Biphasic Equilibrium Dialysis of Poly(N-Isopropyl Acrylamide) Nanogels Synthesized at Decreased Temperatures for Targeted Delivery of Thermosensitive Bioactives
Hydrogel nanoparticles, referred to also as nanogels, are of special interest for medical and pharmaceutical applications. Due to small size in the range below the diameter of the capillaries, they are proposed as drug delivery carriers. The aim of the study was to estimate the influence of composition and reaction conditions during synthesis of poly-N-isopropyl acrylamide cross-linked by polyethylene glycol diacrylate on the purification rates of the polymer. Six types of thermosensitive nanogels were prepared by surfactant-free dispersion polymerization and assessed in terms of process yield, composition, and size at temperatures below and over volume phase temperature. During the diffusion of impurities, in the course of dialysis, assessed by the conductometric method, the remarkable influence of temperature and initiator concentration on the process was revealed. The release rates varied in the range between 9.63 · 10？2 and 1.39 · 10？1？h？1 in the first stage of the process, whereas in the second stage they were between 2.09 · 10？2 and 6.28 · 10？2？h？1. The evaluated time to obtain acceptable purity of the preparation was estimated to be in the range of 18 days. More detailed research should be directed towards the influence of the structure of obtained material on the purification process. 1. Introduction Nanogels are of special interest for medical and pharmaceutical applications [1–3]. Due to small size in the range below the diameter of the capillaries, they are proposed as drug delivery carriers. One of the main problems is to overcome the impurity of the product, which is intended for peroral or parenteral applications. With the diameter range between 10 and 1000？nm severe complications arise, when synthesized entities undergo the purification process. Synthesized in different conditions, nanoparticles contain various amounts of residual organic solvents, monomers, comonomers, surfactants, inorganic salts, initiators, accelerators, and noncrosslinked polymer aggregates. The presence of these impurities should be kept at very low level, to avoid adverse reactions within the human organism. Usually, the nanoparticles are purified by dialysis with the use of semipermeable cellulose membranes. With time the rate in impurities diffusion through the membrane decreases to extremely low values, with parallel decrease of impurities concentration in donor solution retentate, during the process. For enhancement of that procedure, various approaches are evaluated, including concentration/diafiltration process membrane filtration, crossflow membrane
References
[1]
J. K. Oh, D. I. Lee, and J. M. Park, “Biopolymer-based microgels/nanogels for drug delivery applications,” Progress in Polymer Science, vol. 34, no. 12, pp. 1261–1282, 2009.
[2]
J. K. Oh, R. Drumright, D. J. Siegwart, and K. Matyjaszewski, “The development of microgels/nanogels for drug delivery applications,” Progress in Polymer Science, vol. 33, no. 4, pp. 448–477, 2008.
[3]
J. K. Oh, S. A. Bencherif, and K. Matyjaszewski, “Atom transfer radical polymerization in inverse miniemulsion: a versatile route toward preparation and functionalization of microgels/nanogels for targeted drug delivery applications,” Polymer, vol. 50, no. 19, pp. 4407–4423, 2009.
[4]
I. Limayem, C. Charcosset, and H. Fessi, “Purification of nanoparticle suspensions by a concentration/diafiltration process,” Separation and Purification Technology, vol. 38, no. 1, pp. 1–9, 2004.
[5]
D. Jassby, S.-R. Chae, Z. Hendren, and M. Wiesner, “Membrane filtration of fullerene nanoparticle suspensions: effects of derivatization, pressure, electrolyte species and concentration,” Journal of Colloid and Interface Science, vol. 346, no. 2, pp. 296–302, 2010.
[6]
S. Kim, M. Marion, B.-H. Jeong, and E. M. V. Hoek, “Crossflow membrane filtration of interacting nanoparticle suspensions,” Journal of Membrane Science, vol. 284, no. 1-2, pp. 361–372, 2006.
[7]
K. M. Yun, C. J. Hogan Jr., Y. Matsubayashi, M. Kawabe, F. Iskandar, and K. Okuyama, “Nanoparticle filtration by electrospun polymer fibers,” Chemical Engineering Science, vol. 62, no. 17, pp. 4751–4759, 2007.
