2. Academic Validation
  3. Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells

Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells

  • Eur J Med Chem. 2017 Jan 5:125:914-924. doi: 10.1016/j.ejmech.2016.10.015.
Sandeep Pallerla 1,  Ted Gauthier 2,  Rushikesh Sable 1,  Seetharama D Jois 3
Affiliations

Affiliations

  • 1 Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
  • 2 Biotechnology Laboratory, LSU AgCenter, Louisiana State University, Baton Rouge, LA 70803, United States.
  • 3 Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States. Electronic address: jois@ulm.edu.
PMID: 27769032 DOI: 10.1016/j.ejmech.2016.10.015
Abstract

Doxorubicin (DOX) belongs to the anthracycline class of drugs that are used in the treatment of various cancers. It has limited cystostatic effects in therapeutic doses, but higher doses can cause cardiotoxicity. In the current approach, we conjugated a peptidomimetic (Arg-aminonaphthylpropionic acid-Phe, compound 5) known to bind to HER2 protein to DOX via a glutaric anhydride linker. Antiproliferative assays suggest that the DOX-peptidomimetic conjugate has activity in the lower micromolar range. The conjugate exhibited higher toxicity in HER2-overexpressed cells than in MCF-7 and MCF-10A cells that do not overexpress HER2 protein. Cellular uptake studies using confocal microscope experiments showed that the conjugate binds to HER2-overexpressed cells and DOX is taken up into the cells in 4 h compared to conjugate in MCF-7 cells. Binding studies using surface plasmon resonance indicated that the conjugate binds to the HER2 extracellular domain with high affinity compared to compound 5 or DOX alone. The conjugate was stable in the presence of cells with a half-life of nearly 4 h and 1 h in human serum. DOX is released from the conjugate and internalized into the cells in 4 h, causing cellular toxicity. These results suggest that this conjugate can be used to target DOX to HER2-overexpressing cells and can improve the therapeutic index of DOX for HER2-positive Cancer.

Keywords

Breast cancer; Conjugate; Doxorubicin; HER2; Lung cancer; Peptidomimetic.

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