A comparative study of dual thermal- and glucose-responsive nanogel systems

Polymer nano-sized hydrogels (nanogels) as drug delivery carriers have been investigated over the last few decades. Pullulan, a nontoxic and nonimmunogenic hydrophilic polysaccharide derived from fermentation of black yeast like Aureobasidium pullulans with great biocompatibility and biodegradability, is one of the most attractive carriers for drug delivery systems. In this review, we describe the preparation, characterization, and ‘switch-on/off’ mechanism of typical pullulan self-assembled nanogels (self-nanogels), and then introduce the development of hybrid hydrogels that are numerous resources applied for regenerative medicine. A major section is used for biomedical applications of different nanogel systems based on modified pullulan, which exert smart stimuli-responses at ambient conditions such as charge, pH, temperature, light, and redox. Pullulan self-nanogels have found increasingly extensive application in protein delivery, tissue engineering, vaccine development, cancer therapy, and biological imaging. Functional groups are incorporated into self-nanogels and contribute to expressing desirable results such as targeting and modified release. Various molecules, especially insoluble or unstable drugs and encapsulated proteins, present improved solubility and bioavailability as well as reduced side effects when incorporated into self-nanogels. Finally, the advantages and disadvantages of pullulan self-nanogels will be analyzed accordingly, and the development of pullulan nanogel systems will be reviewed.

Chlorhexidine gluconate (CHX) is an antiseptic often preferred for wound care, dental plaque prevention and treatment of fungal infections in the mouth. The aim of the study was to develop dual nanogel systems of alginate and chitosan, biocompatible polymers that can provide controlled release for the treatment of periodontitis. In this context, CHX was loaded into prepared chitosan (CS), alginate (ALG), alginate-chitosan (ALG-coated CS) and chitosan-alginate (CS-coated ALG) nanogels with high efficiency, and its structural, morphological and thermal properties were characterized. The swelling behavior, swelling kinetics and in vitro release studies of CHX-loaded nanogels in artificial saliva were carried out, and the amount of CHX was determined by high pressure liquid chromatography (HPLC). When CHX-loaded and unloaded nanogel systems were examined, it was observed that the size of CHX-unloaded nanogels varied in the range of 100–130 nm, while the size increased with CHX loading. The nanogel systems were prepared with encapsulation efficiencies of 62% (CHX loaded CS NG), 55% (CHX-loaded ALG-coated CS NG), 75% (CHX-loaded ALG NG) and 70% (CHX-loaded CS-coated ALG NG). According to the characterization results obtained, CS, ALG, CS-coated ALG and ALG-coated CS nanogel systems can be carrier systems for the CHX drug.

pH responsive biodegradable nanogels for sustained release of bleomycin

Exploitation of a rod-shaped, acid-labile curcumin-loaded polymeric nanogel system in the treatment of systemic inflammation

Hypoxia-responsive hyaluronic acid nanogels with improved endo/lysosomal escape ability for tumor-targeted cytochrome c delivery

We designed experiments to find optimal thermostable nanogel systems that meet the requirements for use in high temperature oilfield reservoirs. The Response Surface Method is used to build second-order regression functions that correlate statistically gel strength and gelation time with the experimental parameters, like clay concentration and crosslinker concentration. Via in situ intercalative free-radical copolymerization, nanogels have been prepared from acrylamido-2-methylpropane sulfonic acid (AMPS), acrylamide (AM) (weight ratio of which in nanogel systems equals to 1:1) and montmorillonite-alkyl ammonium clay. The mixture of Hexamethylenetetramine (HMTA)/Phenyl acetate (PhAc) was used as a crosslinking system. The Lagrange multiplier method is used to optimise the resulting statistical model and to determine the maximum value of gel strength with the constraint of gelation time for practical applications. After a gelation time of 10.8 hours and storage for 32 days at 150°C the gel strength can reach up to 96%. The optimal nanogel has a clay concentration of 0.55% and a HMTA/PhAc mixture concentration of 0.80%. The characteristics of these nanogel systems meet the requirements for the use as water isolating materials in the White Tiger basement reservoir and provide a good basis for the further design of similar gels.

