温度及pH敏感性共聚物水凝胶的合成及其对辅酶A的控制释放

以N-乙烯基吡咯烷酮(NVP)和甲基丙烯酸-N,N-二甲胺乙酯(DMAEMA)为单体,采用自由基聚合法合成了NVP与DMAEMA的共聚物及其水凝胶。研究发现共聚物的水溶液具有温度及pH双重敏感特性。相分离温度随DMAEMA含量的增加和水溶液浓度的降低而升高,随pH值的增大而减小且相变敏锐。通过对水凝胶溶胀率的考察,发现共聚凝胶在适当的单体浓度及交联剂浓度下,有较敏感的溶胀-退胀行为。在碱性条件下,共聚凝胶随温度的升高迅速退胀。pH=9时,改变温度,对辅酶A有很好的控制释放;而在酸性条件下,则无退胀行为,对辅酶A不能释放。     

Thermo and pH Dual-Responsive Micelles of N-phthaloylchitosan-g-Poly(N-isopropylacrylamide) and Poly(acrylic acid-co-tert-butyl acrylate) for Drug Delivery

A novel amphiphilic copolymer N-phthaloylchitosan graft poly(N-isopropylacrylamide) and poly(acrylic acid-co-tert-butyl acrylate) (PHCS-g-PNIPAAm&P(AA-co-tBA)) was synthesized. The graft copolymer could form micelles in aqueous medium, and the critical micelle concentration (CMC) of the copolymer was 7.5 × 10^{? 3}mg/mL. The lower critical solution temperature (LCST) of the micelles was measured to be 30°C. Transmission electron microscopy (TEM) image showed that the micelles exhibited a regular spherical shape, and the mean diameter of the micelles was 94.1 ± 0.8 nm as determined by dynamic light scattering (DLS). The potential usefulness of the micelles as drug delivery systems was investigated using anti-inflammation drug prednisone acetate as the model. The drug loading capacity of the micelles was measured to be 22.86 wt%, and the DLS results showed that the mean diameter of the drug-loaded micelles was 133.3 ± 2.4 nm. In vitro drug release studies indicated that the micelles exhibited thermo and pH dual-responsive release profiles.     

Self-assembled micellar nanoparticles of a novel star copolymer for thermo and pH dual-responsive drug release

An amphiphilic star block copolymer comprised of a hydrophobic PMMA block and a hydrophilic tri-arm poly(NIPAAm-co-DMAEMA) block was synthesized by copolymerization of NIPAAm and DMAEMA, with Ce(4+) ions and tris(hydroxymethyl)methylamine as a redox initiatory system. The star copolymer undergoes self-assembly to the micellar nanoparticles with a core-shell structure and the thermo/pH dual-response, originated from the thermo-sensitivity of PNIPAAm and the pH-sensitivity of PDMAEMA. A fluorescence probe study showed the pH-dependent low CMCs (7.5 to 11.2 mg/L) of the micelles, confirming the formation of stable micelles. Morphological investigations showed that the blank and drug-loaded micelles both had spherical and uniform shapes. The sizes of the blank and drug-loaded nanoparticles were between 80 and 120 nm, depending on the given pH. The LCSTs of the star copolymer were determined to be 32 degrees C, 36.6 degrees C and 39.5 degrees C, corresponding to pH 5, pH 7.4 and pH 9, respectively, demonstrating a pH-dependent thermo-response. As a drug delivery, the micellar nanoparticles showed the dual-responsive release profiles in vitro, which were confirmed by the drug release studies. The obtained results showed the thermo-triggered accelerated release at pH 7.4, and the pH-triggered accelerated release at 37 degrees C, indicating the micelles nanoparticles would be a promising site-specific drug delivery for enhancing the accumulation of drug in targeting pathological areas.     

