Development Of SiRNA Delivery System Based On Silica Nanopartciles For Cancer Therapy

Mesoporous silica nanoparticles（MSNs） have emerged as one of the most promising chemotherapeutics/protein/nucleic carriers due to their noticeable advantages which including large surface area, pore-size tunability, modifiability and biocompatibility. However, there is still much room to improve the anticancer efficacy using M-MSNs-based si RNA vectors in vivo applications.In this study, we described the effective M-MSN_si RNA@PEIKALA nanocarrier that processed high effectivness of tumor inhibition via intratumoral injection. In view of this M-MSNs-based delivery system, we further introduced the biocompatible macromolecules, polyethylene glycol（PEG）, to construct the M-MSN_si RNA@PEI-PEG-KALA vector, which was capable of treating various tumor models or types via intravenous administration. Later, we developed a novel and fast condelivery system of si RNA and Doxorubicin via self-assembly inorganic silica nanoparticles for drug-resistant cancer therapy synergistically.First of all, we captured the most efficient si RNA that complementary to human VEGF m RNA, firstly. Then, obtained si RNA were encapsulated into M-MSN_si RNA@PEI-KALA nanocarrier that could produce remarkable target gene silencing efficacy in A549 cells（human alveolar basal epithelial cell line）. By targeting VEGF, we further demonstrated that M-MSN_VEGF si RNA@PEI-KALA was highly effective inhibition of A549 xenograft growth by decreased VEGF protein contents in tumor, with reduced angiogenesis, overall leading to tumor suppression. Unfortunately, M-MSN_si RNA@PEI-KALA delivery system was not suitable for systemic administration owing to their aggregation in saline.Then, we presented a new version of M-MSN-based si RNA delivery vector builted on M-MSN_si RNA@PEI-KALA by introducing PEG that born with stereo-hindrance effect and biocompatibility. The achieved M-MSN_si RNA@PEI-PEG-KALA nanovector had improved monodispersity in saline, with highly biocompatible to tumor cells, normal somatic cells and red blood cells, and exhibited excellent down-regulation of targeted gene. This nanocarrier also could prolong their half-life in circulation and resulted in better accumulation in tumor region. We further demonstrated the highly effective inhibition of tumor growth in both the subdermal and orthotopic models of lung cancers（A549 cell line）, while the the secondary tumor site in liver from metastatic lung cancer cells was also significant repressed. Meanwhile, M-MSN_si RNA@PEI-PEG-KALA was observed biocompatibility and biosafety in mice after five repeated injections. In addition, the magnetic property of this nanocarrier could serve as excellent T2 contrast agent for a wide range of in vivo applications including detection of the tumor site, and optimization of dose or therapy window to improve the anticancer efficacy. Taken together, this M-MSN-based nanocarrier provide a promising platform for theranostics applications.For more efficacious anti-cancer efficacy in combination of various modules, we developed a novel and fast codelivery system of si RNA and Doxorubicin via self-assembly inorganic silica nanoparticles. A physical interaction that Doxorubicin preferentially binding to GC sequences in si RNA to form si RNA&Doxorubicin complex, which could be used as templates for synthesizing silica-based si RNA and Doxorubicin codelivery vector by introducing co-structure-directing agent（CSDA） and inorganic silicon successively. The final achieved nanocarrier denoted as si RNA&Doxorubicin@Si O₂. Si RNA and Doxorubicin were encapsulated into this vector with high loading capacities and their own biological functions were not interfered, respectively. Transfected MDR-1 si RNA&Doxorubicin@Si O₂ into MCF-7/MDR cells could improve their sensitivity to Doxorubicin, overall leading to enhanced the chemotherapeutic cytotoxicity.