Abstract
Strategies for treating brain metastases of breast cancer have demonstrated limited efficacy due to the blood–brain barrier (BBB). Gene therapy could improve the efficacy of chemotherapeutic drugs. Exosomes derived from the mesenchymal stem cells (MSCs) are small membrane-based gene vectors that can pass through the BBB. CXCR4 is the most commonly found chemokine receptor in human cancer cells. Furthermore, the SDF-1/CXCR4 axis plays an important role in the homing of MSCs for tumor cell diffusion and metastasis. TRAIL can selectively induce apoptosis in transformed cells without significant toxic side effects in normal tissues. In this study, exosomes were isolated from MSCCXCR4+TRAIL transduced with CXCR4 and TRAIL using a lentiviral vector. Synergistic antitumor study showed that exosomeCXCR4+TRAIL exerted significant activity as a cooperative agent with carboplatin in an MDA-MB-231Br SCID mouse model, potentially engendering a novel strategy for advancing the treatment of brain metastases of breast cancer. Based on this study, further investigation of the effect of the vector on BBB and inducing apoptosis of brain tumors is warranted. In addition, the safety of the vector in animals during the treatment needs to be evaluated.
Highlights
Brain metastasis has become the hot spot in the treatment of breast cancer due to its high morbidity, aggressiveness, and inaccessibility
To evaluate CXCR4 expression, the fluorescence of MSCCXCR4 transduced by lentivirus containing CXCR4 and GFP (LVCXCR4) was observed under fluorescent micrographs, with mesenchymal stem cells (MSCs) transduced by the lentivirus containing GFP (LVGFP) as the positive control group
The results revealed that CXCR4 and TRAIL were transduced into ExoCXCR4+TRAIL
Summary
Brain metastasis has become the hot spot in the treatment of breast cancer due to its high morbidity, aggressiveness, and inaccessibility. More than a quarter of breast cancer patients develop brain metastasis [1]. Considering the high risk of surgery and the apparent neurotoxicity of brain radiotherapy, the use of chemotherapy, such as carboplatin, which is a firstline drug used in metastatic breast cancer therapy, is beneficial for treating orthotopic brain tumor, and brain metastases [2]. Rapid drug clearance by the mononuclear phagocyte system (MPS) and toxicity of the nanoparticles have frequently been observed [6]. Polyethylene glycol is used to decrease drug uptake by the MPS, this can still result in reduced interaction among the target cells, which
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