Abstract
Triple-negative breast cancer (TNBC) is a highly malignant tumor. At present, there are still no targeted drugs for TNBC. Clinical chemotherapeutic drugs, such as doxorubicin (DOX), have the characteristic of nontargeted distribution in treatment of TNBC, causing severe side effects. Therefore, new target treatment strategies for TNBC are of urgent need. It was speculated that glutamine could be a potential target because it is in high demand by TNBC. In this study, we found that the transporter for glutamine, ASCT2 (solute carrier family 1 member 5 (SLC1A5)), is highly expressed in TNBC by analysis of data from The Cancer Genome Atlas (TCGA) and experiments in vitro. Based on this, glutamine was grafted onto a polymeric drug carrier in order to develop a tumor-targeting drug delivery system for treatment of TNBC. Firstly, pH-responsive glutamine-PEG5000-b-PAE10000 (Gln-PEG-b-PAE) copolymers were synthesized using Fmoc-PEG5000-b-PAE10000 (Fmoc-PEG-b-PAE) copolymers. Then, Gln-PEG-b-PAE@DOX micelles were prepared by loading DOX to Gln-PEG-b-PAE copolymer using a solvent casting technology. In vitro, Gln-PEG-b-PAE@DOX micelles exhibited pH-dependent micellization-decellularization behavior; namely, they can rapidly release DOX in acidic environment of pH 6.0 but release very slowly in physiological condition. Moreover, glutamine competition experiment showed that Gln-PEG-b-PAE@DOX micelles had the ability to target MDA-MB-231 cells. Compared to free DOX, Gln-PEG-b-PAE@DOX micelles had significantly greater cytotoxic effect and antiproliferative activity against MDA-MB-231 cells. In vivo, compared to free DOX and mPEG-b-PAE@DOX micelles, Gln-PEG-b-PAE@DOX micelles significantly inhibited tumor growth in tumor-bearing mice. Therefore, Gln-PEG-b-PAE@DOX micelles, as a tumor-targeting drug delivery system, may provide a new method for the treatment of TNBC.
Highlights
Triple-negative breast cancer (TNBC), lacking immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PgR), and human epithelial growth factor 2 (HER2), is the notorious subtype of breast cancer with highly aggressive and lethal behavior
Survival analysis showed that the overall survival (OS) of patients with high SLC1A5 expression was significantly lower compared to that of patients with low SLC1A5 expression (p = 0:048) (see Figure 1(a)), indicating that high expression of SLC1A5 is a poor prognostic factor for breast cancer patients, making SLC1A5 a potential therapeutic target in the treatment of breast cancer
We observed that SLC1A5 was markedly highest in TNBC cell lines compared with other cell lines, especially in the luminal A and luminal B cell lines (see Figure 1(c))
Summary
Triple-negative breast cancer (TNBC), lacking immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PgR), and human epithelial growth factor 2 (HER2), is the notorious subtype of breast cancer with highly aggressive and lethal behavior. DOX is always used limitedly due to the toxicity and some severe side effects, especially cardiotoxicity [1, 2]. Tumor-targeting drug delivery methods were studied to address this deficiency. More and more attention has been paid to tumor-targeting drug delivery methods to increase the availability of chemotherapeutic drugs targeting on reducing toxic side effects [3, 4]. Polymeric micelles are a series of the most promising carriers to realize the precise tumor-targeted therapy and have attracted much attention in drug delivery research [8]. The unique pH-dependent structure of the pH-responsive polymeric micelles is disrupted due to Journal of Nanomaterials the tumoral acidic pH, making the loaded drug more accumulate in tumor tissue than normal tissue [9, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