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(diallyl dimethyl ammonium chloride)] hydrogels and its application as a carrier for notoginsenoside delivery

Novel pH/temperature sensitive hydrogel was synthesized by radiation induced copolymerization and cross-linking of dimethylaminoethyl methacrylate (DMAEMA) and diallyldimethyl ammonium chloride (DADMAC). Reactivity ratio of DADMAC (r₁) and DMAEMA (r₂) was determined as 1.02 and 0.98, which means that poly(DMAEMA-co-DADMAC) is an azeotropic copolymer. Content of DADMAC, i.e., charge density of the hydrogel was found to influence their properties significantly. Compared with polyDMAEMA hydrogel, poly(DMAEMA-co-DADMAC) showed enhanced equilibrium degree of swelling (EDS). Low critical solution temperature (LCST) of the hydrogel increased with the charged density. Content of DADMAC had no effect on the pH dependence of the final gel. Aiming at its application as a carrier for Chinese herb extract delivery system, the embedment and pH/temperature dependence of controlled release were investigated using notoginsenoside as a model drug. The maximum embedment amount of notoginsenoside was obtained in a gel containing 3 mol.% DADMAC. The temperature dependence and pH dependence of notoginsenoside release followed the same trend as that of EDS, for instance, higher ratio of notoginsenoside release occurred at 25 °C and pH 1.7, at which higher EDS was obtained. By these means, the release of notoginsenoside can be controlled by adjusting the pH, ionic strength, temperature of solution as well as the composition and structure of the gel.     

Amphiphilic linear-dendritic triblock copolymers composed of poly(amidoamine) and poly(propylene oxide) and their micellar-phase and encapsulation properties

A novel amphiphilic ABA dendritic-linear-dendritic block copolymer consisting of poly(amidoamine) and poly(propylene oxide) has been synthesized. The solution-phase behavior of the block copolymer was studied as a function of the generation of the dendritic block, ionic strength, and solution pH. The triblock self-assembles in aqueous media to form stable micelles with CMC values ranging from 10(-6) to 10(-5) M. Dynamic light scattering results indicate the formation of particles ranging from 9 to 18 nm in diameter, with smaller diameters exhibited at higher generations. Additional experiments were performed to assess the feasibility of the nanoparticles for drug delivery applications. Drug loading studies were performed with a model hydrophobic drug, triclosan, resulting in high loading efficiencies ranging from 79 to 86%w/w. The dendritic-linear-dendritic block copolymer synthesized was found to be a promising candidate for drug delivery due to its relative stability in aqueous solution and its drug encapsulation and release properties.     

Synthesis and Characterization of Thermo-responsive Poly(N-vinyl-2-pyrrolidinone)-block-poly(N-isopropylacrylamide) Micelles

A novel thermo-responsive diblock copolymer of poly(N-vinyl-2-pyrrolidinone)-block-poly(N-isopropylacrylamide) (PNVP-b-PNIPAM) was synthesized. FT-IR, ¹H-NMR and SEC results confirmed the successful synthesis of PNVP-b-PNIPAM diblock copolymer via anionic polymerization. The polymeric micelles formed from PNVP-b-PNIPAM copolymer in aqueous solution were developed and characterized as a potential thermo-responsive and biocompatible drug delivery system. Micellization of the diblock copolymer in aqueous solution was characterized by dynamic laser scattering (DLS), turbidity measurement, tension measurement and transmission electron microscopy (TEM). The thermo-responsive polymeric micelles with the size ranges of 200 to 260 nm and thickness of 30 nm are localized, selected and targeted for drug release, having a great potential in response to external-stimulus such as temperatures from 35 to 39°C. The critical micellization concentration (cmc) of PNVP-b-PNIPAM in aqueous solution is 0.0026 wt% determined by turbidity measurement. The size of micelles determined by DLS increased from 163 to 329 nm with increasing concentration of PNVP-b-PNIPAM from 0.25 to 0.5 wt% in aqueous solution at 40°C, which is determined by DLS.     

