Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with...

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Bibliographic Details
Published in:Theranostics 2021-01, Vol.11 (14), p.7005-7017
Main Authors: Bhattarai, Nimisha, Wang, Jieqiong, Nguyen, Daniel, Yang, Xiaoxiao, Helmers, Linh, Paruch, Jennifer, Li, Li, Zhang, Yiwei, Meng, Kun, Wang, Alun, Jayawickramarajah, Janarthanan, Wang, Binghe, Zeng, Shelya, Lu, Hua
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Bioavailability
Biocompatibility
Biological Availability
Calibration
Cancer therapies
Cell cycle
Cell Line, Tumor
Cell Movement - drug effects
Cell Proliferation - drug effects
Colorectal cancer
Colorectal Neoplasms - drug therapy
Efficiency
Fibroblasts
Fourier transforms
Humans
Indoles - chemistry
Indoles - pharmacokinetics
Indoles - pharmacology
Indoles - therapeutic use
Investigations
Lung cancer
Lung Neoplasms - drug therapy
Melanoma
Mice
Mice, Inbred C57BL
Microscopy, Electron, Transmission
Nanoparticles
Nanoparticles - chemistry
Nanoparticles - toxicity
Nanoparticles - ultrastructure
NMR
Nuclear magnetic resonance
Peptides
Phenothiazines - chemistry
Phenothiazines - pharmacokinetics
Phenothiazines - pharmacology
Phenothiazines - therapeutic use
Research Paper
Severe acute respiratory syndrome coronavirus 2
Spectroscopy, Fourier Transform Infrared
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Xenograft Model Antitumor Assays
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Summary:The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C and while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.57404