Blockade of CD73 using siRNA loaded chitosan lactate nanoparticles functionalized with TAT-hyaluronate enhances doxorubicin mediated cytotoxicity in cancer cells both in vitro and in vivo.

Abstract

Chemotherapy drugs are still one of the first treatment options used in many cancers; however, problems such as cytotoxic side effects on normal cells after systemic administration and resistance to treatment have reduced the use of chemotherapeutics day by day. Targeted delivery of these drugs to the tumor site and sensitization of cancer cells to death induced by chemotherapy drugs are ways that can overcome the limitations of the use of these drugs. In this study, we designed and generated a novel nanocarrier composed of chitosan lactate nanoparticles (NPs) functionalized by HIV-1 derived TAT peptide (Transactivating transcriptional activator) and hyaluronate (HA) to deliver CD73 siRNA and doxorubicin to 4T1 and CT26 cancer cells, both in vivo and in vitro, as a novel combinatorial treatment strategy. The CD73 molecule plays a key role in many cancer cell behaviors such as proliferation, angiogenesis, metastasis, imunosuppression, and resistance to chemotherapy. Therefore, we decided to reduce the side effects of DOX by simultaneously transmitting CD73 siRNA and DOX by CL-TAT-HA NPs, increase the susceptibility of cancer cells to DOX-induced cell death, and stimulate anti-tumor immune responses, for the first time. These results indicated that simultaneous transfer of CD73 siRNA and DOX to cancer cells (4 T1 and CT26) increased cell death and inhibited the prolifration and spread of cancer cells. Also, the preferential aggregation of NPs in the tumor microenvironment reduced tumor growh, promoted the survival of tumor-bearing mice, and induced anti-tumor immune responses. These findings indicate that CL-TAT-HA NPs are a good candidate for targeted siRNA/drug delivery to cancer cells and the simultaneous transfer of CD73 siRNA and DOX to cancer cells using this nanocarrier can be used to treat cancer.

• Authors: Armin Mahmoud Salehi Khesht, Vahid Karpisheh, Parisa Sahami Gilan, Lyubov A Melnikova, Angelina Olegovna Zekiy, Mahdis Mohammadi, Mohammad Hojjat-Farsangi, Naime Majidi Zolbanin, Ata Mahmoodpoor, Hadi Hassannia, Leili Aghebati-Maleki, Reza Jafari, Farhad Jadidi-Niaragh
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 186 Pg. 849-863 (Sep 01 2021) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 34245737 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Antibiotics, Antineoplastic
• GPI-Linked Proteins
• Lactates
• RNA, Small Interfering
• chitosan lactate
• tat Gene Products, Human Immunodeficiency Virus
• Doxorubicin
• Hyaluronic Acid
• Chitosan
• 5'-Nucleotidase
• Nt5e protein, mouse

Topics

• 5'-Nucleotidase (genetics, metabolism)
• Animals
• Antibiotics, Antineoplastic (chemistry, pharmacology, toxicity)
• Apoptosis (drug effects)
• Breast Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chitosan (analogs & derivatives, chemistry)
• Colorectal Neoplasms (genetics, metabolism, pathology, therapy)
• Doxorubicin (chemistry, pharmacology, toxicity)
• Drug Compounding
• Female
• GPI-Linked Proteins (genetics, metabolism)
• Hyaluronic Acid (chemistry)
• Lactates (chemistry)
• Mice
• Mice, Inbred BALB C
• Nanoparticles
• Nanotechnology
• Neoplasm Invasiveness
• Neovascularization, Pathologic
• RNA, Small Interfering (chemistry, genetics, metabolism)
• RNAi Therapeutics
• tat Gene Products, Human Immunodeficiency Virus (chemistry)