Thermosensitive N-isopropylacrylamide-N-propylacrylamide-vinyl pyrrolidone terpolymers: Synthesis, characterization and preliminary application as embolic agents
ABSTRACT In this article, thermosensitive N-isopropylacrylamide (NIPAAm)-N-propylacrylamide (NPAAm)-vinyl pyrrolidone (VP) terpolymers (PNINAVP) were prepared by varying feed ratios with free radical copolymerization method. The composition ratios and molecular weights of PNINAVP were examined by NMR and GPC. The thermo-responsive behaviors of copolymer solutions in the absence and with addition of Iohexol, a radiopaque agent, were investigated by differential scanning calorimetry (DSC) and rheometer. The sol-gel transition of the copolymer solutions occurred reversibly within 1 min in response to temperature. Incorporation of Iohexol increased the transition time and transition temperature of PNINAVP solutions; the rheological properties were also influenced. It was observed that at body temperature, PNINAVP and Iohexol could form an integrated bulky hydrogel presumably due to the hydrogen bonding between them, which was favorable for the clinical follow-up and reducing toxic side effects. In vitro embolic model experiment indicated that 5 wt% 16:16:1H PNINAVP solution containing Iohexol displayed a satisfactory embolization effect. This solution was injected into the rete mirabiles (RM) of six swines through a microcatheter. The angiographical results obtained immediately after the operation showed a complete occlusion of the RM, and no recanalization was observed at postoperative month 1. The histological examination demonstrated no acute inflammatory reaction inside the RM and surrounding tissue. This work could provide a beneficial guidance for designing a new temperature-sensitive polymer-based embolic agent.
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- "The space among the glass beads could mimic arteriolar structure. A peristaltic pump (Beijing Xinkangyida technology Co., Ltd., China) was used to circulate normal saline in the system, and the flow rate of normal saline through the column was initially maintained at 0.3 mL/s, close to the velocity of the blood stream (Li et al., 2005). Each IL was injected into the mimetic vascular bed from the branch of the column by an injection pump at 36 mL/h. "
ABSTRACT: New type of liquid embolic agents based on a liquid crystalline material of glyceryl monooleate (GMO) was developed and evaluated in this study. Ternary phase diagram of GMO, water and ethanol was constructed and three isotropic liquids (ILs, GMO: ethanol: water=49:21:30, 60:20:20 and 72:18:10 (w/w/w)) were selected as potential liquid embolic agents, which could spontaneously form viscous gel cast when contacting with water or physiological fluid. The ILs exhibited excellent microcatheter deliverability due to low viscosity, and were proved to successfully block the saline flow when performed in a device to simulate embolization in vitro. The ILs also showed good cytocompatibility on L929 mouse fibroblast cell line. The embolization of ILs to rabbit kidneys was performed successfully under monitoring of digital subtraction angiography (DSA), and embolic degree was affected by the initial formulation composition and used volume. At 5(th) week after embolization, DSA and computed tomography (CT) confirmed the renal arteries embolized with IL did not recanalize in follow-up period, and an obvious atrophy of the embolized kidney was observed. Therefore, the GMO-based liquid embolic agents showed feasible and effective to embolize, and potential use in clinical interventional embolization therapy.International Journal of Pharmaceutics 05/2014; 471(1-2). DOI:10.1016/j.ijpharm.2014.05.036 · 3.65 Impact Factor
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ABSTRACT: This work investigates the differential reaction rates seen among several Michael-Type acceptors when reacted with poly(NIPAAm-co-cysteamine). This work differs from many of the previous studies upon mercaptans in that it examines systems used for network and gel formation. We find that the reaction rates of poly(NIPAAm-co-cysteamine) cross-linked with Michael type acceptors follow traditional second order rate laws. In addition, we further confirm that these reactions are pH sensitive, reliant upon the pK a of the conjugated thiols, and on local chain chemistry. Additionally, this work determines that the reaction of difunctional acrylates with the macromolecular NIPAAm molecules leads to an apparent, but not significant, increase in the rate of reaction. The low magnitude of this increase is likely indicative of increased steric hindrance arising from network formation, or reduced diffusion in the NIPAAm polymer chains. Statistical analysis shows pH and ratio of thiol to acrylates significantly affect reaction rates (p<0.05). The type of acrylate (PEGDA, PEGMA, or HEA) does not return as significant globally or within a pH range. Since localizing charge on a chain raises the effective pK a of nearby acids, gains in reaction rate from increasing chain functionality are shown to increase much less than would be expected from the increased concentration.Annals of Biomedical Engineering 11/2009; 37(11):2416-2425. DOI:10.1007/s10439-009-9776-0 · 3.20 Impact Factor
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ABSTRACT: A unique and rapid method was used to synthesize thermosensitive self-crosslinked nano (N-isopropylacrylamidevinylpyrrolidone-acrylamide) (NIPAAm-VP-AAm) terpolymers. Nanohydrogels were obtained within 30 min during a polymerization reaction with a convenient yield due to the high dilution of aqueous solution at an elevated temperature. Furthermore, hydrogen peroxide (H2O2) was employed for the first time as a safe initiator without any toxic segments for the thermosensitive polymer synthesis. Different nanohydrogels were obtained by modulating the molar ratio of monomers to initiators and their influences on the composition ratios, thermoresponsive behavior, size distribution, phase separation, and nanohydrogel drug release were investigated. As the synthetic route is crosslinker free, the obtained nanohydrogels can be introduced as a non-toxic efficient drug delivery system (DDS). The possibility of free radical formation on the PNIPAAm chains, which leads to the crosslinked structure, has been investigated theoretically by quantum mechanical calculations. The potential energy surface of the reaction was examined by changing the distance between the OH radical and the H atoms. Considering these calculations, the reaction can proceed from all pathways as it is observed experimentally. The average size of nanohydrogels, as revealed by dynamic light scattering (DLS) and transmission electronic microscopy (TEM), is <50 nm. Finally, naltrexone as an opiate antagonist was selected as a model drug for the investigation of nanohydrogel drug delivery capabilities. Nanohydrogels show sustained naltrexone release beyond 3 months without any initial burst release.Macromolecular Research 01/2012; 21(1). DOI:10.1007/s13233-012-0181-4 · 1.60 Impact Factor