Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression.,Pharmaceutical Research

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Codelivery of HIF-1α siRNA and Dinaciclib by Carboxylated Graphene Oxide-Trimethyl Chitosan-Hyaluronate Nanoparticles Significantly Suppresses Cancer Cell Progression.
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-09-17 , DOI: 10.1007/s11095-020-02892-y
Sepideh Izadi _{1,

2} , Asma Moslehi ₁ , Hadiseh Kheiry ₃ , Fariba Karoon Kiani ₁ , Armin Ahmadi ₄ , Ali Masjedi ₅ , Sepideh Ghani ₆ , Behnam Rafiee ₇ , Vahid Karpisheh ₁ , Farnaz Hajizadeh ₁ , Fatemeh Atyabi ₈ , Akram Assali ₈ , Farnaz Sadat Mirzazadeh Tekie ₉ , Afshin Namdar ₁₀ , Ghasem Ghalamfarsa ₁₁ , Mozhdeh Sojoodi ₁₂ , Farhad Jadidi-Niaragh _{1,

13}

Affiliation

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran.
Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, Huntsville, Alabama, 35899, USA.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Department of radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, Alberta, Canada.
Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, USA.
Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

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.

中文翻译：

通过羧化氧化石墨烯-三甲基壳聚糖-透明质酸盐纳米颗粒共同递送 HIF-1α siRNA 和 Dinaciclib 可显着抑制癌细胞进展。

目的

缺氧诱导因子 (HIF) 是参与肿瘤发展的肿瘤微环境的关键成分之一。HIF-1α 在功能上和物理上与 CDK1、2 和 5 相互作用，并刺激细胞周期进程和细胞周期蛋白依赖性激酶 (CDK) 表达。因此，低氧肿瘤微环境和 CDK 过度表达导致细胞周期进展和肿瘤扩张增加。因此，我们决定通过阻断 HIF-1α 和 CDK 分子来抑制癌细胞扩张。

方法

在本研究中，我们使用羧化氧化石墨烯 (CGO) 与三甲基壳聚糖 (TMC) 和透明质酸盐 (HA) 纳米颗粒 (NPs) 结合，负载 HIF-1α-siRNA 和 Dinaciclib，CDK 抑制剂，用于沉默 HIF-1α 和阻断表达 CD44 的癌细胞中的 CDK，并评估联合治疗对增殖、转移、细胞凋亡和肿瘤生长的影响。