pH-Responsive mineralized nanoparticles as stable nanocarriers for intracellular nitric oxide delivery

Yung

Journal of Controlled Release

et al. 2017

173

119

Chemotherapeutic drugs have made significant contributions to anticancer therapy, along with other therapeutic methods including surgery and radiotherapy over the past century. However, multidrug resistance (MDR) of cancer cells has remained as a significant obstacle in the achievement of efficient chemotherapy. Recently, there has been increasing evidence for the potential function of nitric oxide (NO) to overcome MDR. NO is an endogenous and biocompatible molecule, contrasting with other potentially toxic chemosensitizing agents that reverse MDR effects, which has raised expectations in the development of efficient therapeutics with low side effects. In particular, nanoparticle-based drug delivery systems not only facilitate the delivery of multiple therapeutic agents, but also help bypass MDR pathways, which are conducive for the efficient delivery of NO and anticancer drugs, simultaneously. Therefore, this review will discuss the mechanism of nitric oxide (NO) in overcoming MDR and recent progress of combined NO and drug delivery systems.

Section: Progress Of Combined No and Drug Delivery Systemsmentioning

confidence: 99%

Section: Conclusion and Perspectivementioning

confidence: 99%

See 1 more Smart Citation

Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy

Yung

Journal of Controlled Release

et al. 2017

173

119

“…[20] Additionally,t he acidic stimulus can trigger NO release from pH-responsive NO nanomedicines.For example, Lee et al prepared S-nitrosoglutathione (GSNO)-incorporated CaCO 3 -mineralized nanoparticles (GSNO-MNPs) for pH-responsive NO release. [21] Owing to the protection by the crystalline CaCO 3 core,t he stability of GSNO was greatly improved in the neutral aqueous phase.However,CaCO 3 was easily dissolved within the acidic organelles to accelerate the release of GSNO,w hich could react with reductive ascorbic acid to generate NO ( Figure 1a). As clearly shown in Figure 1b,a bout 85.3 %o fNO was released from GSNO at acidic pH (ca.…”

Section: Phmentioning

confidence: 99%

Stimuli‐Responsive NO Release for On‐Demand Gas‐Sensitized Synergistic Cancer Therapy

2018

Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state-of-the-art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli-responsive NO-releasing nanomedicines and their biomedical applications for on-demand NO-sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area.

“…The iNOS-MNPs were fabricated using a PEG-PAsp-templated CaCO 3 mineralization approach developed in our laboratory [29]. The addition of Ca 2+ and CO 3 2-ions to a stirred solution of PEG-PAsp induced ionic supersaturation around the anionic moieties of the PAsp blocks.…”

Section: Fabrication and Characterization Of Inos-loaded Mineralized mentioning

confidence: 99%

Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells

Lee¹,

Lee²,

Lee³

et al. 2018

Cell Physiol Biochem

Background/Aims: This study investigated the effect of inducible nitric oxide synthase-loaded mineralized nanoparticles (iNOS-MNPs) on the osteogenic differentiation of mouse embryonic stem cells (ESCs). Methods: We prepared iNOS-MNPs using an anionic block copolymer template-mediated calcium carbonate (CaCO₃) mineralization process in the presence of iNOS. iNOS-MNPs were spherical and had a narrow size distribution. iNOS was stably loaded within MNPs without denaturation. In order to confirm the successful introduction of iNOS-MNPs into the cytosol of ESCs, intracellular levels of nitric oxide (NO) was determined with a fluorometric analysis. A NO effector molecule, cyclic guanosine 3’,5’ monophosphate (cGMP) was also quantified with a competitive enzyme immunoassay. Cell viability in response to iNOS-MNP treatment was determined using the cell counting kit-8 (CCK-8) assay. Alkaline phosphatase (ALP) activity assay, intracellular calcium quantification assay, and Alizarin red S staining for matrix mineralization were performed to investigate osteogenic differentiation of ESCs. The protein levels of Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osterix (OSX) as osteogenic-related factors were also assessed by immunofluorescence staining and Western blot analysis. The complex pathways associated with iNOS-MNP-derived osteogenic differentiation of ESCs were evaluated by network-based analysis. Results: Cells with iNOS-MNPs displayed a significant increase in NO and cGMP concentration compared with the control group. When cells were exposed to iNOS-MNPs, there were no adverse effects on cell viability. Importantly, iNOS-MNP uptake promoted the osteogenic differentiation of ESCs. Using transcriptome profiling, we obtained 1,836 differentially-induced genes and performed functional enrichment analysis with ClueGO and KEGG. These analyses identified significantly enriched and interconnected molecular pathways such as protein kinase activity, estrogen receptor activity, bone morphogenetic protein (BMP) receptor binding, ligand-gated ion channel activity, and phosphatidylinositol 3-phosphate binding. Conclusion: These findings suggest that iNOS-MNPs can induce osteogenic differentiation in ESCs by integrating complex signaling pathways.