Journal
ADVANCED FUNCTIONAL MATERIALS
Volume 28, Issue 28, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201801118
Keywords
combination treatment; doxorubicin; mesoporous silica nanoparticles; miRNA-145; orthotopic colorectal cancer model
Categories
Funding
- National Natural Science Foundation of China [81572998, 81602729, 81773274]
- Shanghai Municipal Science and Technology Commission [16520710700]
- Shu Guang Program of Shanghai Education Development Foundation
- Shu Guang Program of Shanghai Municipal Education Commission [16SG13]
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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.
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