Aurica P. Chiriac

Basic concepts and recent advances in nanogels as carriers for medical applications

Abstract Nanogels in biomedical field are promising and innovative materials as dispersions of hydrogel nanoparticles based on crosslinked polymeric networks that have been called as next generation drug delivery systems due to their relatively high drug encapsulation capacity, uniformity, tunable size, ease of preparation, minimal toxicity, stability in the presence of serum, and stimuli responsiveness. Nanogels show a great potential in chemotherapy, diagnosis, organ targeting and delivery of bioactive substances. The main subjects reviewed in this article concentrates on: (i) Nanogel assimilation in the nanomedicine domain; (ii) Features and advantages of nanogels, the main characteristics, such as: swelling capacity, stimuli sensitivity, the great surface area, functionalization, bioconjugation and encapsulation of bioactive substances, which are taken into account in designing the structures according to the application; some data on the advantages and limitations of the preparation techniques; (iii) Recent progress in nanogels as a carrier of genetic material, protein and vaccine. The majority of the scientific literature presents the multivalency potential of bioconjugated nanogels in various conditions. Today’s research focuses over the overcoming of the restrictions imposed by cost, some medical requirements and technological issues, for nanogels’ commercial scale production and their integration as a new platform in biomedicine.

Synergistic behavior of poly(aspartic acid) and Pluronic F127 in aqueous solution as studied by viscometry and dynamic light scattering.

Pluronic F127/poly(aspartic acid) mixtures were investigated in dilute solutions by viscometry and dynamic light scattering. The two polymers were chosen due to well known applications in biomedical field, taking into account the final purpose (the use of the complex structure as drug delivery systems). The central item was to identify the possibility of complexation between the poly(carboxylic acid) and a non-ionic polymer and to investigate the conditions of the interpolymer complex formation. The ability of Pluronic F127 to form micelle is well known. Poly(aspartic acid), as a polycarboxylic acid with resemblance with polyacrylic acid, can act as dispersant, antiscalant, superabsorber, being also able to form micelles. Due to its functional groups, -COOH and -NH(2), poly(aspartic acid) can make physical and/or chemical bonds with other macromolecular compounds. The intrinsic viscosity and the dynamic light scattering data obtained for PLU/PAS mixtures at 25 °C have shown that interpolymer complex formation occurs around 1/1 wt. ratio between the two polymers.

Hybrid collagen-based hydrogels with embedded montmorillonite nanoparticles.

Montmorillonite nanoparticles have been physically incorporated within a crosslinked collagen/poly(N-isopropyl acrylamide) network in order to adjust the properties of the stimuli-responsive hybrid systems. The research underlines both the influence of hydrogel composition and nanoparticle type on hybrid hydrogel properties. The dispersion of the montmorillonite nanoparticles in polymeric matrix have been visualized by SEM, TEM and AFM techniques and quantitatively and qualitatively estimated using near infrared chemical imaging. The electrical charge of the nanoparticles influenced the polymeric chain arrangement and the pore size. The morphologies of the nanoparticulated layers are partially exfoliated or intercalated and uniformly dispersed through the polymeric semi-interpenetrated network based on collagen and poly(N-isopropyl acrylamide). The hybrid hydrogels exhibit pseudoplastic behavior and the addition of nanoparticles has resulted in the increase of the complex viscosity. The adhesion capacity was affected mainly by the presence of organically modified montmorillonites.

Novel Environmentally Friendly Copolymers Carboxymethyl Starch Grafted Poly(Lactic Acid)

Modified natural polymers have been gaining increasing scientific interest for many years. In this study carboxymethyl starch (CMS) was grafted with L(+)-lactic acid (LA) in different molar ratios CMS/LA (1/36, 1/22 and 1/12), resulting carboxymethyl starch-g-poly(lactic acid) (CMS-g-PLA) copolymers. The grafting reaction was carried out by solution polycondensation procedure in toluene and stannous 2-ethyl hexanoate Sn(Oct)2 as catalyst was utilized. Poly(lactic acid) (PLA) was synthesized in the same conditions with the copolymers for comparative analyses of the physico-chemical and thermal properties. The copolymers and PLA were structurally and morphologically characterized by FT-IR, 1H-NMR spectroscopy, WAXD and SEM analyses, taking CMS as reference. The molecular weight of the copolymers, CMS and PLA were determined, using a dynamic light scattering technique. The thermal behavior of the products was studied by DSC and TG-DTG analyses. The CMS-g-PLA graft copolymers exhibited lower Tg and thermal stability than pure CMS.

Biocompatibility, biodegradability, and drug carrier ability of hybrid collagen-based hydrogel nanocomposites

The biocompatibility, biodegradability, and drug carrier capacity of new types of hybrid hydrogels were evaluated for potential medical applications. The effects of swelling and deswelling of the hybrid hydrogels on drug loading and release capacity were evaluated. The hybrid hydrogels with Dellite® 67G and Cloisite® 93A had superior collagenase resistance compared to hydrogels without the inorganic nanoparticles. The effect of the hybrid hydrogels on the immune response parameters was followed by evaluating the chronic inflammation in rats. These hybrid hydrogels have the potential for medical and pharmaceutical applications as well as for scaffolds production in the reconstruction and regeneration of burned tissues with control of inflammatory processes.

Characterization of the semi-interpenetrated network based on collagen and poly(N-isopropyl acrylamide-co-diethylene glycol diacrylate).

