Sol-gel Phase Transition Behavior Research Articles

New features of edge-selectively hydroxylated graphene nanosheets as NIR-II photothermal agent and sonothermal agent for tumor therapy.

Second near-infrared (NIR-II) laser-mediated photothermal therapy and sonothermal therapy using low-intensity focused ultrasound exposure for tumors have attracted increasing attention owing to their ability to penetrate deep tissues and provide noninvasive ablation with high therapeutic efficacy. However, their applications were limited by the shortness of optimal NIR-II photothermal agents and sonothermal agents. In this study, we discovered that the edge-selectively hydroxylated graphene nanosheets (EHG NSs) with excellent water dispersibility and an "intact conjugated plane" were not only an outstanding NIR-II photothermal agent but also an effective sonothermal agent for tumor therapy. EHG NSs were incorporated into an injectable adhesive thermosensitive hydrogel with a characteristic sol-gel phase transition behavior. EHG NSs endowed the injectable hydrogel with an exceptional photothermal effect under the laser irradiation (1064 nm, 1.0 W cm-2) as well as an effective sonothermal effect under ultrasonic exposure (3.0 MHz, 2.1 W cm-2), effectively killing tumor cells in vitro and inhibiting tumor growth after intratumoral injection. Especially, the NIR-II photothermal therapy based on the hybrid hydrogel completely ablated the primary tumors and effectively activated systemic anti-tumor immune responses benefiting from the protein adsorption capacity of the injectable hydrogel, significantly inhibiting the growth of the distal tumors. Collectively, EHG nanosheets loaded in the injectable hydrogel will be a promising "all-rounder" for noninvasive deep penetrating thermotherapy and a potent platform that integrates various therapies.

Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer

Surgical resection remains the prefer option for bladder cancer treatment. However, the effectiveness of surgery is usually limited for the high recurrence rate and poor prognosis. Consequently, intravesical chemotherapy synergize with immunotherapy in situ is an attractive way to improve therapeutic effect. Herein, a combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system was developed. GEM loaded PLEL hydrogel was intravesical instilled to kill tumor cells directly, then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses synergize with GEM. The results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior in response to physiological temperature and presented sustained drug release, and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo. Hence, this combined treatment with PLEL hydrogel system has great potential and suggests a clinically-relevant and valuable option for bladder cancer.

Photothermal nanohybrid hydrogels for biomedical applications.

In the past decades, diseases such as wound infection, cancer, bone defect and osteoarthritis have constantly threatened the public health. However, the traditional treatment has many insufficiencies, such as high cost, easy recurrence and high biological toxicity. Hydrogel is a material with three-dimensional network structure, which has a series of advantages, such as injectability, self-heal ability, easy loading and controllability of drug release, and excellent biocompatibility. Therefore, it is extensively used in drug delivery, antibacterial, anti-cancer and other fields. However, the traditional hydrogels have the single performance, and therapeutic efficacy is often rely on the drugs loaded on them to cure diseases, which cannot achieve sustainable therapeutic effect. In order to solve this problem, photothermal nano hydrogel with photothermal agent (PTA) has become an ideal material due to its excellent physical and chemical properties. Photothermal nano hydrogels used in photothermal therapy (PTT) can exploit the photothermal effect of photothermal agent to increase local temperature and control the sol-gel phase transition behavior of hydrogels, so they are widely used in drug release, photothermal sterilization, photothermal inhibition of cancer cells and enhancement of bone repair. To sum up, this paper introduces the preparation of hydrogels with photothermal nanomaterials, and discusses their applications in the fields of drug release, photothermal sterilization, photothermal cancer cell inhibition and enhanced bone repair.

Injectable in Situ Forming Hydrogels of Thermosensitive Polypyrrole Nanoplatforms for Precisely Synergistic Photothermo-Chemotherapy.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol-gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π-π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy-chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.

CO2 Responsive Imidazolium-Type Poly(Ionic Liquid) Gels.