Many existing drugs, which are effective in anticancer such as paclitaxel (PTX), docetaxel (DTX), and campothecin (CPC), are limited in clinical applications due to their poor water solubility. This study aimed to design a nanocarrier system for the efficient delivery of poorly soluble drugs in cancer treatment. Nanogel systems were prepared from copolymers of Heparin and different Pluronics, in which the Hep‐Plu conjugates were formed via disulfide bridges of cystamine molecules. The obtained Hep‐Plu systems were proved and characterized using specific techniques including H‐NMR, zeta potential, DLS and FT‐IR. Pluronics with different numbers of polypropylene oxide (PPO) and polyethylene oxide (PEO) units such as L64, F68 and F108 were investigated to improve the poorly soluble drug loading capacity of the Hep‐Plu system. Besides, the drug release profile in response to redox potential thanks to the disulfide bridges presented in Hep‐Plu system was also evaluated. This Hep‐Plu nanogel system is expected to be a promising carrier for redox‐responsive delivery of poorly water‐soluble drugs in cancer treatment.

Removal of old deteriorated varnish layers from an easel painting is one of the most common but also most delicate restoration treatments. Apart from purely mechanical methods various solvents or mixtures of solvents have been used for this task over the last hundred years. Most often these chemicals were applied mechanically by swabbing, but also in a form of gels. However, the resulting formation of secondary and detrimental effects (such as swelling, leaching, solvent retention as well as high toxicity to the user) forced the development of new cleaning methodologies, aimed to overcome these drawbacks, guaranteeing a safe and effective removal of the damaged material. The aim of this paper is to discuss the applicability of optical coherence tomography for a multi-faceted and complementary assessment of different varnish removal processes, including the application of a novel nanogel system, the PHB-GVL. Since some effects, like swelling, may develop in a time span of hours, which is not a typical examination time for OCT, long-lasting stability of the measurement system had been ensured. For this task, a lab-developed high-resolution OCT instrument (3 µm axial resolution in the air) was adopted and the repeatability of surface recognition of 1.5 μm over 17 hours was achieved. This permitted for tracing of swelling effects in a multi-hour scale. The most desirable effect of such a restoration treatment is the removal of varnish without any alteration to the paint layer underneath. With the use of OCT, it was possible to trace this process by a direct comparison of the topography of the paint layer under varnish (before treatment) and after treatment. The results pointing at superior properties of the PHB-GVL nanogel applied with an electrospun polymeric tissue will be presented.

Nanogel is administered via various routes to overcome physiological barriers and achieve the desired therapeutic effect in vivo. However, developing a stable nanogel system is required to retain its therapeutic efficacy after storage. Therefore, a nanogel system composed of inorganic material (Laponite) was developed using Quality by Design (QbD) and Design of Experiments (DoE), using curcumin (CUR) as a model drug. Through a comprehensive literature review, single-factor experiments and Box–Behnken Design (BBD) experiments, we identified the CQAs and critical process parameters (CPPs), ultimately obtaining the optimal formulation. The DL, EE, Ps and PDI were determined as the CQAs and the optimal formulation was successfully prepared (LAP:CUR:TPGS = 6:2:36.6; mg;10 mL). FTIR, DSC and TEM analyses confirmed the successful loading of CUR, with a Ps in100nm, exhibiting biphasic drug release characteristics and maintaining stability for 28 days at 4 °C. QbD combined with DOE successfully facilitated stable CUR-TPGS-LAP nanogels. This study helps to better understand the critical factors in the development of nanogels and lays the foundation for the future integration of AI technology to promote a “first-time-right” drug formulation for future AI-promoted ‘one-stop’ drug formulation development model.

This study describes the preparation of a core-shell nanogel system for active-targeted delivery of antigenic proteins to dendritic cells (DC cells), which play a critical role in inducing cytotoxic T lymphocytes (CTL) for effective immune response against cancer and infectious diseases. Mannose-type glycan block copolymers were synthesized and modified onto hydrophilic silica nanoparticles to create mannose-presenting nanoparticles (SiNP-Man), which were shown to selectively bind to lectin and inhibit aggregation in the presence of free mannose. This nanogel system has potential as an effective and stable antigen delivery method for CTL induction. Thus, the newly designed mannose block copolymer would have promising property to install nature of active-targeting towards mannose specific c type lectin on DC cells.

