Loredana E. Nita

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.

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.

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.

Investigation of Poly(vinyl alcohol)/Pluronic F127 Physical Gels

The application of Pluronic F127 as injectable gel-forming solution is limited by poor mechanical properties. The purpose of this study was to develop low viscosity formulations at ambient temperature that undergo a transition to gel under physiological conditions. Mixtures of Pluronic F127 and poly(vinyl alcohol) with different compositions were prepared in aqueous solutions and their in-situ gelation was investigated by dynamic light scattering and rheology. The results obtained for different formulations showed synergistic effects of polymer mixtures in aqueous media and their properties can be tuned by varying polymer concentration, system composition or changing temperature.

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.

Indomethacin uptake into poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2, 4,8,10-tetraoxaspiro (5.5)-undecane) network: In vitro and in vivo controlled release study

Networks based on poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane), synthesized through radical dispersion polymerization, were used as template for indomethacin (INN) as model drug. The copolymers were characterized by swelling studies at three pH values (2.4, 5.5 and 7.4) and two temperatures (room temperature 24 °C and physiological temperature 37 °C). Fourier transform infrared (FTIR) spectroscopic analysis was used to sustain the copolymer structures. Scanning electron microscopy (SEM) and thermogravimetric (TG) investigations were used to examine microstructure and appreciate the thermal stability of the polymer samples. The studies of the INN drug release from the copolymer networks were in vitro performed. The in vivo study results (biocompatibility tests, somatic nociceptive experimental model (tail flick test) and visceral nociceptive experimental model (writhing test)) are also reported in this paper.

Sulfadiazine—Chitosan Conjugates and Their Polyelectrolyte Complexes with Hyaluronate Destined to the Management of Burn Wounds

In the present study polyelectrolyte complexes (PECs) based on new sulfadiazine-chitosan conjugates with sodium hyaluronate have been developed with potential use in treatment of burn wounds. The PECs were chemically characterized using Fourier Transform—Infrared Spectroscopy, Scanning Electon Microscopy and Near Infrared Chemical Imaging Technique. The swelling behavior and in vitro sulfadiazine release were also investigated. The antimicrobial activity was evaluated towards three bacterial strains: Escherichia coli, Listeria monocytogenes and Salmonella thyphymurium. The developed PECs demonstrated their antimicrobial efficiency against tested bacterial strains, the PECs containing sulfadiazine-modified chitosan being more active than PECs containing unmodified chitosan.

Patterning poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) copolymer bioconjugates for controlled release of drugs.

Owing to the special characteristics and abilities polymeric networks have received special interest for a range of biomedical applications especially for drug delivery systems. This study was devoted to preparation of new polymeric compounds based on maleic anhydride and 3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane copolymer (poly maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) (PMAU) patterned as a network for bioconjugation and tested as drug carrier systems. The PMAU copolymer was improved in its functionality by opening the maleic anhydride ring with different amounts of erythritol, which is free of side effects in regular use and a multifunctional compound, and also confers antioxidant character for the new compounds. The new polymeric matrices were loaded with acetaminophen, codeine and their fixed dose combinations. The investigation demonstrated the capability of the new structures to be used as polymer networks for linking bioactive compounds and to perform controlled delivery. The physico-chemical investigations--Fourier transform infrared spectroscopy (FTIR) spectra, contact angle, zeta potential (ZP - z, PMAU and its derivatives samples loaded with medicines present decreased values of zeta potential attesting the bioconjugate formation and as well their stability), and hydrodynamic radius, near infrared chemical imaging evaluation (new specific bands being registered for bio-conjugate with acetaminophen around of 1150-1200 nm and 1700 nm, and also between 1150 and 1200 nm in case of the codeine bio-conjugate), scanning electron microscopy (SEM) studies, X-ray diffraction analysis--evidenced the formation of the bioconjugates in relation to the chemical composition of the polymer matrices, while in vitro release study and in vivo tests confirm the capacity for drug delivery of the prepared bioactive systems.

Upon some multi-membrane hydrogels based on poly( N , N -dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) Undecane): preparation, characterization and in vivo tests

The study presents the possibility of preparation of multi-membrane gel systems with different morphologies and properties, based on poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) copolymer and crosslinked with N,N′-methylene-bis-acrylamide. The basic copolymer has dual thermo- and pH sensitive character. After the core hydrogel is realized, the preformed gel is immersed in the aqueous solutions of ammonia, sodium chloride and sodium citrate for further edge constructing of the supramolecular assemblies. Then, the new layers by adding new sets of gelifying components are realized. The new multi-membrane gel systems are intended to be used as matrix for bioactive substances embedding. In this context the systems were loaded with norfloxacin as drug model. The in vivo tests show good biocompatibility for the implants based on multi-membrane gel structures loaded with drug.