Poly(ionic liquid) (PIL) gels with CO2 stimulus responsiveness have been synthesized through the copolymerization of an imidazolium-type ionic liquid monomer with 2-(dimethyl amino) ethyl methacrylate. Upon bubbling with CO2 gas, the prepared PIL solution is converted to a transparent and stable gel, which can be turned back to the initial solution state after N2 bubbling. The reversible sol-gel phase transition behavior is proved by the reversible values of viscosity and ionic conductivity. The possible mechanism for such a reversible sol-gel phase transition is demonstrated by NMR, conductivity, and rheological measurements.

The stimuli-responsive multiphase behavior of core–shell nanogels with opposite charges and their potential application in in situ gelling system

Concentrated p(N-isopropylacrylamide) (PNIPAM) nanogel dispersions exhibited rich temperature-sensitive sol–gel phase transition behavior. In the present work, the influence of electrostatic forces between nanogel particles, including attraction and repulsion, on the sol–gel phase transition behavior of PNIPAM nanogel dispersions has been studied. Both oppositely charged nanogels with core–shell structures (NIA and PND nanogels) were synthesized, and their shell charges were calculated to −0.33 and 0.082mmol/g by potentiometric titration method. When mixed with various ratio of negative and positive charge (NC value), the resultant mixture dispersions of NIA and PND nanogel (OCNs) exhibited different aggregating behavior from NIA and PND nanogels. OCN-e aggregates (NC value=1/4), which exhibited temperature-independence of electric neutrality, had the maximum size, about 1.9–2.2 times larger than NIA or PND nanogels. Concentrated OCN-e dispersions exhibited stronger ability to form shrunken gel. Its CGC was about 2.0wt%, 4-times lower than that of NIA and PND nanogels (about 8.0wt%). In vitro and in vivo gelling results indicated that OCN-e aggregates could form free-standing gel with good mechanical strength, and were promising to be developed as new in situ gelling system.

Biodegradable and stimuli sensitive amphiphilic graft copolymers and their sol–gel phase transition behavior

pH and temperature‐sensitive biodegradable poly(β‐aminoester)‐graft‐poly(ε‐caprolactone)‐block‐methoxy poly(ethylene glycol) (PBAE‐g‐PCL‐b‐mPEG) amphiphilic graft copolymers with different molecular weights were synthesized. The structure of these copolymers was adjusted by varying the feed ratios of ε‐caprolactone to methoxy poly(ethylene glycol)s (mPEG), amine and diacrylate monomer amounts and the molecular weight of mPEG. Aqueous solutions of these copolymers formed micelles at lower concentrations; however, the concentrated solutions showed a reversible sol–gel transition property depending on both pH and temperature changes under representative physiological conditions (pH 7.4, 37°C). The effects of the molecular weight of pH‐sensitive poly(β‐aminoester) block and mPEG group, the hydrophobic to hydrophilic block ratio (PCL/mPEG) and the concentration of the copolymer on the sol–gel transition were investigated. Proton nuclear magnetic resonance (1H NMR) and gel permeation chromatography measurements were used to characterize the structure of the synthesized copolymers. The self‐assemble behavior and critical micelle concentration of the amphiphilic copolymers were estimated in phosphate buffer solution using fluorescence spectroscopy. The gelling behavior was measured by using tube inversion method. At pH 7.4, all copolymer solutions prepared 20 wt% concentration indicated sol–gel transition with increasing temperature. In vitro degradation experiments displayed that the synthesized graft copolymers mostly degraded hydrolytically within 20 days under physiological conditions. In order to investigate the potential application of synthesized hydrogels in drug delivery, Methylene Blue was used and approximately 70% of the loaded amount was released in 120 hr. The findings indicate that obtained graft copolymers can be used as injectable biodegradable carriers for pharmaceutical drugs. Copyright © 2015 John Wiley & Sons, Ltd.

