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PEGylated lipid bilayer-supported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi-targeted cancer therapy

Paper ID Volume ID Publish Year Pages File Format Full-Text
10 3 2016 12 PDF Available
Title
PEGylated lipid bilayer-supported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi-targeted cancer therapy
Abstract

Small-molecule drug combination therapies are an attractive approach to enhancing cancer chemotherapeutic responses. Therefore, this study aimed to investigate the potential of axitinib (AXT) and celastrol (CST) in targeting angiogenesis and mitochondrial-based apoptosis in cancer. Therefore, we prepared AXT/CST-loaded combination nanoparticles (ACML) with CST loaded in the mesoporous silica nanoparticles (MSN) and AXT in PEGylated lipidic bilayers. We showed that ACML effectively inhibited angiogenesis and mitochondrial function and was efficiently internalized in SCC-7, BT-474, and SH-SY5Y cells. Furthermore, hypoxia-inducible factor (HIF)-1α expression, which increased under hypoxic conditions in all cell lines exposed to ACML, markedly decreased, which may be critical for tumor inhibition. Western blotting showed the superior anticancer effect of combination nanoparticles in different cancer cells. Compared to the cocktail (AXT/CST), ACML induced synergistic cancer cell apoptosis. The AXT/CST-based combination nanoparticle synergism might be mediated by AXT, which controls vascular endothelial growth factor receptors while CST acts on target cell mitochondria. Importantly, ACML-treated mice showed remarkably higher tumor inhibition (64%) than other groups did in tumor xenograft models. Tumor xenograft immunohistochemistry revealed elevated caspase-3 and poly (ADP-ribose) polymerase and reduced CD31 and Ki-67 expression, clearly suggesting tumor apoptosis through mitochondrial and antiangiogenic effects. Overall, our results indicate that ACML potentially inhibited cell proliferation and induced apoptosis by blocking mitochondrial function, leading to enhanced antitumor efficacy.Statement of SignificanceIn this research, we formulated an anticancer drug combination nanoparticle loaded with axitinib (AXT) in the lipidic bilayer of PEGylated liposomes and celastrol (CST) in mesoporous silica nanoparticles. The anticancer effects of the AXT/CST-loaded combination nanoparticle (ACML) were synergistic and superior to the other formulations and involved more efficient drug delivery to the tumor site with enhanced effects on angiogenesis and mitochondrial function. Therefore, our study demonstrated that the inhibition of cell proliferation and induction of apoptosis by ACML, which was mediated by blockade of mitochondrial function and anti-angiogenesis, led to enhanced antitumor efficacy, which may be potentially useful in the clinical treatment of cancer.

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Keywords
Axitinib; Celastrol; Mitochondria; Mesoporous silica nanoparticle; Lipid
First Page Preview
PEGylated lipid bilayer-supported mesoporous silica nanoparticle composite for synergistic co-delivery of axitinib and celastrol in multi-targeted cancer therapy
Publisher
Database: Elsevier - ScienceDirect
Journal: Acta Biomaterialia - Volume 39, 15 July 2016, Pages 94–105
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering