2. Academic Validation
  3. Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells

Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells

  • Int J Biol Macromol. 2021 Jan 15;167:1006-1019. doi: 10.1016/j.ijbiomac.2020.11.056.
Vahid Karpisheh 1,  Javad Fakkari Afjadi 2,  Mohsen Nabi Afjadi 3,  Melika Sadat Haeri 4,  Tayebeh Sadat Abdpoor Sough 5,  Sim Heydarzadeh Asl 5,  Mehdi Edalati 6,  Fatemeh Atyabi 7,  Ali Masjedi 5,  Farnaz Hajizadeh 8,  Sepideh Izadi 9,  Farnaz Sadat Mirzazadeh Tekie 7,  Maliheh Hajiramezanali 10,  Mozhdeh Sojoodi 11,  Farhad Jadidi-Niaragh 12
Affiliations

Affiliations

  • 1 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 2 Department of Biology, Faculty of Science, Islamic Azad University, Ashkezar Branch, Yazd, Iran.
  • 3 Department of Biochemistry, Faculty of Biological Sciences, University of Tarbiat Modares, Tehran, Iran.
  • 4 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 5 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 6 Department of Laboratory Sciences, Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 7 Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 8 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 9 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 10 Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 11 Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, USA. Electronic address: msojoodi@mgh.harvard.edu.
  • 12 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: jadidif@tbzmed.ac.ir.
PMID: 33227333 DOI: 10.1016/j.ijbiomac.2020.11.056
Abstract

Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of Cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes Cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of Cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat Cancer cells and assessed the effect of combination therapy on Cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on Cancer cells could deliver siRNAs to Cancer cells and significantly suppress the HIF-1α in them. Combination therapy of Cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the Cancer cells, remarkably.

Keywords

CD44; Cancer; EP4; Hyaluronate; Prostaglandin E2; Superparamagnetic iron oxide nanoparticles; Trimethyl chitosan; siRNA.

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