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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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;
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ABSTRACT: Protein and peptide delivery by the use of stimuli triggered polymers remains to be the area of interest among the scientist and innovators. In-situ forming gel for the parenteral route in the form of hydrogel and implants are being utilized for various biomedical applications. The formulation of gel depends upon factors like temperature modulation, pH changes, presence of ions and ultra-violet irradiation, from which drug is released in a sustained and controlled manner. Among various stimuli triggered factors, thermoresponsive is the most potential one for the delivery of protein and peptides. Poly (ethylene glycol) (PEG) based copolymers plays a crucial role as a biomedical material for biomedical applications, because of its biocompatibility, biodegradability, thermosensitivity and easy controlled characters. This review, stresses on the physicochemical property, stability and compositions prospects of smart thermoresponsive polymer specifically, PEG/Poly (N-isopropylacrylamide) (PNIPAAm) based thermoresponsive injectable hydrogels, recently utilized for biomedical applications. PEG-PNIPAAm based hydrogel exhibits good gelling mechanical strength and minimizes the initial burst effect of the drug. In addition, upon changing the composition and proportion of the copolymer molecular weight and ratio, the gelling time can be reduced to a great extent providing better sol-gel transition. The hydrogel formed by the same are able to release the drug over a long duration of time, meanwhile is also biocompatible and biodegradable. Manuscript will give the new researchers an idea about the potential and benefits of PNIPAAm based thermoresponsive hydrogels for the biomedical application.European Journal of Pharmaceutics and Biopharmaceutics. 08/2014;
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ABSTRACT: Poly(NIPAAm-co-hydroxyethylmethacarylate (HEMA)) acrylate and poly(NIPAAm-co-cysteine ethyl ester (CysOEt)) were synthesized and characterized by GPC(gel permeation chromatography), rheology, NMR (nuclear magnetic resonance), and Ellman's method. Upon mixing of these materials in aqueous solution, they formed gels immediately at body temperature owing to temperature-driven physical gelling, and gradually cured by chemical cross-linking through Michael-type addition reactions between thiols and acrylates. The rate of nucleophilic attack in the Michael-type addition reaction was shown to be highly dependent on the mole ratio of thiol to acrylate at neutral pH. Physical and chemical gelation improved the mechanical properties of the materials compared to purely physical gels. In vitro and in vivo results revealed that chemical and physical gels formed stiffer less viscoelastic materials compared to purely physical gels. Physical and chemical gel systems using thermosensitive polymer with acrylates and thermosensitive polymer with thiols showed minimum toxicity. Introduction One of the main treatment methods for several vascular disorders such as arteriovenous malformations (AVMs) and aneurysms is embolization. 1 Basically, embolization is a way of blocking flow from entering the aneurysm or malformation. The current materials used for embolization include cyanoacrylates (N-butyl-2cyanoacrylate [NBCA]), polyvinyl alcohol particles, and precipitant gels. Such embolic materials, however, have several drawbacks for clinical use. Cyanoacrylate derivatives can glue the delivery catheter to tissue resulting in vessel damage on removal of the catheter. Other occlusion materials are delivered in organic sol-vents such as dimethylformamide (DMF), ethyl alcohol, and N-methylpyrrolidone (NMP); these materials precipitate after injection into the vasculature as the solvents are replaced with water. Even though these systems (Onyx ® (EVOH) received FDA approval for clinical use, several studies about solvent toxicity have been reported.[2,3] Onyx also requires, on average, one and a half hours for injection into an aneurysm. 2 Therefore, a waterborne polymer system with no adhesion to the tissue and that can be applied and gelled in less than 10 min would be a superior