[8]
R. Mihaila, S. Chang, A. T. Wei et al., “Lipid nanoparticle purification by Spin Centrifugation-Dialysis (SCD): a facile and high-throughput approach for small scale preparation of siRNA-lipid complexes,” International Journal of Pharmaceutics, vol. 420, no. 1, pp. 118–121, 2011.
[9]
Z. Ding, G. Chen, and A. S. Hoffman, “Synthesis and purification of thermally sensitive oligomer-enzyme conjugates of poly(n-isopropylacrylamide)-trypsin,” Bioconjugate Chemistry, vol. 7, no. 1, pp. 121–126, 1996.
[10]
J. Gao and B. J. Frisken, “Cross-linker-free N-isopropylacrylamide gel nanospheres,” Langmuir, vol. 19, no. 13, pp. 5212–5216, 2003.
[11]
T. Gilányi, I. Varga, R. Mészáros, G. Filipcsei, and M. Zrínyi, “Interaction of monodisperse poly(N-isopropylacrylamide) microgel particles with sodium dodecyl sulfate in aqueous solution,” Langmuir, vol. 17, no. 16, pp. 4764–4769, 2001.
[12]
M. M. Yallapu, J. K. Vasir, T. K. Jain, S. Vijayaraghavalu, and V. Labhasetwar, “Synthesis, characterization and antiproliferative activity of rapamycin-loaded poly(N-isopropylacrylamide)-based nanogels in vascular smooth muscle cells,” Journal of Biomedical Nanotechnology, vol. 4, no. 1, pp. 16–24, 2008.
[13]
N. Singh and L. A. Lyon, “Au nanoparticle templated synthesis of pNIPAm nanogels,” Chemistry of Materials, vol. 19, no. 4, pp. 719–726, 2007.
[14]
H. Ayame, N. Morimoto, and K. Akiyoshi, “Self-assembled cationic nanogels for intracellular protein delivery,” Bioconjugate Chemistry, vol. 19, no. 4, pp. 882–890, 2008.
[15]
X. He, S. Yu, Y. Dong, F. Yan, and L. Chen, “Preparation and properties of a novel thermo-responsive poly(N-isopropylacrylamide) hydrogel containing glycyrrhetinic acid,” Journal of Materials Science, vol. 44, no. 15, pp. 4078–4086, 2009.
[16]
A. Qin, M. Lu, Q. Liu, and P. Zhang, “Synthesis and characterization of thermo-sensitive poly (N-isopropylacrylamide) hydrogel with fast response rate,” Frontiers of Chemistry in China, vol. 2, no. 2, pp. 135–139, 2007.
[17]
K. Du？ek, “Phase separation during the formation of three-dimensional polymers,” Journal of Polymer Science C, vol. 16, pp. 1289–1299, 1967.
[18]
K. Du？ek, “Quasichemical equilibrium approach to crosslinked polymer solutions,” Journal of Polymer Science C, vol. 39, no. 1, pp. 83–106, 1972.
[19]
K. Du？ek, “Network build-up and structure in curing of epoxy resins,” Makromolekulare Chemie. Macromolecular Symposia, vol. 7, no. 1, pp. 37–53, 1987.
[20]
J. I. Ngadaonye, M. O. Cloonan, L. M. Geever, and C. L. Higginbotham, “Synthesis and characterisation of thermo-sensitive terpolymer hydrogels for drug delivery applications,” Journal of Polymer Research, vol. 18, no. 6, pp. 2307–2324, 2011.
[21]
R. H. Pelton and P. Chibante, “Preparation of aqueous latices with N-isopropylacrylamide,” Colloids and Surfaces, vol. 20, no. 3, pp. 247–256, 1986.
[22]
R. Pelton, “Temperature-sensitive aqueous microgels,” Advances in Colloid and Interface Science, vol. 85, no. 1, pp. 1–33, 2000.
[23]
J. S. Lowe, B. Z. Chowdhry, J. R. Parsonage, and M. J. Snowden, “The preparation and physico-chemical properties of poly(N-ethylacrylamide) microgels,” Polymer, vol. 39, no. 5, pp. 1207–1212, 1998.
