title: Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells.
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.
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors: Sandeep
authors: S
authors: Pallerla
authors: Biotechnology Laboratory, LSU AgCenter, Louisiana State University, Baton Rouge, LA 70803, United States.
authors: Ted
authors: T
authors: Gauthier
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors: Rushikesh
authors: R
authors: Sable
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States. Electronic address: jois@ulm.edu.
authors: Seetharama D
authors: SD
authors: Jois
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001665:Binding Sites; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D061986:MCF-7 Cells; D057786:Peptidomimetics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D057786:Peptidomimetics; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Breast cancer; Conjugate; Doxorubicin; HER2; Lung cancer; Peptidomimetic