Abstract
Tumor-targeting nanomaterial-based chemotherapeutic drug delivery systems have been shown to represent an efficacious approach for the treatment of cancer because of their stability in blood circulation and predictable delivery patterns, enhanced tumor-selective drug accumulation, and decreased toxicity to normal tissues. The cell-surface transmembrane glycoprotein CD44 binds to the extracellular domain of hyaluronic acid (HA), and is overexpressed in breast, ovarian, lung, and stomach cancer. In this study, an HA-based nano-carrier incorporating doxorubicin (DOX) and cisplatin (CDDP) was synthesized as a CD44-targeting anti-cancer drug delivery system, and its tumor inhibition effects against CD44+ breast cancer cells were evaluated in vitro and in vivo. These dual drug-loaded HA micelles (HA-DOX-CDDP) exhibited significantly enhanced drug release under acidic conditions, and showed higher cellular uptake and stronger cellular growth inhibition than free drugs against 4T1 (CD44+) breast cancer cells. In contrast, no significant differences in growth inhibition and cellular uptake were observed between HA-DOX-CDDP and free drugs in NIH-3T3 (CD44-) control cells. Furthermore, HA-DOX-CDDP micelles exhibited stronger inhibitory effects and lower systemic toxicity than free drugs in a 4T1 mammary cancer-bearing mouse model, as determined using immunofluorescence and histological analyses. Therefore, HA-DOX-CDDP micelles represent a promising drug delivery system that exhibits acid-sensitive drug release, CD44-targeted delivery, and excellent biocompatibility and biodegradation. These properties resulted in excellent tumor accumulation and reduced adverse effects, indicating that HA-DOX-CDDP micelles have promising potential applications in chemotherapy for breast cancer.
Highlights
Breast cancer is the most serious threat to female health globally because of the associated high morbidity, poor prognosis, and limited availability of effective therapies
The relative smaller size from transmission electron microscopy (TEM) detection should be attributed shrinking of nanoparticles during preparing the samples for TEM detection (Figure 1C)
The stability and pH-sensitivity of HADOX-CDDP were verified at pH 7.4, 6.8, and 5.5 in our study to simulate normal physiological microenvironments, acidic tumor tissue, and lysosomal microenvironments, respectively (Fan et al, 2015; Cheng et al, 2019)
Summary
Breast cancer is the most serious threat to female health globally because of the associated high morbidity, poor prognosis, and limited availability of effective therapies. The development of targeted anticancer drug delivery systems with low toxicity and good biocompatibility is critical to improve the efficacy of breast cancer chemotherapy. Previous studies have shown that polymeric nanoparticles (NPs) can be surface-engineered to act as drug delivery vehicles to improve biocompatibility, increased cellular uptake, and specific tumor targeting, which may result in targeted drug delivery and reduced adverse effects (Bahrami et al, 2017; Mu et al, 2017; Parashar et al, 2018). Previous studies show that HA can be used as tumor site-specific drug delivery vehicle towing to its high binding affinity for the CD44 receptor (a member of the cell adhesion protein family), which is over-expressed on the surface of various carcinoma cells, including breast cancer (Louhichi et al, 2018) and lung cancer (Mattheolabakis et al, 2015). HA-modified nanoparticles or micelles are promising as potential carriers for CD44-targeted chemotherapeutic agents
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