Integrated Combination Treatment Using a “Smart” Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model

Abstract

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.

Unique SiO2 Nanourchins Enable Amplification in Living Cells for In Situ Imaging of mRNAs

“…Synthesis of SNUs—Synthesis of NH 2 ‐Modified MSNs : According to a previous report, the MSN surfaces were amino‐functionalized by APTES. Briefly, 1 mL of MSNs was dispersed in 4 mL ethanol, and 10 µL of APTES was added into the solution and allowed to react for 3 h under stirring at room temperature.…”

“…Herein, unique two‐pronged SiO 2 nanourchins (SNUs) were synthesized, exploiting the unique structural and biodegradable features of functionalized mesoporous silica nanospheres (MSNs), to achieve efficient reagents delivery with a low toxicity. Further, given their high loading capacity, efficient activity without any spatial mutual interference, sufficient delivery of nucleic acid reagents into cells, and sustainable reactivity, SNUs were employed for the intracellular amplification for in situ imaging of mRNAs in living cells.…”

Targeting of CXCR1 on Osteosarcoma Circulating Tumor Cells and Precise Treatment via Cisplatin Nanodelivery

“…Pulmonary metastasis in this orthotopic OS model was also evaluated using bioluminescence imaging and histopathological observation at day 30. The bioluminescence imaging approach is thought to be sufficiently sensitive and able to detect as few as 100 tumor cells in vitro, and thus, tiny metastases that cannot be tracked by the naked eye can be captured . As shown in Figure e, all the mice in the saline group and peptide group had obvious metastases in the lung, while pulmonary metastasis was inhibited after treatment with Cis, Cis plus peptide, and Cis@MFPP.…”

Sol–Gel‐Based Advanced Porous Silica Materials for Biomedical Applications

“…Fang and co-workers constructed a colorectal carcinoma SW480 cell targeting system for codelivery of DOX and nucleic acid (miRNA-145). [59] They loaded DOX in the pores of MSNs and grafted electropositive polyethylenimine (PEI) on the surface for miRNA condensation, and further decorated the particle surface with WL8 peptide-capped polyethylene glycol (PEG) to confer to the NPs both stealth and tumor cell targeting properties. WL8 peptide modification increased the NP uptake in SW480 cells by 2.9-fold, while the enhancement in SW480 cells was completely inhibited in the presence of free WL8 peptide, confirming the targeting capability of WL8 in this nanoplatform.…”

“…The biomedical imaging field, which has become the cornerstone of modern oncology, calls for improvements to contrast agents to make faster, more precise and more robust diagnoses. Several in vivo imaging techniques have been shown to be useful for investigations in disease diagnosis and imageguided drug delivery, including magnetic resonance imaging (MRI), [57a,94d] computed tomography (CT), [108] positron emission tomography (PET), [42,109] single photon emission computed tomography (SPECT), [110] and optical imaging (OI) methods such as those based on luminescence or fluorescence, [59] which are often applied in a hybrid manner to yield complementary information. [111] MSNs with tunable mesopores can be applied as a carrier for molecular imaging agents with high loading efficiency, such as aforementioned "Cornell Dots."…”