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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
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Treating Tumors at Low Drug Doses Using an Aptamer-Peptide Synergistic Drug Conjugate

Anusha Pusuluri1,2,3, Vinu Krishnan1,2, Valerie Lensch3

  • 1John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.

Angewandte Chemie (International Ed. in English)
|December 12, 2018
PubMed

Insights

This study introduces a novel aptamer-based system for targeted drug delivery, enabling effective low-dose combination chemotherapy. The approach enhances safety and efficacy by precisely delivering synergistic drug ratios to tumors.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Oncology

Background:

  • Combination chemotherapy faces challenges balancing efficacy and safety.
  • Current Maximum Tolerated Dose (MTD) regimens lead to high toxicity and suboptimal drug ratios.
  • Tumor-targeting strategies are needed for improved therapeutic outcomes.

Purpose of the Study:

  • To develop a modular framework for selective delivery of synergistic drug combinations at low doses.
  • To engineer a tumor-targeting aptamer construct for enhanced cancer treatment.
  • To improve the safety and efficacy profile of combination chemotherapy.

Main Methods:

  • A nucleolin-recognizing aptamer was conjugated to peptide scaffolds.
  • Doxorubicin (DOX) and camptothecin (CPT) were precisely loaded onto the scaffolds in synergistic ratios.
  • In vitro cytotoxicity assays (IC50) and in vivo efficacy studies were performed.

Main Results:

  • The aptamer-drug conjugate exhibited a low IC50 of 31.9 nM against MDA-MB-231 breast cancer cells.
  • In vivo studies demonstrated significant efficacy with micro-doses of DOX and CPT (500 and 350 μg/kg).
  • These doses were 20-30 fold lower than previously reported MTDs, indicating reduced toxicity.

Conclusions:

  • The developed modular framework enables safe and effective low-dose combination chemotherapy.
  • Tumor-targeting aptamers facilitate precise delivery of synergistic drug ratios.
  • This strategy offers a generalizable approach for improved oncology drug delivery.
Keywords:
aptamer-drug conjugatecancerpeptide scaffoldssynergytargeted drug-delivery

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