[24]
H. Nur, V. T. Pinkrah, J. C. Mitchell, L. S. Benée, and M. J. Snowden, “Synthesis and properties of polyelectrolyte microgel particles,” Advances in Colloid and Interface Science, vol. 158, no. 1-2, pp. 15–20, 2010.
[25]
M. Rasmusson, A. Routh, and B. Vincent, “Flocculation of microgel particles with sodium chloride and sodium polystyrene sulfonate as a function of temperature,” Langmuir, vol. 20, no. 9, pp. 3536–3542, 2004.
[26]
H. Senff and W. Richtering, “Influence of cross-link density on rheological properties of temperature-sensitive microgel suspensions,” Colloid and Polymer Science, vol. 278, no. 9, pp. 830–840, 2000.
[27]
B. R. Saunders, N. Laajam, E. Daly, S. Teow, X. Hu, and R. Stepto, “Microgels: from responsive polymer colloids to biomaterials,” Advances in Colloid and Interface Science, vol. 147-148, pp. 251–262, 2009.
[28]
A. A. Kubis, W. Musial, and M. Szczesniak, “Influence of some polysorbates on hydrocortisone release from hydrophilic gels considered as two-compartment models,” Pharmazie, vol. 57, no. 7, pp. 479–481, 2002.
[29]
Y. Y. Chiu and L. J. Lee, “Microgel formation in the free radical crosslinking polymerization of ethylene glycol dimethacrylate (EGDMA). I. Experimental,” Journal of Polymer Science A, vol. 33, no. 2, pp. 257–267, 1995.
[30]
Y. Y. Chiu and L. J. Lee, “Microgel formation in the free radical crosslinking polymerization of ethylene glycol dimethacrylate (EGDMA). II. Simulation,” Journal of Polymer Science A, vol. 33, no. 2, pp. 269–283, 1995.
[31]
K. Dusek, “Formation-structure relationships in polymer networks,” British Polymer Journal, vol. 17, no. 2, pp. 185–189, 1985.
[32]
K. Du？ek, “Formation process, structure, and properties of polymer networks,” in Polymer Networks, pp. 1–6, VSP, Utrecht, The Netherlands, 1992.
[33]
I. Berndt, J. S. Pedersen, and W. Richtering, “Structure of multiresponsive “intelligent” core-shell microgels,” Journal of the American Chemical Society, vol. 127, no. 26, pp. 9372–9373, 2005.
[34]
X. Wu, R. H. Pelton, A. E. Hamielec, D. R. Woods, and W. McPhee, “The kinetics of poly(N-isopropylacrylamide) microgel latex formation,” Colloid & Polymer Science, vol. 272, no. 4, pp. 467–477, 1994.
[35]
I. Varga, T. Gilányi, R. Mészáros, G. Filipcsei, and M. Zrínyi, “Effect of cross-link density on the internal structure of poly(N-isopropylacrylamide) microgels,” Journal of Physical Chemistry B, vol. 105, no. 38, pp. 9071–9076, 2001.
[36]
B. R. Saunders, “On the structure of poly(N-isopropylacrylamide) microgel particles,” Langmuir, vol. 20, no. 10, pp. 3925–3932, 2004.
[37]
T. G. Mason and M. Y. Lin, “Density profiles of temperature-sensitive microgel particles,” Physical Review E, vol. 71, no. 4, Article ID 040801, 2005.
[38]
M. Stieger, J. S. Pedersen, P. Lindner, and W. Richtering, “Are thermoresponsive microgels model systems for concentrated colloidal suspensions? A rheology and small-angle neutron scattering study,” Langmuir, vol. 20, no. 17, pp. 7283–7292, 2004.
[39]
C. Wu and X. Wang, “Globule-to-coil transition of a single homopolymer chain in solution,” Physical Review Letters, vol. 80, no. 18, pp. 4092–4094, 1998.
[40]
I. Berndt, J. S. Pedersen, and W. Richtering, “Temperature-sensitive core-shell microgel particles with dense shell,” Angewandte Chemie—International Edition, vol. 45, no. 11, pp. 1737–1741, 2006.
