose treatment. A nucleolin‐recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC50 (31.9 nm) against MDA‐MB‐231 breast cancer cells in vitro, and exhibited in vivo efficacy at micro‐dose injections (500 and 350 μg kg−1 dose−1 of DOX and CPT, respectively) that are 20–30‐fold lower than their previously‐reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology. Targeted drug‐delivery: Combination chemotherapy regimens can be effective, but are often highly toxic and fail in clinics since drugs are given at their maximum tolerated doses. To achieve potent antitumor effects at extremely low doses, an aptamer–drug combination vehicle is described, designed to selectively deliver multiple therapeutic agents at a pre‐defined ratio for maximum effectiveness.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201812650