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Integrated Combination Treatment Using a “Smart” Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model
Author(s) -
Liu HaiJun,
Luan Xin,
Feng HaiYi,
Dong Xiao,
Yang SiCong,
Chen ZhongJian,
Cai QinYi,
Lu Qin,
Zhang Yunpeng,
Sun Peng,
Zhao Mei,
Chen HongZhuan,
Lovell Jonathan F.,
Fang Chao
Publication year - 2018
Publication title -
advanced functional materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.069
H-Index - 322
eISSN - 1616-3028
pISSN - 1616-301X
DOI - 10.1002/adfm.201801118
Subject(s) - doxorubicin , microrna , in vivo , drug delivery , cancer research , cancer cell , small molecule , microvesicles , materials science , cancer , nanotechnology , chemistry , chemotherapy , biology , biochemistry , genetics , microbiology and biotechnology , gene
Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH‐driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by “weaving” polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA‐145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose‐regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of “smart” MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.