Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth

Hendrik Setia Budi; Sepideh Izadi; Anton Timoshin; Sima Heydarzadeh Asl; Behzad Beyzai; Amir Ghaderpour; Fatemeh Alian; Farzaneh Sadat Eshaghi; Seyedeh Mahboubeh Mousavi; Behnam Rafiee; Afshin Nikkhoo; Armin Ahmadi; Hadi Hassannia; Majid Ahmadi; Mozhdeh Sojoodi; Farhad Jadidi-Niaragh

doi:10.1016/j.nano.2021.102373

Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth

Nanomedicine. 2021 Jun:34:102373. doi: 10.1016/j.nano.2021.102373. Epub 2021 Mar 3.

Authors

Hendrik Setia Budi¹, Sepideh Izadi², Anton Timoshin³, Sima Heydarzadeh Asl⁴, Behzad Beyzai⁴, Amir Ghaderpour⁵, Fatemeh Alian⁶, Farzaneh Sadat Eshaghi⁷, Seyedeh Mahboubeh Mousavi⁴, Behnam Rafiee⁸, Afshin Nikkhoo⁴, Armin Ahmadi⁹, Hadi Hassannia¹⁰, Majid Ahmadi¹¹, Mozhdeh Sojoodi¹², Farhad Jadidi-Niaragh¹³

Affiliations

¹ Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
² Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
³ I.M. Sechenov First Moscow State Medical University (Sechenov University), Department of propaedeutics of dental diseases, Moscow, Russia.
⁴ Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
⁵ Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
⁶ Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
⁷ Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
⁸ Department of Pathobiology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.
⁹ iepartment of Chemical and Materials Engineering, The University of Alabama in Huntsville, AL, USA.
¹⁰ Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
¹¹ Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
¹² Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, USA.
¹³ Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: [email protected].

PMID: 33667724
DOI: 10.1016/j.nano.2021.102373

Abstract

HIF-1α and STAT3 are two of the critical factors in the growth, proliferation, and metastasis of cancer cells and play a crucial role in inhibiting anti-cancer immune responses. Therefore, we used superparamagnetic iron oxide (SPION) nanoparticles (NPs) coated with thiolated chitosan (ChT) and trimethyl chitosan (TMC) and functionalized with hyaluronate (H) and TAT peptide for delivery of siRNA molecules against STAT3 and HIF-1α to cancer cells both in vivo and in vitro. The results indicated that tumor cell transfection with siRNA-encapsulated NPs robustly inhibited proliferation and migration and induced apoptosis in tumor cells. Furthermore, simultaneous silencing of HIF-1α and STAT3 significantly repressed cancer development in two different tumor types (4T1 breast cancer and CT26 colon cancer) which were associated with upregulation of cytotoxic T lymphocytes and IFN-γ secretion. The findings suggest inhibiting the HIF-1α/STAT3 axis by SPION-TMC-ChT-TAT-H NPs as an effective way to treat cancer.

Keywords: Chitosan; Hyaluronate; Hypoxia inducible factor; Nanoparticle; SPION; STAT3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / pathology*
Cell Line, Tumor
Cell Proliferation*
Chitosan / chemistry*
Colonic Neoplasms / pathology*
Female
Humans
Hyaluronic Acid / chemistry*
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Magnetic Iron Oxide Nanoparticles / administration & dosage*
Magnetic Iron Oxide Nanoparticles / chemistry
Mice
Mice, Inbred BALB C
RNA, Small Interfering / administration & dosage*
STAT3 Transcription Factor / antagonists & inhibitors*

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Small Interfering
STAT3 Transcription Factor
STAT3 protein, human
Hyaluronic Acid
Chitosan