Abstract
The human breast adenocarcinoma cell line MDA-MB-231 has the triple-negative breast cancer (TNBC) phenotype, which is an aggressive subtype with no specific treatment. MDA-MB-231 cells express neurotensin receptor type 1 (NTSR1), which makes these cells an attractive target of therapeutic genes that are delivered by the neurotensin (NTS)-polyplex nanocarrier via the bloodstream. We addressed the relevance of this strategy for TNBC treatment using NTS-polyplex nanoparticles harboring the herpes simplex virus thymidine kinase (HSVtk) suicide gene and its complementary prodrug ganciclovir (GCV). The reporter gene encoding green fluorescent protein (GFP) was used as a control. NTS-polyplex successfully transfected both genes in cultured MDA-MB-231 cells. The transfection was demonstrated pharmacologically to be dependent on activation of NTSR1. The expression of HSVtk gene decreased cell viability by 49% (P<0.0001) and induced apoptosis in cultured MDA-MB-231 cells after complementary GCV treatment. In the MDA-MB-231 xenograft model, NTS-polyplex nanoparticles carrying either the HSVtk gene or GFP gene were injected into the tumors or via the bloodstream. Both routes of administration allowed the NTS-polyplex nanoparticles to reach and transfect tumorous cells. HSVtk expression and GCV led to apoptosis, as shown by the presence of cleaved caspase-3 and Apostain immunoreactivity, and significantly inhibited the tumor growth (55–60%) (P<0.001). At the end of the experiment, the weight of tumors transfected with the HSVtk gene was 55% less than that of control tumors (P<0.05). The intravenous transfection did not induce apoptosis in peripheral organs. Our results offer a promising gene therapy for TNBC using the NTS-polyplex nanocarrier.
Highlights
The targeted gene delivery by synthetic nanoparticles has a potential application for the treatment of aggressive forms of breast cancer, which is the leading cause of cancer deaths among women worldwide [1]
neurotensin receptor type 1 (NTSR1) internalization, which is overactive in cancer cells [11], has become an efficient pathway to introduce therapeutic genes that are intravenously delivered by the NTSpolyplex nanoparticles as we previously demonstrated in a murine neuroblastoma model [24]
NTS-polyplex nanoparticles result from the compaction of pEGFP-N1 or pORF-herpes simplex virus thymidine kinase (HSVtk) plasmids via the electrostatic binding of the Vp1 SV40 karyophilic peptide (KP) and the NTS-carrier, which is a conjugate of poly-L-lysine, NTS, and the hemagglutinin-derived HA2 fusogenic peptide (FP) [25,30]
Summary
The targeted gene delivery by synthetic nanoparticles has a potential application for the treatment of aggressive forms of breast cancer, which is the leading cause of cancer deaths among women worldwide [1]. The delivery of therapeutic nanoparticles can be advantageously oriented with the presence of ligands that target an overexpressed or selectively expressed receptor in breast cancer cells. TNBC is relatively sensitive to chemotherapy, the lack of a specific treatment presents a poor prognosis to TNBC patients, which present a high risk of relapse within 3 years of diagnosis and an increased mortality rate 5 years after diagnosis [8,9,10]. These issues have prompted the development of more effective therapies against TNBC
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