Abstract
BackgroundTriple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC.ResultsHerein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours.ConclusionBased on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.
Highlights
Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis
The function of hyaluronic acid (HA) on tumour cells is related to its molecular weight, and oligomeric hyaluronic acid (o-HA) with a molecular weight of approximately 2000 Da increases the adhesion of tumour cells and inhibits tumour cell invasion and metastasis [36]
A hydrazone bond was used to connect mPEG and o-HA, followed by the linkage of o-HA and PC through a disulfide bond. mPEG-HA-PC together with phosphatidylcholine (PC), cholesterol and CaP was prepared into a calcium phosphate composite lipid nanosystem (CaP/LNS)
Summary
Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. TNBC is a type of breast cancer that does not express the estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER-2), and accounts for 15–20% of all breast cancers [1, 2]. It always shows strong invasiveness and results in a poor prognosis, because it presents an invasive course in the clinic with a high recurrence rate within 1–3 years and results in high distant metastasis and mortality rates [3,4,5]. The combination of PTX and miR124 may be a superior strategy for the treatment of TNBC
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