Abstract
Chitosan-tripolyphosphate (TPP) nanoparticles have received great interest as a drug delivery system due to the simple and mild procedure of ionic gelation and the biocompatibility of chitosan. We have studied the formation of chitosan nano- and microparticles through ionic gelation with TPP in the absence and presence of NaCl, by measuring the kinetics of formation, particle size, and zeta potential. Depending on the experimental conditions (concentrations of chitosan and TPP and the presence or absence of NaCl), particle formation displays an exponential or a sigmoidal time dependency. In order to explain the kinetics measurements, we have set up a simple kinetics model involving four different species. The model is constructed on the basis of previously proposed mechanisms of particle formation and our measurements of particle size and kinetics of formation. The model can simulate all the different time dependencies of particle formation. We also determined the effect of small interfering RNA (siRNA) on the rate of particle formation, but apparently siRNA has little or no influence on particle formation when TPP is present.
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Yang W-Q, Zhang Y (2012) RNAi-mediated gene silencing in cancer therapy. Expert Opin Biol Ther 12:1495–1504. doi:10.1517/14712598.2012.712107
Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK (2011) RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 11(1):59–67
Scholz C, Wagner E (2012) Therapeutic plasmid DNA versus siRNA delivery: common and different tasks for synthetic carriers. J Control Release 161(2):554–565. doi:10.1016/j.jconrel.2011.11.014
Dash M, Chiellini F, Ottenbrite RM, Chiellini E (2011) Chitosan—a versatile semi-synthetic polymer in biomedical applications. Prog Polym Sci 36(8):981–1014. doi:10.1016/j.progpolymsci.2011.02.001
Leong KW, Mao HQ, Truong-Le VL, Roy K, Walsh SM, August JT (1998) DNA-polycation nanospheres as non-viral gene delivery vehicles. J Control Release 53(1–3):183–193. doi:10.1016/s0168-3659(97)00252-6
Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MO, Hovgaard MB, Schmitz A, Nyengaard JR, Besenbacher F, Kjems J (2006) RNA Interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther 14:476–484. doi:10.1016/j.ymthe.2006.04.010
Katas H, Alpar HO (2006) Development and characterization of chitosan nanoparticles for siRNA delivery. J Control Release 115:216–225. doi:10.1016/j.jconrel.2006.07.021
Csaba N, Koping-Hoggard M, Alonso MJ (2009) Ionically crosslinked chitosan/tripolyphosphate nanoparticles for oligonucleotide and plasmid DNA delivery. Int J Pharm 382:205–214. doi:10.1016/j.ijpharm.2009.07.028
Gaspar VM, Sousa F, Queiroz JA, Correia IJ (2011) Formulation of chitosan-TPP-pDNA nanocapsules for gene therapy applications. Nanotechnology 22 (1). doi:10.1088/0957-4484/22/1/015101
Lee DW, Yun K-S, Ban H-S, Choe W, Lee SK, Lee KY (2009) Preparation and characterization of chitosan/polyguluronate nanoparticles for siRNA delivery. J Control Release 139(2):146–152. doi:10.1016/j.jconrel.2009.06.018
Calvo P, Remuñán-López C, Vila-Jato JL, Alonso MJ (1997) Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 63(1):125–132. doi:10.1002/(sici)1097-4628(19970103)63:1<125::aid-app13>3.0.co;2-4
Zhang H, Oh M, Allen C, Kumacheva E (2004) Monodisperse chitosan nanoparticles for mucosal drug delivery. Biomacromolecules 5(6):2461–2468. doi:10.1021/bm0496211
Gan Q, Wang T, Cochrane C, McCarron P (2005) Modulation of surface charge, particle size and morphological properties of chitosan–TPP nanoparticles intended for gene delivery. Colloids Surf B 44(2–3):65–73. doi:10.1016/j.colsurfb.2005.06.001
Abdel-Hafez SM, Hathout RM, Sammour OA (2014) Towards better modeling of chitosan nanoparticles production: screening different factors and comparing two experimental designs. Int J Biol Macromol 64:334–340. doi:10.1016/j.ijbiomac.2013.11.041
Kaloti M, Bohidar HB (2010) Kinetics of coacervation transition versus nanoparticle formation in chitosan-sodium tripolyphosphate solutions. Colloids Surf B 81(1):165–173. doi:10.1016/j.colsurfb.2010.07.006
Huang Y, Lapitsky Y (2012) Salt-assisted mechanistic analysis of chitosan/tripolyphosphate micro- and nanogel formation. Biomacromolecules 13(11):3868–3876. doi:10.1021/bm3014236
Shu XZ, Zhu KJ (2002) The influence of multivalent phosphate structure on the properties of ionically cross-linked chitosan films for controlled drug release. Eur J Pharm Biopharm 54(2):235–243. doi:10.1016/S0939-6411(02)00052-8
Huang Y, Lapitsky Y (2011) Monovalent salt enhances colloidal stability during the formation of chitosan/tripolyphosphate microgels. Langmuir 27(17):10392–10399. doi:10.1021/la201194a