Fabrication of Reversible Phase Transition Polymer Gels toward Metal Ion Sensing

We report the synthesis of a new type of triple stimuli-responsive, i.e., thermo-, pH-, and metal ion-responsive copolymers based on poly(N-vinylimidazole-co-methacrylic acid) (poly(VI-co-MAA)) and their application as metal ion sensors. The copolymers exhibit reversible sol–gel phase transition behavior in aqueous media. The sol-to-gel transition temperature (Tsol–gel) can be shifted in the range of 20–80 °C, by varying monomer ratio and feeding glycerol content, by adjusting the copolymer concentration in aqueous solution, by tuning the pH of the solution, or by adding various divalent metal ions. Metal ion sensors were designed upon an inverse opal photonic film loaded with aqueous solution of poly(VI-co-MAA), which allows the easy reorganization of various divalent metal ions by combining the diversity of Tsol–gel of the copolymers on different metal ions and flexible reflection spectra of the film. In addition, a fluorescent reversible sol–gel transition system was established by in situ generation of nanocrystals in the copolymer matrix. These extensions may provide the multiresponsive copolymers great flexibility for applications in biomedical, optical, and sensory fields.

Controlled release of insulin from self-assembling nanofiber hydrogel, PuraMatrix™: Application for the subcutaneous injection in rats

The concept of this research is, using the acetyl-(Arg-Ala-Asp-Ala) 4-CONH 2 peptide hydrosol (PuraMatrix™, PM), to develop an new injectable formula of controlled insulin delivery for subcutaneous injection. PM has sol–gel phase transition behavior, and was developed as a scaffold in the field of tissue engineering. The aqueous media of the PM including insulin changed from a sol to a gel phase with increasing ion strength of phosphate ion and pH in working environments in vitro and in vivo. In this study, we examined the in vitro insulin dissolution behavior and the in vivo pharmacokinetics and pharmacodynamics after subcutaneous administration of PM-insulin sol (PM-Isol). In the in vitro release study, after PM-Isol was converted to a gel phase (PM-Igel), PM concentration-dependent and controlled release of insulin were observed at the final concentrations of PM between 0.1% and 2.0% (w/v). The PM-Isol is changed to gel form in vivo, and exhibited a sustained-release pharmacokinetics of insulin, where PM concentration-dependent prolongation of efficacy was found. The plasma glucose level markedly decreased, and the lowest plasma glucose level was maintained up to 24 h when 2.0% (w/v) PM-Isol was administered subcutaneously to rats. The PM-Isol, we developed here, is applicable for the wild-type of insulin, and increased the bioavailability and hypoglycemic efficacy of insulin after subcutaneous injection. Hence, the PM is a useful inactive ingredient to produce various types of control-released system of insulin by making just a few changes in PM content of the formulation.

Synthesis and characterization of novel thermo-responsive F68 block copolymers with cell-adhesive RGD peptide

Thermosensitive poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) triblock copolymer, Pluronic F68, containing a hydrophobic unit, oligo-(lactic acid)(oligo-LA) or oligo-caprolactone (oligo-CL), 2-META and RGD as side groups was successfully synthesized and characterized by 1H NMR, FTIR, and elemental analysis. Their aqueous solution displayed special gel–sol–gel phase transition behavior with increasing temperature from 10 to 70°C, when the polymer concentration was above critical micelle concentration (CMC). The gel–sol phase diagram was investigated using tube inversion method, rheological measurement, and dynamic light scattering. Based on these results, the gelation properties of modified F68 were affected by several factors such as the composition of the substituents, chain length of oligo l-LA or oligo ε-CL, and the concentration of the polymer solutions. The unique phase transition behavior with temperature was observed by modified F68 triblock copolymer, composed of the PPO blocks core and the PEO blocks shell in aqueous solution. This phenomenon was elucidated using 1H NMR data; the alteration of hydrophobic interaction and chain mobility led to the formation of transparent gel, coexistence of gel–sol, and opaque gel. These hydrogels may be useful in drug delivery and tissue engineering.

