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RETRACTED ARTICLE: Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression

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This article was retracted on 11 November 2022

This article has been updated

Abstract

Purpose

Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules.

Methods

In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth.

Results

The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells.

Conclusions

These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo.

The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFβ, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to thank the financial support of Tabriz University of Medical Sciences to perform thiswork (grant number: 61627), and Student Research Committee of Tabriz University of Medical Sciences (grant number: 61345). We are also thankful for the grant provided by the National Institute for Medical Research Development (NIMAD) for performing this study (Grant number: 976852).

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Authors and Affiliations

  1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Sepideh Izadi, Asma Moslehi, Fariba Karoon Kiani, Vahid Karpisheh, Farnaz Hajizadeh & Farhad Jadidi-Niaragh

  2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Sepideh Izadi

  3. Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran

    Hadiseh Kheiry

  4. Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, Huntsville, Alabama, 35899, USA

    Armin Ahmadi

  5. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Ali Masjedi

  6. Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sepideh Ghani

  7. Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran

    Behnam Rafiee

  8. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Atyabi & Akram Assali

  9. Department of radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Farnaz Sadat Mirzazadeh tekie

  10. Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, Alberta, Canada

    Afshin Namdar

  11. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Ghasem Ghalamfarsa

  12. Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, USA

    Mozhdeh Sojoodi

  13. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Farhad Jadidi-Niaragh

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  1. Sepideh Izadi
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Correspondence to Mozhdeh Sojoodi or Farhad Jadidi-Niaragh.

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Izadi, S., Moslehi, A., Kheiry, H. et al. RETRACTED ARTICLE: Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression. Pharm Res 37, 196 (2020). https://doi.org/10.1007/s11095-020-02892-y

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