Petros RA, DeSimone JM (2010) Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov 9(8):615–627
Yue Z-G, Wei W, Lv P-P, Yue H, Wang L-Y, Su Z-G, Ma G-H (2011) Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles. Biomacromolecules 12(7):2440–2446. doi:10.1021/bm101482r
Hillaireau H, Couvreur P (2009) Nanocarriers’ entry into the cell: relevance to drug delivery. Cell Mol Life Sci 66(17):2873–2896. doi:10.1007/s00018-009-0053-z
Huang M, Ma ZS, Khor E, Lim LY (2002) Uptake of FITC-chitosan nanoparticles by a549 cells. Pharm Res 19(10):1488–1494
Rejman J, Oberle V, Zuhorn IS, Hoekstra D (2004) Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 377(1):159–169. doi:10.1042/bj20031253
Wang Z, Tiruppathi C, Minshall RD, Malik AB (2009) Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano 3(12):4110–4116. doi:10.1021/nn9012274
Brasen JC, Barington T, Olsen LF (2010) On the mechanism of oscillations in neutrophils. Biophys Chem 148(1–3):82–92. doi:10.1016/j.bpc.2010.02.013
Finsy R, de Jaeger N, Sneyers R, Geladé E (1992) Particle sizing by photon correlation spectroscopy. Part III: mono and bimodal distributions and data analysis. Part Part Syst Charact 9(1–4):125–137. doi:10.1002/ppsc.19920090117
Carneiro-da-Cunha MG, Cerqueira MA, Souza BWS, Teixeira JA, Vicente AA (2011) Influence of concentration, ionic strength and pH on zeta potential and mean hydrodynamic diameter of edible polysaccharide solutions envisaged for multinanolayered films production. Carbohydr Polym 85(3):522–528. doi:10.1016/j.carbpol.2011.03.001
Pedroni VI, Schulz PC, Gschaider ME, Andreucetti N (2003) Chitosan structure in aqueous solution. Colloid Polym Sci 282(1):100–102. doi:10.1007/s00396-003-0965-3
Van Holde KE, Johnson WC, Ho PS (2006) Principles of physical biochemistry, 2nd edn. Pearson/Prentice Hall, Upper Saddle River
Fan W, Yan W, Xu ZS, Ni H (2012) Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids Surf B 90:21–27. doi:10.1016/j.colsurfb.2011.09.042
Tsai ML, Bai SW, Chen RH (2008) Cavitation effects versus stretch effects resulted in different size and polydispersity of ionotropic gelation chitosan-sodium tripolyphosphate nanoparticle. Carbohydr Polym 71(3):448–457. doi:10.1016/j.carbpol.2007.06.015
Nguyen J, Reul R, Roesler S, Dayyoub E, Schmehl T, Gessler T, Seeger W, Kissel TH (2010) Amine-modified poly(vinyl alcohol)s as non-viral vectors for siRNA delivery: effects of the degree of amine substitution on physicochemical properties and knockdown efficiency. Pharm Res 27(12):2670–2682. doi:10.1007/s11095-010-0266-8
Hu B, Pan C, Sun Y, Hou Z, Ye H, Zeng X (2008) Optimization of fabrication parameters to produce chitosan − tripolyphosphate nanoparticles for delivery of tea catechins. J Agric Food Chem 56(16):7451–7458. doi:10.1021/jf801111c
Nasti A, Zaki N, Leonardis P, Ungphaiboon S, Sansongsak P, Rimoli M, Tirelli N (2009) Chitosan/TPP and chitosan/TPP-hyaluronic acid nanoparticles: systematic optimisation of the preparative process and preliminary biological evaluation. Pharm Res 26(8):1918–1930. doi:10.1007/s11095-009-9908-0
Barber J (1980) Membrane surface charges and potentials in relation to photosynthesis. Biochim Biophys Acta 594(4):253–308. doi:10.1016/0304-4173(80)90003-8
Weber RE, Olsen LF (1984) Does macromolecules surface pH explain the cation dependence of erythrocruorin oxygen affinity? Mol Physiol 6:1–8
Belliveau NM, Huft J, Lin PJC, Chen S, Leung AKK, Leaver TJ, Wild AW, Lee JB, Taylor RJ, Tam YK, Hansen CL, Cullis PR (2012) Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Mol Ther-Nucleic acids 1:e37. doi:10.1038/mtna.2012.28
Jonassen H, Kjøniksen A-L, Hiorth M (2012) Stability of chitosan nanoparticles cross-linked with tripolyphosphate. Biomacromolecules 13(11):3747–3756. doi:10.1021/bm301207a
Jonassen H, Kjøniksen A-L, Hiorth M (2012) Effects of ionic strength on the size and compactness of chitosan nanoparticles. Colloid Polym Sci 290(10):919–929. doi:10.1007/s00396-012-2604-3
Acknowledgments
The authors would like to thank the Lundbeck foundation for funding and Karin Trampedach from the Pathology research unit at Institute of Clinical Research, University of Southern Denmark for her assistance with TEM imaging. LFO also acknowledges support from the Danish Research Council for Technology and Production under the program NaKIM.
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Schrøder, T.D., Long, Y. & Olsen, L.F. Experimental and model study of the formation of chitosan-tripolyphosphate-siRNA nanoparticles. Colloid Polym Sci 292, 2869–2880 (2014). https://doi.org/10.1007/s00396-014-3331-8
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DOI: https://doi.org/10.1007/s00396-014-3331-8