Studies on chitosan-g-polyethyleneimine copolymer as drug carriers for PolyI:C
Kai Zhang A , Qian Sun A , Peng Liu A , Xiaoyu Bai A , Xingtong Gao A , Kai Liu A , Aixiang Li
A * , Zijian LYu A and Qiuhong Li A
+ Author Affiliations
- Author Affiliations
A School of Material Science and Engineering, Shandong University of Technology, Zibo, 255049, People’s Republic of China.
Australian Journal of Chemistry 75(7) 467-476 https://doi.org/10.1071/CH22076
Submitted: 4 April 2022 Accepted: 27 June 2022 Published: 11 August 2022
© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing.
Abstract
PolyI:C is an immunomodulatory agent that can be used in immunotherapy, but its transportation in the body is hindered. In this study, a chitosan (CS)-graft-polyethyleneimine (PEI) copolymer (C-g-P) is prepared by an N,N′-carbonyl diimidazole (CDI) coupling method as a drug carrier for PolyI:C and simulated antigen ovalbumin (OVA). The results of FT-IR, 1H NMR, elemental analysis and cytotoxicity studies show that PEI is successfully grafted onto CS, and a low cytotoxicity of C-g-P-x (x = 1, 2, 3) with different PEI grafting rates are obtained. C-g-P-x-PolyI:C/OVA (C-g-P-x-PO) (x = 1, 2, 3) nanoparticles are prepared by combining C-g-P-x (x = 1, 2, 3), PolyI:C and OVA by electrostatic self-assembly. The results of agarose gel electrophoresis show that PolyI:C is well coated by the graft copolymer and protected from nuclease degradation. The results show that C-g-P-1-PO nanoparticles with graft copolymer to PolyI:C (N/P) ratios of 80:1 have the best solution stability, and the OVA encapsulation efficiency is 60.6%. The nanoparticles also have a suitable size and regular shape to be absorbed by cells. In vitro immunoassay results show that PolyI:C and OVA-loaded nanoparticles promote the secretion of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). CS-g-PEI is a reliable drug carrier for the delivery of PolyI:C and OVA, and it also provides the possibility to carry other drugs.
Keywords: chitosan, copolymerization, CS-graft-PEI copolymer, drug delivery, electrostatic interactions, nanochemistry and supramolecular chemistry, PolyI:C, self-assembly.
References
[1] S Joshi, DL Durden, Combinatorial approach to improve cancer immunotherapy: rational drug design strategy to simultaneously hit multiple targets to kill tumor cells and to activate the immune system. J Oncol 2019, 2019, 5245034.| Combinatorial approach to improve cancer immunotherapy: rational drug design strategy to simultaneously hit multiple targets to kill tumor cells and to activate the immune system.Crossref | GoogleScholarGoogle Scholar |
[2] Z Wu, S Li, X Zhu, The mechanism of stimulating and mobilizing the immune system enhancing the anti-tumor immunity. Front Immunol 2021, 12, 682435.
| The mechanism of stimulating and mobilizing the immune system enhancing the anti-tumor immunity.Crossref | GoogleScholarGoogle Scholar |
[3] L Sun, L Chen, H Li, Checkpoint-modulating immunotherapies in tumor treatment: Targets, drugs, and mechanisms. Int Immunopharmacol 2019, 67, 160.
| Checkpoint-modulating immunotherapies in tumor treatment: Targets, drugs, and mechanisms.Crossref | GoogleScholarGoogle Scholar |
[4] ME Fortier, S Kent, H Ashdown, S Poole, P Boksa, GN Luheshi, The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 2004, 287, R759.
| The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism.Crossref | GoogleScholarGoogle Scholar |
[5] LN Pan, W Zhu, C Li, X Xu, L Guo, Q Lu, Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol Sin 2012, 33, 1246.
| Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo.Crossref | GoogleScholarGoogle Scholar |
[6] L Alexopoulou, AC Holt, R Medzhitov, RA Flavell, Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 2001, 413, 732.
| Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3.Crossref | GoogleScholarGoogle Scholar |
[7] S Sivori, M Falco, MD Chiesa, S Carlomagno, M Vitale, L Moretta, A Moretta, CpG and double-stranded RNA trigger human NK cells by toll-like receptors: induction of cytokine release and cytotoxicity against tumors dendritic cells. Proc Natl Acad Sci U S A 2004, 101, 10116.
