Abstract
Although targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high heterogeneity of these cancers. Mammaglobin-A (Mam-A), which is overexpressed in most breast carcinomas, has been proposed as a promising target. However, the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational study. Here, seven potential epitopes of Mam-A were disclosed, and a unique epitope was then identified in most types of breast cancers, despite the genotypic heterogeneity. With phage display technology, the epitope was determined to be N-terminal amino acids 42–51 of Mam-A (N42–51). Then, the N42–51 epitope-specific monoclonal antibody, mAb785, was conjugated to poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with therapeutic agents, thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast cancers. The computer simulation of the N42–51 epitope and the mAb785 structures, as well as their interactions, further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.
Highlights
Breast cancer is the leading cause of cancer-related death in women.[1,2,3] Currently, the most classic molecular targets for breast cancers include human epidermal growth factor receptor 2 (HER-2/ neu), oestrogen receptor (ER), and progesterone receptor (PR).[4,5,6,7]due to the heterogeneous molecular alterations in the breast cancer cells, patients with highly aggressive triple-negative breast cancer (TNBC) cannot benefit from HER-2/ER/PR-targeted therapies.[8,9] The development of new targeting strategies, for TNBCs, is urgently needed
Mammaglobin A (Mam-A) was reported to be highly specific to the mammary gland and upregulated in most mammary carcinomas of different genotypes, including TNBCs10-12 and it has been proposed as a promising molecular target for breast cancer therapy.[12,13]
We further explored the feasibility of this targeting immunofluorescent staining of the breast cancer cell ZR75.1, a Mam-A high-expressing cell line,[28] was chosen to determine the system for the delivery of doxorubicin (Dox) to four genotypes of breast cancer cells
Summary
Breast cancer is the leading cause of cancer-related death in women.[1,2,3] Currently, the most classic molecular targets for breast cancers include human epidermal growth factor receptor 2 (HER-2/ neu), oestrogen receptor (ER), and progesterone receptor (PR).[4,5,6,7]due to the heterogeneous molecular alterations in the breast cancer cells, patients with highly aggressive triple-negative breast cancer (TNBC) cannot benefit from HER-2/ER/PR-targeted therapies.[8,9] The development of new targeting strategies, for TNBCs, is urgently needed. Mam-A expression in breast cancers has been investi- cence than NP-treated cells, indicating the enhanced uptake of gated by different groups, with an upregulation rate of 40% to more than 90%.11,29,30 The above results from different mAb
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