Trastuzumab-mediated selective delivery for platinum drug to HER2-positive breast cancer cells

Abstract

Oxaliplatin is used widely as an anticancer drug for clinical treatment. However, its applications are limited because of its poor selectivity. In this work, we described the design, synthesis, and characterization of conjugates combining trastuzumab with a platinum (IV) analog of oxaliplatin, in which the trastuzumab acted as an active targeting agent for HER2-positive cancer cells. Indirect enzyme-linked immunosorbent assay and immunofluorescence study indicated the platinum (IV)-trastuzumab conjugates retained specific binding activity to HER2 overexpressed SK-BR-3 cells. In the presence of ascorbic acid, platinum (IV)-trastuzumab conjugates were reduced to platinum (II) analogs, which could bind to and unwind PUC19 DNA in a manner similar to oxaliplatin. The cytotoxic study was tested on three breast cell lines: SK-BR-3, MCF-7, and MDA-MB-231. Platinum (IV)-trastuzumab conjugates showed promising antiproliferative activity against SK-BR-3 cells, but significantly decreased the inhibition to MDA-MB-231 and MCF-7 cells. The flow cytometric analysis showed that the conjugates arrested the cell cycle mainly at the G2/M phase and killed the cells through an apoptotic pathway.

Effects of trastuzumab on the proliferation and apoptosis of ovarian cancer cells

“…This supports our finding that HER2 expression in ovarian cancer tissues is significantly higher than in normal ovarian tissues and suggests it is involved in the cancer's occurrence and development. anti-tumor activity and effectively promote cell apoptosis [20]. However, the exact mechanism by how trastuzumab induces apoptosis of SKOV3 cells remains unclear and requires further investigations.…”

A Multi‐action PtIV Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells

“…An evaluation of the distribution of the treated cells populations,i na greement with the previously reported data. [17] Contrastingly,f ree trans-CA significantly reduced the population in S-phase inducing G2/M-arrest;t he treatment with OA had no significant effect on cell cycle distribution. Interestingly,t he treatment with 1 arrested the cells in S-phase similarly to cisplatin, however as ignificantly higher population of cells was able to proceed to G2-phase where they accumulated, as indicated by the increase of G2/ M-related peak (Figures 3a nd Supporting Information, Figure S8).…”

High-Affinity Human Anti-c-Met IgG Conjugated to Oxaliplatin as Targeted Chemotherapy for Hepatocellular Carcinoma

“…The conjugated compound was qualitatively investigated by HPLC (Waters, Milford, MA, USA) using a C18 (4.6 × 250 mm, 5 μm) with UV detection at 280 nm. The oxaliplatin concentrations were detected by flameless atomic absorption spectrometry, and a micro bicinchoninic acid (BCA) protein assay kit was used to measure the concentrations of anti c-Met IgG and unrelated IgG (41).…”