| CpG and double-stranded RNA trigger human NK cells by toll-like receptors: induction of cytokine release and cytotoxicity against tumors dendritic cells.Crossref | GoogleScholarGoogle Scholar |
[8] MV Girart, MB Fuertes, CI Domaica, LE Rossi, NW Zwirner, Engagement of TLR3, TLR7, and NKG2D regulate IFN-γ secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12. J Immunol 2007, 179, 3472.
| Engagement of TLR3, TLR7, and NKG2D regulate IFN-γ secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12.Crossref | GoogleScholarGoogle Scholar |
[9] S Pisegna, G Pirozzi, M Piccoli, L Frati, A Santoni, G Palmieri, p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells. Blood 2004, 104, 4157.
| p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells.Crossref | GoogleScholarGoogle Scholar |
[10] C Zong, Y Sun, N Zhang, F Wang, A Li, Q Li, Z Lyu, Synthesis of chitosan-g-poly(ethylene glycol)-g-polyethyleneimine copolymer and its research as drug carrier. Macromol Res 2019, 27, 772.
| Synthesis of chitosan-g-poly(ethylene glycol)-g-polyethyleneimine copolymer and its research as drug carrier.Crossref | GoogleScholarGoogle Scholar |
[11] R Molinaro, J Wolfram, C Federico, F Cilurzo, L Di Marzio, CA Ventura, M Carafa, C Celia, M Fresta, Polyethylenimine and chitosan carriers for the delivery of RNA interference effectors. Expert Opin Drug Deliv 2013, 10, 1653.
| Polyethylenimine and chitosan carriers for the delivery of RNA interference effectors.Crossref | GoogleScholarGoogle Scholar |
[12] T Merdan, J Kopeček, T Kissel, Prospects for cationic polymers in gene and oligonucleotide therapy against cancer. Adv Drug Delivery Rev 2002, 54, 715.
| Prospects for cationic polymers in gene and oligonucleotide therapy against cancer.Crossref | GoogleScholarGoogle Scholar |
[13] B Urban-Klein, S Werth, S Abuharbeid, F Czubayko, A Aigner, RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther 2005, 12, 461.
| RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo.Crossref | GoogleScholarGoogle Scholar |
[14] R Moriguchi, K Kogure, H Akita, S Futaki, M Miyagishi, K Taira, H Harashima, A multifunctional envelope-type nano device for novel gene delivery of siRNA plasmids. Int J Pharm 2005, 301, 277.
| A multifunctional envelope-type nano device for novel gene delivery of siRNA plasmids.Crossref | GoogleScholarGoogle Scholar |
[15] HS Kim, HD Han, GN Armaiz-Pena, RL Stone, EJ Nam, JW Lee, MMK Shahzad, AM Nick, SJ Lee, JW Roh, M Nishimura, LS Mangala, J Bottsford-Miller, GE Gallick, G Lopez-Berestein, AK Sood, Functional roles of Src and Fgr in ovarian carcinoma. Clin Cancer Res 2011, 17, 1713.
| Functional roles of Src and Fgr in ovarian carcinoma.Crossref | GoogleScholarGoogle Scholar |
[16] S Monteagudo, FC Pérez-Martínez, MD Pérez-Carrión, J Guerra, S Merino, MP Sánchez-Verdú, V Ceña, Inhibition of p42 MAPK using a nonviral vector-delivered siRNA potentiates the anti-tumor effect of metformin in prostate cancer cells. Nanomedicine 2012, 7, 493.
| Inhibition of p42 MAPK using a nonviral vector-delivered siRNA potentiates the anti-tumor effect of metformin in prostate cancer cells.Crossref | GoogleScholarGoogle Scholar |
[17] J Cai, W Zhang, J Xu, W Xue, Z Liu, Evaluation of N-phosphonium chitosan as a novel vaccine carrier for intramuscular immunization. J Biomater Appl 2017, 32, 677.
| Evaluation of N-phosphonium chitosan as a novel vaccine carrier for intramuscular immunization.Crossref | GoogleScholarGoogle Scholar |
[18] Y Shi, M Yin, Y Song, T Wang, S Guo, X Zhang, K Sun, Y Li, Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: preparation, characterization, and pharmacokinetics. J Biomater Appl 2021, 35, 754.
| Oral delivery of liraglutide-loaded Poly-N-(2-hydroxypropyl) methacrylamide/chitosan nanoparticles: preparation, characterization, and pharmacokinetics.Crossref | GoogleScholarGoogle Scholar |
[19] X Liu, KA Howard, M Dong, MØ Andersen, UL Rahbek, MG Johnsen, OC Hansen, F Besenbacher, J Kjems, The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing. Biomaterials 2007, 28, 1280.