Controlling the degradation rate of thermoresponsive photo-cross-linked poly(organophosphazene) hydrogels with compositions of depsipeptide and PEG chain lengths

Thermosensitive and photo-cross-linkable poly(organophosphazenes) containing various amounts of isoleucine ethyl ester, AMPEG550, AMPEG750, aminoethyl methacrylate, and depsipeptide were synthesized, characterized, and were investigated for in vitro and in vivo degradation rates. The aqueous solutions of all polymers showed a sol–gel phase transition behavior against the temperature changes. The polymer degradation rate was majorly affected by the type and degree of the side group’s substitutions. The rate of degradation was initially dependent on the degree of photo-cross-linking, and in later stages on the amounts of the depsipeptide and PEG chain lengths in the polymer network. The amount of the pendant depsipeptide and chain length of the α-amino-ω-methoxy-poly(ethylene glycol) had significant impact on the polymer degradation rates. The polymers with high amount of the depsipeptide, and PEG750 showed fast degradation. These results suggest that the degradation rate of the injectable and dual cross-linkable gels can be tuned to the desired extent and may find wide utilities in various biomedical applications, where the gel strength and degradation rate are needed to be tightly regulated.

In vitro and in vivo degradation behaviors of thermosensitive poly(organophosphazene) hydrogels

Biodegradable and thermosensitive poly(organophosphazenes) with various substituents were synthesized and their hydrolytic degradation properties were investigated in vitro and in vivo. The aqueous solutions of all polymers showed a sol–gel phase transition behavior depending on temperature changes. The side groups of polymers significantly affected the polymer degradation and accelerated hydrolysis of polymers in the order of carboxylic acid > depsipeptide > without carboxylic acid and depsipeptide. The increased gel strength led to the decreased hydrolysis rate. The polymer hydrogels with 750 Da of α-amino-ω-methoxy poly(ethylene glycol) were rapidly decreased by dissolution. The polymer degradation was also influenced by pH and temperature. The in vivo behaviors of mass decrease of the polymer hydrogels were similar with the in vitro results. These results suggest that the biodegradable and thermosensitive poly(organophosphazenes) hold great potentials as an injectable and biodegradable hydrogel for biomedical applications with controllable degradation rate.

Controlling the degradation of pH/temperature-sensitive injectable hydrogels based on poly(β-amino ester)

Poly (ethylene glycol) (PEG) — poly(e-caprolactone(CL)-co-D,L-lactide (LA)) (PCLA-PEG-PCLA) was synthesized by ring-opening polymerization to form a temperature sensitive hydrogel triblock copolymer. Poly(β-amino ester) (PAE) obtained from 1,4-butanediol diacrylate (BDA), and 4,4′-trimethylene dipiperidine (TMDP) was used as a pH sensitive moiety to conjugate to the triblock copolymer. The physicochemical properties of the temperature-sensitive triblock and pH/temperature-sensitive pentablock copolymers (PAE-PCLA-PEG-PCLA-PAE) were characterized by 1H NMR spectroscopy and gel permeation spectroscopy. The sol-gel phase transition behavior of the PAE-PCLA-PEG-PCLA-PAE block copolymers was investigated. An aqueous solution of the copolymers (20 wt%) changed from a sol phase at pH 6.4 and 10°C to a gel phase at pH 7.4 and 37°C. In addition, the degradation of PAE-PCLA-PEG-PCLA-PAE was compared with that of poly(ethylene glycol) — poly(e-caprolactone) — poly (β-amino ester) (PAE-PCL-PEG-PCL-PAE) using both in vitro and in vivo experiments. The relationship between the insulin release profile from the matrix and the degradation of these materials also investigated.