Synthesis and characterization of a biodegradable amphiphilic copolymer based on branched poly(ϵ‐caprolactone) and poly(ethylene glycol)

A novel biodegradable amphiphilic copolymer with hydrophobic poly(ε‐caprolactone) branches containing cholic acid moiety and a hydrophilic poly(ethylene glycol) chain was synthesized. The copolymer was characterized by FTIR, ¹H NMR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), polarizing light microscopy (PLM), and wide‐angle X‐ray diffraction (WAXD) analysis. The amphiphilic copolymer could self‐assemble into micelles in an aqueous solution. The critical micelle concentration of the amphiphilic copolymer was determined by fluorescence spectroscopy. A nanoparticle drug delivery system with a regularly spherical shape was prepared with high encapsulation efficiency. The in vitro drug release from the drug‐loaded polymeric nanoparticles was investigated. Because of the branched structure of the hydrophobic part of the copolymer and the relatively fast degradation rate of the copolymer, an improved release behavior was observed. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5256–5265, 2007     

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(ethyleneglycol dimethacrylate)] hydrogels and its application as a carrier for anticancer delivery

The use of hydrogels as carriers for anticancer delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion-controlled delivery of flutamide from hydrogels containing poly (dimethylaminoethyl methacrylate (DMAEMA)/ethyleneglycol dimethacrylate (EGDMA)) can be possible and controlled by the three-dimensional structure. Hydrogels based essentially on dimethylaminoethyl methacrylate and different ratios of ethyleneglycol dimethacrylate monomers were synthesized using gamma radiation copolymerization. The influence of copolymer composition and pH value of the surrounding medium on swelling behavior into the glassy polymer were discussed. The results showed that the ratio of EGDMA in the comonomer feeding solution has a great effect on the gel fraction and water content in the final hydrogel. In this regard, it was observed that the increase of EGDMA ratio decreased these properties. The ability of the prepared copolymer to be used as drug carrier for anticancer drug-delivery system was estimated using flutamide as a model drug. In vitro drug-release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and DMAEMA content of hydrogel.     

Synthesis and physicochemical characterization of amphiphilic triblock copolymer brush containing pH-sensitive linkage for oral drug delivery

A novel and well-defined pH-sensitive amphiphilic triblock copolymer brush poly(lactide)-b-poly(methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) (PLA-b-PMAA-b-PPEGMA) and its self-assembled micelles were developed for oral administration of hydrophobic drugs. The copolymer and its precursors were synthesized by the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring-opening polymerization (ROP) techniques. The molecular structures and characteristics were confirmed by GPC, (1)H NMR, and FT-IR. The critical micelle concentration (CMC) values of PLA-b-PMAA-b-PPEGMA in aqueous medium varied from 1.4 to 2.6 mg/L, and the partition equilibrium constant (K(v)) of pyrene in micellar solutions ranged from 2.873 × 10(5) to 3.312 × 10(5). The average sizes of the self-assembled blank and drug-loaded micelles were 140-250 nm determined by DLS in aqueous solution. The morphology of the micelles was found to be spherical by SEM. Nifedipine (NFD), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. The in vitro release behavior of NFD from the micelles was pH-dependent. In simulated gastric fluid (SGF, pH 1.2), the cumulative release percent of NFD was relative low, while in simulated intestinal fluid (SIF, pH 7.4), more than 96% was released within 24 h. All the results showed that the pH-sensitive PLA-b-PMAA-b-PPEGMA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.     

Temperature- and pH-responsive behavior of a novel copolymer of (PP-g-DMAEMA)-g-AAc

Graft copolymers of 2-(dimethylamino)ethylmethacrylate (DMAEMA) and acrylic acid (AAc) onto polypropylene films were investigated for obtaining a pH- and thermo-sensitive material. DMAEMA and AAc were grafted by direct irradiation and pre-irradiation methods, respectively, using a ⁶⁰Co γ-source. Due to the acidic and basic nature of the monomers, this novel copolymer corresponds to the class of polyzwitterions. Their behavior was studied in presence of different buffer solutions from pH 2 to 12 for different grafting percentages (from 9 to 362%) of AAc and keeping the DMAEMA grafting percentage constant. These modified films showed the same critical pH point at 7.6 in a range of temperatures from 23 to 37 °C. The swelling percentage showed a dependence on AAc content and pH. The lower critical solution temperature was observed at 36 °C when AAc content was less than 30% of grafting. The grafted films were characterized by swelling behavior, FTIR-ATR and UV–Vis spectrometry for study of loading and release of vancomycin as a model drug at room temperature.