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Polyethylene Glycol-Encapsulated Histone Deacetylase Inhibitor Drug-Composite Nanoparticles for Combination Therapy with Artesunate.

ABSTRACT: Combination drug therapy has become an effective clinical practice for cancer treatment because of low cytotoxicity by the synergistic effect of each medicine. Luminescent Au nanoclusters (Au NCs) were formulated into spherical polyethylene glycol (PEG)-Au NC-encapsulated drug-sodium butyrate (NaB) composite nanoparticles (PEG-Au NC-NaB-NPs) in the presence of PEG and NaB. Their effect on cancer cells was investigated using bio imaging, unravelling the mechanism of the endocytosis pathway and combination therapeutic interventions with a plant-based antimalarial drug artesunate (ART). PEG-Au NC-NaB-NPs showed bright red luminescence in the lysosomal compartment of the cells upon uptake predominantly through a caveolae-mediated pathway. Combination of PEG-Au NC-NaB-NPs with ART displayed enhanced therapeutic activity at a reduced dose compared to its individual doses and revealed heightened synergistic activity as identified from the combination index. The mechanism of synergism revealed elevated generation of reactive oxygen species with both NaB and ART, which disrupts mitochondrial membrane potential as evident from JC-1 staining. Remarkably, the histone deacetylase (HDAC) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling assay enlightened the role of NaB and ART in HDAC inhibition and DNA fragmentation, respectively. Thus, induction of apoptosis with the synergistic effect of both NaB and ART with its meticulous mechanism makes it a promising tool for combinational cancer therapy. In vivo activity of the NPs was evaluated on Daltons lymphoma ascites bearing mice, which exhibited significant reduction of tumor volume and viable tumor cells with a prolonged life span.

SUBMITTER: Goswami U

PROVIDER: S-EPMC6173507 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Polyethylene Glycol-Encapsulated Histone Deacetylase Inhibitor Drug-Composite Nanoparticles for Combination Therapy with Artesunate.

Goswami Upashi U Kandimalla Raghuram R Kalita Sanjeeb S Chattopadhyay Arun A Ghosh Siddhartha Sankar SS

ACS omega 20180920 9

Combination drug therapy has become an effective clinical practice for cancer treatment because of low cytotoxicity by the synergistic effect of each medicine. Luminescent Au nanoclusters (Au NCs) were formulated into spherical polyethylene glycol (PEG)-Au NC-encapsulated drug-sodium butyrate (NaB) composite nanoparticles (PEG-Au NC-NaB-NPs) in the presence of PEG and NaB. Their effect on cancer cells was investigated using bio imaging, unravelling the mechanism of the endocytosis pathway and co ...[more]

PMID: 30320264

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Project description:BackgroundThe emergence of cancer immunotherapies, notably immune checkpoint inhibitors, has revolutionized anti-cancer treatments. These treatments, however, have been reported to be effective in a limited range of cancers and cause immune-related adverse effects. Thus, for a broader applicability and enhanced responsiveness to solid tumor immunotherapy, immunomodulation of the tumor microenvironment is crucial. Transforming growth factor-β (TGF-β) has been implicated in reducing immunotherapy responsiveness by promoting M2-type differentiation of macrophages and facilitating cancer cell metastasis.MethodsIn this study, we developed macrophage membrane-coated nanoparticles loaded with a TGF-βR1 kinase inhibitor, SD-208 (M[Formula: see text]-SDNP). Inhibitions of M2 macrophage polarization and epithelial-to-mesenchymal transition (EMT) of cancer cells were comprehensively evaluated through in vitro and in vivo experiments. Bio-distribution study and in vivo therapeutic effects of M[Formula: see text]-SDNP were investigated in orthotopic breast cancer model and intraveneously injected metastasis model.ResultsM[Formula: see text]-SDNPs effectively inhibited cancer metastasis and converted the immunosuppressive tumor microenvironment (cold tumor) into an immunostimulatory tumor microenvironment (hot tumor), through specific tumor targeting and blockade of M2-type macrophage differentiation. Administration of M[Formula: see text]-SDNPs considerably augmented the population of cytotoxic T lymphocytes (CTLs) in the tumor tissue, thereby significantly enhancing responsiveness to immune checkpoint inhibitors, which demonstrates a robust anti-cancer effect in conjunction with anti-PD-1 antibodies.ConclusionCollectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M[Formula: see text]-SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy.

Dataset Information

Polyethylene Glycol-Encapsulated Histone Deacetylase Inhibitor Drug-Composite Nanoparticles for Combination Therapy with Artesunate.

Publications

Polyethylene Glycol-Encapsulated Histone Deacetylase Inhibitor Drug-Composite Nanoparticles for Combination Therapy with Artesunate.

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