Molecular design of novel pH/temperature-sensitive hydrogels

A series of poly(β-amino ester)–poly(ɛ-caprolactone)–poly(ethylene glycol)–poly(ɛ-caprolactone)–poly(β-amino ester) pentablock copolymers (PAE–PCL–PEG–PCL–PAE) were designed and prepared to examine factors affecting sol–gel phase transition behavior. First, the composition of a series of PCL–PEG–PCL copolymers was controlled by changing the feed ratios of PCL/PEG and the molecular weight of PEG. Second, the composition of pentablock copolymers was varied using different PCL–PEG–PCL copolymers and several feed ratios of PAE monomers. The physicochemical properties of triblock and pentablock copolymers were characterized by 1H NMR and gel permeation spectroscopy. The PAE–PCL–PEG–PCL–PAE copolymers in aqueous solution (20–30 wt%) underwent sol–gel transitions with changes in both pH change and temperature. With increasing molecular weight of PAE, the sol–gel transition zone became narrower because the hydrophobic character of the copolymers decreased. Also, with increases in PCL/PEG ratio and PEG molecular weight, changes in the hydrophobic/hydrophilic balance within copolymers resulted in alterations in sol–gel phase transitions.

Functionalized injectable hydrogels for controlled insulin delivery

The concept of this research is using poly(β-amino ester) (PAE) as a duo-functional group for synthesis of the novel sensitive injectable hydrogel for controlled drug/protein delivery. Firstly, PAE made of 1,4-butanediol diacrylate and 4,4′-trimethylene dipiperidine is used as a pH-sensitive moiety to conjugat to the temperature-sensitive biodegradable triblock copolymer of poly(ethylene glycol)–poly(ɛ-caprolactone) (PCL–PEG–PCL) to manufacture pH/temperature-sensitive injectable hydrogel of pentablock copolymer PAE–PCL–PEG–PCL–PAE. Furthermore, the cationic nature of PAE is used as the second function to make the ionic complexes with anionic biomolecule loaded into the hydrogel such as insulin. As a result, the release of drug/protein from this hydrogel device can be controlled by the degradation of copolymer. Sol–gel phase transition behavior of PAE–PCL–PEG–PCL–PAE block copolymer was investigated; the results showed that the aqueous media of the pentablock copolymer changed from a sol to a gel phase with increasing temperature and pH. The effect of anionic biomolecule such as insulin on sol–gel phase transition, degradation of the complex gel of the material with insulin was studied in vitro. Then the schematic of the ionic complexes between positive charges in PAE and the negatively charges in protein was simulated. In addition, the mechanism of controlled release behavior of insulin from the complex gel was supposed, which includes the chemically-controlled and diffusion-controlled stages. To prove the simulations, the cumulative release of the protein from the complex gel was investigated in vitro with different methods. Furthermore, the pharmacokinetic release of insulin from the complex gel in vivo on male Sprague-Dawley (SD) rats was compared with that from triblock copolymer hydrogel of PCL–PEG–PCL.

PH/temperature sensitive poly(ethylene glycol)-based biodegradable polyester block copolymer hydrogels

Novel pH and temperature sensitive biodegradable block copolymers composed of poly(ethylene glycol) (PEG), polyglycolide (GA), ɛ-caprolactone (CL) and sulfamethazine oligomers (OSMs) were synthesized by ring opening polymerization and 1,3-dicyclohexyl-carbodiimide (DCC) mediated coupling reactions. Their physicochemical properties in aqueous media were characterized by 1H NMR spectroscopy and gel permeation spectroscopy. The sol–gel phase transition behavior of OSM–PCGA–PEG–PCGA–OSM block copolymers was investigated both in solution and injection to PBS buffer at pH 7.4 and 37 °C. Aqueous solutions of OSM–PCGA–PEG–PCGA–OSM changed from a sol to a gel phase with increasing temperature and decreasing pH. The sol–gel transition properties of these block copolymers are influenced by the hydrophobic/hydrophilic balance of the copolymers, block length, hydrophobicity, stereoregularity of the hydrophobic components within the block copolymer, and the ionization of the pH functional groups in the copolymer, which depends on the environmental pH. Degradation of the triblock and pentablock copolymers at 37 °C (pH 7.4), and at 0 °C and 5 °C both at pH 8.0, was investigated. It was demonstrated here using the in vitro test method, that the anticancer agent paclitaxel (PTX) could be loaded and released by the pH and temperature sensitive OSM–PCGA–PEG–PCGA–OSM block copolymer, such that this could be used as a suitable matrix for subcutaneous injection in drug delivery systems.