Chitosan-Coated-PLGA Nanoparticles Enhance the Antitumor and Antimigration Activity of Stattic – A STAT3 Dimerization Blocker

Abstract

Stephanie Sally Fong,1,* Yiing Yee Foo,1,* Wen Shang Saw,2 Bey Fen Leo,3 Yin Yin Teo,4 Ivy Chung,1 Boon Tong Goh,5 Misni Misran,4 Toyoko Imae,6 Chia-Ching Chang,7– 11 Lip Yong Chung,2 Lik Voon Kiew1,7 1Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, 50603, Malaysia; 3Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 4Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, 50603, Malaysia; 5Low Dimensional Materials Research Center, Department of Physics, Faculty of Science, University of Malaya, Kuala Lumpur, 50603, Malaysia; 6Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan; 7Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan; 8Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, 30050, Taiwan; 9Department of Electrophysics, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan; 10Institute of Physics, Academia Sinica, Nankang, Taipei, Taiwan; 11Taiwan-Malaysia Semiconductor and Biomedical Oversea Science and Technology Innovation Center, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan*These authors contributed equally to this workCorrespondence: Lik Voon KiewDepartment of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, MalaysiaTel [phone]Email [email protected] ChangDepartment of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, TaiwanTel [phone]Email [email protected]: The use of nanocarriers to improve the delivery and efficacy of antimetastatic agents is less explored when compared to cytotoxic agents. This study reports the entrapment of an antimetastatic Signal Transducer and Activator of Transcription 3 (STAT3) dimerization blocker, Stattic (S) into a chitosan-coated-poly(lactic-co-glycolic acid) (C-PLGA) nanocarrier and the improvement on the drug’s physicochemical, in vitro and in vivo antimetastatic properties post entrapment.Methods: In vitro, physicochemical properties of the Stattic-entrapped C-PLGA nanoparticles (S@C-PLGA) and Stattic-entrapped PLGA nanoparticles (S@PLGA, control) in terms of size, zeta potential, polydispersity index, drug loading, entrapment efficiency, Stattic release in different medium and cytotoxicity were firstly evaluated. The in vitro antimigration properties of the nanoparticles on breast cancer cell lines were then studied by Scratch assay and Transwell assay. Study on the in vivo antitumor efficacy and antimetastatic properties of S@C-PLGA compared to Stattic were then performed on 4T1 tumor bearing mice.Results: The S@C-PLGA nanoparticles (141.8 ± 2.3 nm) was hemocompatible and exhibited low Stattic release (12%) in plasma. S@C-PLGA also exhibited enhanced in vitro anti-cell migration potency (by > 10-fold in MDA-MB-231 and 5-fold in 4T1 cells) and in vivo tumor growth suppression (by 33.6%) in 4T1 murine metastatic mammary tumor bearing mice when compared to that of the Stattic-treated group. Interestingly, the number of lung and liver metastatic foci was found to reduce by 50% and 56.6%, respectively, and the average size of the lung metastatic foci was reduced by 75.4% in 4T1 tumor-bearing mice treated with S@C-PLGA compared to Stattic-treated group (p < 0.001).Conclusion: These findings suggest the usage of C-PLGA nanocarrier to improve the delivery and efficacy of antimetastatic agents, such as Stattic, in cancer therapy.Keywords: nanocarrier, STAT3 protein, breast cancer, metastasis, chitosan-coating

Keywords

• nanocarrier
• stat3 protein
• breast cancer
• metastasis
• chitosan-coating