Poly(l-aspartic acid) nanogels for lysosome-selective antitumor drug delivery

This work aims to provide a basic understanding of the water dispersibility of a 1:1 stoichiometric polyelectrolyte complex (SPEC) in water in the absence of low-molecular-weight salts. We studied the complexation of a linear polyanion, potassium poly(vinyl alcohol sulfate) (KPVS), with a cationic polyelectrolyte nanogel (CPENG) composed of a lightly cross-linked copolymer of N-isopropylacrylamide and 1-vinylimidazole, in an aqueous salt-free solution (pH 3 and 25 °C), as a function of the molar mixing ratio (Mmr) of anionic to cationic groups. Also studied for comparison was the complexation of KPVS with poly(diallyldimethylammonium chloride) (PDDA), which is a standard reaction in colloid titration. Turbidimetric and conductometric measurements were used in combination of dynamic light scattering (DLS). An abrupt increase of turbidity curve and a break of conductivity curve were observed at Mmr =1 when KPVS was added to the CPENG or PDDA solution, indicating the formation of SPEC. All the complexes formed at Mmr ≤ 1 were water-dispersible and hence characterized by DLS. The CONTIN analysis of DLS data showed that (i) an increase of Mmr causes a decrease of the hydrodynamic radius (R(h)) of the nanogel complex particle but (ii) the R(h) of the PDDA complex remains unchanged at Mmr < 0.8. Taking these into account, we discussed the conductometric results in terms of the random model (RM) and all-or-none model (AONM) in polyelectrolyte complex formations. It was found that KPVS and PDDA yield a water-dispersible SPEC particle at each Mmr, accompanying the uptake of counterions (K(+) and Cl(-)) by the complex. This uptake amount was about 7% of the stoichiometric release of the counterions. In the nanogel system, a complete release of the counterions was observed at Mmr < 0.2 at which one or two KPVS chains were bound to a CPENG particle, but further KPVS binding led to about 20% of the counterion uptake to maintain electroneutrality. Thus, we suggest that the counterion uptake becomes a key factor to understand the water dispersibility of SPEC particles.

Cell-targeted, dual reduction- and pH-responsive saccharide/lipoic acid-modified poly(L-lysine) and poly(acrylic acid) polyionic complex nanogels for drug delivery

Infiltration of a long-lasting anaesthetic is helpful during the post-operative period. The recently developed local drug delivery system, biodegradable nanoparticles in a thermo-sensitive hydrogel (nanogel system), may possibly provide an extended duration of drugs. Therefore, we evaluated whether prolonged infiltration anaesthesia could be achieved by loading lidocaine into this delivery system. Thirty male rats were randomized into five groups of six rats each: saline; 2% hydrochloride lidocaine solution; lidocaine-loaded nanogel system and its compositing formulations, namely lido-nano gel; lido-nano; and lidogel. Durations of local anaesthesia with subcutaneously injected agents were measured by tail flick latency tests in a randomized, blind fashion. Lido-nano gel produced effective anaesthesia for 360+/-113 min, compared with 150+/-33 min by lidogel, 180+/-37 min by lido-nano, and 110+/-45 min by lidocaine solution (P<0.001, means+/-SD), and elicited complete sensory blockade for 300+/-114 min, compared with 75+/-37 min by lidogel, 105+/-53 min by lido-nano, and 60+/-33 min by lidocaine solution (P<0.001, means+/-SD) without severe skin/systemic toxicity. Lidocaine-loaded biodegradable nanoparticles in hydrogel produced prolonged infiltration anaesthesia in rats without severe toxicity, indicating a possible way to develop long-lasting local anaesthetics.

The aim of this was to develop a well-balanced, replaceable, and patient non-infringing innovative transdermal drug delivery system "nano-vesicle transdermal gel" (NVTG) approaches for inhibiting inflammation. To consummate this objective, we developed a skin permeation nanogel system containing surface active agent along with ethanol. Carbopol 971p, hydroxypropyl methyl cellulose (HPMC K15M), and chitosan were used to fabricate the nanogels. The nanogel system was evaluated for pH, content uniformity, spreadability, rheological studies, in vitro skin permeation, and drug release. Carbapol 971p with the desired in vitro skin permeation was utilized to investigate skin irritation test and effects on inflammation using acute inflammatory paw edema models. Moreover, in vivo pharmacokinetic study was assessed. pH of this nanogels was found within the range of 6.1-7.2, whereas the viscosity was found 310.13 to 6361cps. The ex vivo skin permeation gels showed permeation flux range, 5.9 ± 0.80 to 17.92 ± 1.13μg/cm2h. The highest permeation flux (17.92 ± 1.13μg/cm2h) was observed, which was 3.14-folds higher than that of the plain DH gel (10.72 ± 0.84μg/cm2h. Additionally, from toxicological study, no obvious signs of toxicity such as skin irritation (of laboratory rats) were identified. The in vivo anti-inflammatory behavior in carrageenan-induced rats showed comparatively higher inhibition of rat paw edema swelling by the prepared nanogel compared to that of the plain DH gel and marketed ibuprofen over 6h. The amount of drug accumulated in the skin after topical application was much higher than oral application. In conclusion, developed NVTG formulation loaded with dapoxetine HCl (DH) offers new opportunities for creating novel therapeutic modality for inflammation patients with fewer adverse effects.