Targeted multidrug delivery system to overcome chemoresistance in breast cancer

Abstract

Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX) into immunoliposomes where the human epidermal growth factor receptor 2 (HER2) antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR), and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly delayed in the combinational liposomal drug delivery group. This novel combinational therapy has great potential for the treatment of patients with HER2/MDR double positive breast cancer.

LAPTM4B gene copy number gain is associated with inferior response to anthracycline-based chemotherapy in hormone receptor negative breast carcinomas

“…Anthracyclines are still the most widely used chemotherapeutic agents given as either adjuvant or neoadjuvant therapy [11,12]. Considering that approximately 30% of the early stage breast cancers progress to the metastatic stage, and the fact that the response rate to anthracycline or taxane-based chemotherapy ranges from 30 to 70%, predictors of treatment efficacy to the various chemotherapeutic agents would have significant clinical importance [1,3,13,14].…”

Nanomedicine applications in the treatment of breast cancer: current state of the art

“…Table 4 summarizes a number of recent studies on HER2-targeted nanomedicine. [55][56][57][58][59] Although HER2 antibody is a targeting moiety commonly used for HER2+ cancer, other HER2 targeting ligands have also been studied. For instance, Ding et al used trastuzumab-mimetic peptide with promising results, and suggested that this may reduce the immunogenicity, production costs and technical efforts associated with the antibody.…”

Liposomal Nanoformulations as Current Tumor-Targeting Approach to Cancer Therapy

“…HER2 antibody was used in a recent study as a targeting ligand in PEGylated immunoliposomes loaded with DOX. The formulation was tested for combination therapy in association with liposomal bevacizumab, and animal studies revealed increased accumulation of DOX at the tumor site and a significant delay of tumor growth in the combinational liposomal drug delivery group compared to free DOX, liposomal DOX, immunoliposomal DOX, and liposomal bevacizumab [71].…”