Dual-targeting hybrid peptide-conjugated doxorubicin for drug resistance reversal in breast cancer

In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer (i.e., GGCG) and transferrin receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using 1H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC50 (20.8±1.1μM) and its in vivo extent of inhibition in mice was more evident (72.2±4.6%). Induction of various apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in cancer therapy. Graphical abstract
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research