Silencing of IL-6 and STAT3 by siRNA loaded hyaluronate-N,N,N-trimethyl chitosan nanoparticles potently reduces cancer cell progression.

Abstract

The immunosuppressive nature of the tumor microenvironment is a critical problem that should be considered before the design of immunotherapies. Interleukin (IL)-6 and its related downstream molecules such as signal transducer and activator of transcription (STAT)3 play an important role in the cancer progression, which can be considered as potential therapeutic targets. In the present study, we generated the active-targeted hyaluronate (HA) recoated N, N, N-trimethyl chitosan (TMC) nanoparticles (NPs) to deliver IL-6- and STAT3-specific small interfering RNAs (siRNAs) to the CD44-expressing cancer cells. We utilized the interaction between HA and CD44 to increase the specificity and efficacy of cellular uptake in NPs. The results showed that the synthesized NPs had efficient physicochemical characteristics, high transfection efficiency, low toxicity, and controlled siRNA release. siRNA-loaded NPs significantly inhibited the IL-6/STAT3 expression, which was associated with blockade of proliferation, colony formation, migration, and angiogenesis in cancer cells. These findings imply the potential of HA-TMC NPs as potent vectors in gene therapy and their application for the silencing of IL-6 and STAT3, as a novel anti-cancer combination therapeutic strategy, for the first time.

• Authors: Ali Masjedi, Armin Ahmadi, Fatemeh Atyabi, Shohreh Farhadi, Mahzad Irandoust, Yalda Khazaei-Poul, Mitra Ghasemi Chaleshtari, Mahdi Edalati Fathabad, Masoumeh Baghaei, Navideh Haghnavaz, Behzad Baradaran, Mohammad Hojjat-Farsangi, Ghasem Ghalamfarsa, Gholamabas Sabz, Sajad Hasanzadeh, Farhad Jadidi-Niaragh
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 149 Pg. 487-500 (Apr 15 2020) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 32004600 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• CD44 protein, human
• Hyaluronan Receptors
• Interleukin-6
• N-trimethyl chitosan chloride
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• Hyaluronic Acid
• Chitosan

Topics

• Breast Neoplasms (genetics, pathology, therapy)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chitosan (chemistry, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hyaluronan Receptors (genetics)
• Hyaluronic Acid (chemistry)
• Interleukin-6 (antagonists & inhibitors, genetics)
• Nanoparticles (chemistry)
• Neovascularization, Pathologic (genetics, pathology, therapy)
• RNA, Small Interfering (chemistry, genetics, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics)
• Tumor Microenvironment (drug effects)