| The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing.Crossref | GoogleScholarGoogle Scholar |
[20] WE Rudzinski, TM Aminabhavi, Chitosan as a carrier for targeted delivery of small interfering RNA. Int J Pharm 2010, 399, 1.
| Chitosan as a carrier for targeted delivery of small interfering RNA.Crossref | GoogleScholarGoogle Scholar |
[21] HD Han, Y Byeon, JH Jang, HN Jeon, GH Kim, MG Kim, CG Pack, TH Kang, ID Jung, YT Lim, YJ Lee, JW Lee, BC Shin, HJ Ahn, AK Sood, YM Park, In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy. Sci Rep 2016, 6, 38348.
| In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy.Crossref | GoogleScholarGoogle Scholar |
[22] KA Howard, SR Paludan, MA Behlke, F Besenbacher, B Deleuran, J Kjems, Chitosan/siRNA nanoparticle-mediated TNF-α knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol Ther 2009, 17, 162.
| Chitosan/siRNA nanoparticle-mediated TNF-α knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model.Crossref | GoogleScholarGoogle Scholar |
[23] I Nawroth, J Alsner, MA Behlke, F Besenbacher, J Overgaard, KA Howard, J Kjems, Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis. Radiother Oncol 2010, 97, 143.
| Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis.Crossref | GoogleScholarGoogle Scholar |
[24] E Zhang, R Xing, S Liu, Y Qin, K Li, P Li, Advances in chitosan-based nanoparticles for oncotherapy. Carbohydr Polym 2019, 222, 115004.
| Advances in chitosan-based nanoparticles for oncotherapy.Crossref | GoogleScholarGoogle Scholar |
[25] AC Richards Grayson, AM Doody, D Putnam, Biophysical and structural characterization of polyethylenimine-mediated siRNA delivery in vitro. Pharm Res 2006, 23, 1868.
| Biophysical and structural characterization of polyethylenimine-mediated siRNA delivery in vitro.Crossref | GoogleScholarGoogle Scholar |
[26] O Boussif, F Lezoualc’h, MA Zanta, MD Mergny, D Scherman, B Demeneix, JP Behr, A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc Natl Acad Sci U S A 1995, 92, 7297.
| A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine.Crossref | GoogleScholarGoogle Scholar |
[27] S Höbel, I Koburger, M John, F Czubayko, P Hadwiger, HP Vornlocher, A Aigner, Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. J Gene Med 2010, 12, 287.
| Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab.Crossref | GoogleScholarGoogle Scholar |
[28] K Zhang, Q Sun, X Bai, P Liu, Z Lyu, Q Li, A Li, Preparation and performance study of COS/PEI@PolyI:C/OVA nanocomposite using the blend system of chitooligosaccharide and polyethyleneimine as a drug carrier. Macromol Res 2021, 29, 800.
| Preparation and performance study of COS/PEI@PolyI:C/OVA nanocomposite using the blend system of chitooligosaccharide and polyethyleneimine as a drug carrier.Crossref | GoogleScholarGoogle Scholar |
[29] J Rejman, V Oberle, IS Zuhorn, D Hoekstra, Size-dependent internalization of particles via the pathways of clathrin-and caveolae-mediated endocytosis. Biochem J 2004, 377, 159.
| Size-dependent internalization of particles via the pathways of clathrin-and caveolae-mediated endocytosis.Crossref | GoogleScholarGoogle Scholar |
[30] BD Chithrani, WCW Chan, Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett 2007, 7, 1542.
| Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes.Crossref | GoogleScholarGoogle Scholar |
[31] BD Chithrani, AA Ghazani, WCW Chan, Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett 2006, 6, 662.
| Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells.Crossref | GoogleScholarGoogle Scholar |
[32] D-i Jang, A-H Lee, H-Y Shin, H-R Song, J-H Park, T-B Kang, S-R Lee, S-H Yang, The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci 2021, 22, 2719.
| The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics.Crossref | GoogleScholarGoogle Scholar |
[33] D Jorgovanovic, M Song, L Wang, Y Zhang, Roles of IFN-γ in tumor progression and regression: a review. Biomark Res 2020, 8, 49.
| Roles of IFN-γ in tumor progression and regression: a review.Crossref | GoogleScholarGoogle Scholar |
