Enhancement of tumor tropism of mPEGylated nanoparticles by anti-mPEG bispecific antibody for ovarian cancer therapy

Wen-Wei Lin,Bo-Cheng Huang,Hung-Wen Lai,Chiu-Min Cheng,Chia-Ching Li,Hui-Ju Liu,Tian-Lu Cheng,I.-J.U Chen,Yun-Chi Lu,Yi-An Cheng,Huei-Jen Chen,Kai-Wen Ho,Ming-Yii Huang

doi:10.1038/s41598-021-87271-2

Abstract

Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide. It is important to elevate the drug susceptibility and cytotoxicity of ovarian cancer cells, thereby eliminating resident cancer cells for more effective therapeutic efficacy. Here, we developed a bispecific antibody (BsAb; mPEG × HER2) that can easily provide HER2+ tumor tropism to mPEGylated liposomal doxorubicin (PLD) and further increase the drug accumulation in cancer cells via receptor-mediated endocytosis, and improve the cytotoxicity and therapeutic efficacy of HER2+ ovarian tumors. The mPEG × HER2 can simultaneously bind to mPEG molecules on the surface of PLD and HER2 antigen on the surface of ovarian cancer cells. Simply mixing the mPEG × HER2 with PLD was able to confer HER2 specificity of PLD to HER2+ ovarian cancer cells and efficiently trigger endocytosis and enhance cytotoxicity by 5.4-fold as compared to non-targeted PLD. mPEG × HER2-modified PLD was able to significantly increase the targeting and accumulation of HER2+ ovarian tumor by 220% as compared with non-targeted PLD. It could also significantly improve the anti-tumor activity of PLD (P < 0.05) with minimal obvious toxicity in a tumor-bearing mouse model. We believe that the mPEG × HER2 can significantly improve the therapeutic efficacy, potentially reduce the relapse freqency and thereby achieve good prognosis in ovarian cancer patients.

Highlights

Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide
To examine whether the Methoxyl-polyethylene glycol (mPEG) × human epidermal growth factor receptor 2 (HER2) can simultaneously binding to mPEG and HER2 antigen, sandwich cellbased Enzyme‐linked immunosorbent assay (ELISA) was performed by immobilizing SKOV-3 ( HER2+) cells on a 96-well cell culture plate, followed by subsequent incubation with mPEG × HER2 or mPEG × DNS, m PEG2K-BSA, anti-PEG monoclonal Ab 6.3 and Horseradish peroxidase (HRP)-conjugated secondary Ab
In order to examine whether the mPEG × HER2 can confer PEGylated-liposomal doxorubicin (PLD) to HER2 specificity, sandwich cellbased ELISA was performed by immobilized SKOV-3 (HER2+) or MDA-MB-468 (HER2−) cells into a 96-well cell culture plate, followed by subsequent incubation with mPEG × H ER2− or mPEG × DNS-modified PLD, antiPEG monoclonal Ab 6.3 and HRP-conjugated secondary Ab

Summary

Introduction

Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide. We developed a bispecific antibody (BsAb; mPEG × HER2) that can provide HER2+ tumor tropism to mPEGylated liposomal doxorubicin (PLD) and further increase the drug accumulation in cancer cells via receptor-mediated endocytosis, and improve the cytotoxicity and therapeutic efficacy of HER2+ ovarian tumors. Mixing the mPEG × HER2 with PLD was able to confer HER2 specificity of PLD to HER2+ ovarian cancer cells and efficiently trigger endocytosis and enhance cytotoxicity by 5.4-fold as compared to non-targeted PLD. We believe that the increased cytotoxicity of targeted PLD can reduce the opportunity of residual ovarian cancer cell survival from conventional PLD treatment and improve the prognosis of ovarian cancer patients

Methods

Results

Conclusion