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.

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

“…DOX is a chemotherapy drug of the anthracycline class widely used in clinical practice [ 66 , 67 ]. Although DOX has a relevant role in cancer therapy, its adverse effects, such as mucositis, have an important impact in the treatment and quality of life of patients [ 18 , 19 ].…”

Recent advances in biosensor devices for HER-2 cancer biomarker detection

“…84 Compound 5 of peptidomimetics can suppress HER-2 dimerization with other EGFRs and binding to the extracellular domain IV of HER-2. 85 In a study, the HER-2 Ag was immobilized on a carboxymethylated (CM5) dextran sensor chip SPR and the data demonstrated the conjugation of DOX–peptidomimetics binding to the HER-2 extracellular domain with good affinity compared to DOX or compound 5 alone 86 (Table 2).…”

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

“…This conjugate accumulated in HER2-overexpressing cell lines and was observed to inhibit protein-protein interactions in vitro via a PLA assay. These peptidomimetics were also conjugated with fluorophores and doxorubicin to target the EGFR related cancer [ 161 , 162 ].…”