The study is devoted to the characterization of the semi-interpenetrating polymeric network (semi-IPN) structures, prepared as dual sensitive networks, based on poly(N-isopropyl acrylamide-co-diethylene glycol diacrylate) inserted into a collagen porous membrane with potential biomedical-applications. The pharmaceutical applications are related to the possibility of using the semi-synthetic networks for inclusion, retention, transportation and release of drug molecules. The insertion and the homogeneity distribution of the drug into the polymeric network were evaluated by near infrared-chemical imaging (NIR-CI) technique. The drug release was investigated from the kinetically viewpoint in simulated biological environment by using UV-vis spectrophotometric technique. The zeta potential measurement results showed meaningful change of the electric potential of the network surface at the interfacial double layer with the environment in the interdependence with the network composition and environment characteristics. The biodegradable character of the semi-synthetic network, also presented, undergoes with tissue engineering request for achievement of tissue substituents. Texture analysis of the semi-IPN was realized in order to evidence the potential applications of the prepared compounds in tissue engineering. The adhesion properties reveal the possibility to control the surface adhesion by: network composition, the ratio between the polymer types, and the crosslinking degree of polymeric networks. The evaluation of the semi-IPN characteristics in medical terms, concerned the surface electrical charge, the loading, retention and release properties of an active compound, the adhesion properties and the effect of collagenase enzyme over the collagen fibres as component in semi-IPN, and from the pharmaceutical terms emphasizes the potential applications of the new polymeric semi-IPN networks.

Upon synthesis of a polymeric matrix with pH and temperature responsiveness and antioxidant bioactivity based on poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane) derivatives.

Poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane), acquired through radical polymerization, was synthesized with the aim to prepare an alternant copolymer with precise placement of functional groups along the polymer backbones. The new structure owing to the suitable and specific functionalities is anticipated to be used as reactive polymer to link bioactive compounds via maleic anhydride moiety. The copolymer was improved in its functionality by maleic anhydride ring opening with different amounts of erythritol in order to confer antioxidant characteristics to the polymeric structure. The chemical structure of the new prepared polymers was confirmed by FTIR and (1)H NMR spectra, and the polymers were also characterized from the viewpoint of their thermal stability. The dual sensitivity of the polymeric structure, at temperature and pH, was evaluated by determining the hydrodynamic radius and zeta potential in interdependence with the environment conditions. The polymer morphology was investigated by SEM. The antioxidant character was evaluated measuring the scavenger properties of the functionalized copolymer with erythritol against the 2,2-diphenyl-1-picrylhydrazyl radicals. The acute toxicity investigation, realized in vivo for the copolymer and the derivatives, allows the inclusion of the compounds into the group of moderately toxic accordingly to Hodge and Sterner toxicity scale owing to the lethal dose 50 determined values.

Polymerisation in a magnetic field: 12. A comparative study regarding some properties of poly(acrylamide) synthesised in a magnetic field

Poly(acrylamide) synthesised in a continuous external magnetic field procedure is characterised in comparison with some properties of the homopolymer obtained by classic procedures. The observed changes in the structure of the macromolecular compounds synthesised in magnetic field by determination of molecular weights, IR and UV spectra and thermal stability are detailed.

Design and synthesis of a new polymer network containing pendant spiroacetal moieties

The present work describes the synthesis, properties, and sensitive behavior of a set of copolymers based on itaconic anhydride with different molar ratios of 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5] undecane prepared through radical polymerization process, in the presence of 2,2-azobisisobutyronitrile as initiator. The chemical structure of the prepared copolymers was confirmed by FTIR and 1H NMR. The macromolecular compounds were characterized from the viewpoint of their thermal stability. The sensitivity of the new structures was evaluated by determining the hydrodynamic radius in interdependence with environmental conditions, and rheological properties were studied in terms of shear rate and viscosity. The versatility and untapped potential of these stimuli-sensitive polymeric systems generated by both comonomers – network formation, biodegradability and biocompatibility, gel formation capacity, binding properties, amphilicity, good oxidative and thermal stability, good films formers, acid pH sensitivity, the possibilities to modify the anhydride ring through suitably reactions – makes them promising agents for pharmaceutical delivery systems or support for bioactive compounds, among other applications.

Multifunctional nanogels with dual temperature and pH responsiveness

Over the last 10 years, the development of intelligent biomaterials for medical and pharmaceutical applications has attracted growing interest by combining interdisciplinary efforts. Between them nanogels represent one of the most attractive carriers for innovative drug delivery systems. In the present investigation new variants of multi-responsive nanogels have been synthesized by crosslinking poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane) copolymer (having different molar ratios between comonomers) with 1,12-dodecandiol. The new structures were obtained by using modification of itaconic anhydride moieties in the copolymer. This is a convenient method for the preparation of a network with increased functionality, which further may ensure new strategies for coupling various bioactive compounds, especially owing to the behavior of the used copolymers, which present dual pH and temperature sensitive characteristics. The chemical structure of the new compounds was confirmed by FTIR and 1H RMN spectra. Also, the evaluation of thermal stability by thermogravimetric analysis sustains the covalent bonds occurring between the copolymer and diol. The dual responsiveness of the nanogel structures to temperature and pH was put into evidence by DLS studies. This feature can be used for the development of drug delivery systems, which can mimic biological response behavior to a certain extent. The new synthesized nanogels were tested as drug delivery systems by using diclofenac as a model drug. The results obtained from in vitro and in vivo investigation confirm the bioactivity of the nanogel networks.