Targeted Liposomal Chemotherapies to Treat Triple-Negative Breast Cancer.

Yingnan Si,Eddy S Yang,Kai Chen,Yuanxin Xu,Xiaoguang (Margaret) Liu,Lufang Zhou,Ajeet Pal Singh,Hanh Giai Ngo,Ya Zhang,Jia-Shiung Guan,Qing Wang

doi:10.3390/cancers13153749

Yingnan Si, Eddy S Yang + Show 9 more

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https://doi.org/10.3390/cancers13153749

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Journal: Cancers	Publication Date: Jul 26, 2021
Citations: 14	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

Simple SummaryTriple-negative breast cancers (TNBCs) are mainly treated with standard chemotherapies. Combined therapies have been demonstrated as a promising treatment strategy in clinics. The aim of this study was to develop a new formulation of combined chemotherapies facilitated with a targeted delivery vehicle. We found that the mertansine and gemcitabine with different anti-cancer mechanisms resulted in high cytotoxicity in TNBC cells. The in vivo evaluations using two TNBC xenograft models confirmed the anti-tumor efficacy, i.e., significantly reduced tumor growth rate. Furthermore, the antibody-tagged liposomes effectively delivered the therapeutic drugs to TNBC tumor, which could reduce the side effects. This study is highly translational and the targeted liposomal drug formulation can be further investigated in future clinical trials for TNBC treatment.Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.

Highlights

Triple-negative breast cancers (TNBCs) are the breast cancers that lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2/neu
The DOPC and cholesterol were mixed together with DMPE-PEG-NHS that links the tumortargeting antibody and liposomes, DSPE-mPEG that integrates into liposomes membrane to improve the circulation stability of liposomes [15,38,39], and the two chemotherapeutic drugs GC and DM1 (Figure 1A)
In addition to loading therapies, the fluorescent dye, such as 18:0 Cyanine 7 (Cy7) which was used in this study, can be encapsulated into liposomes to monitor the in vivo distribution of the delivered drugs facilitated with In Vivo Imaging System (IVIS)

Summary

Introduction

Triple-negative breast cancers (TNBCs) are the breast cancers that lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2/neu. Chemotherapeutic agents are the most common clinical treatment strategies employed to suppress tumor growth, but TNBC patient responses differ from case to case. Patients usually suffer from side effects, such as fatigue, emesis, hair loss, and anemia, due to a lack of an effective tumor targeting method. The U.S Food and Drug Administration (FDA) has approved liposomes as a drug delivery vehicle with guidance of “Chemistry, manufacturing, and controls; human pharmacokinetics and bioavailability; and labeling documentation” (FDA-2016-D-2817). The targeted liposomes have been developed and utilized to deliver drugs to the tumor or tumor microenvironment with minimal non-specific distribution in normal tissues or organs

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