Long-term doxorubicin release from multiple stimuli-responsive hydrogels based on α-amino-acid residues.

We have developed a series of pH- and temperature-stimuli-sensitive vinyl hydrogels, bearing α-amino acid residues (L-phenylalanine, L-valine) and incorporating magnetic nanoparticles of different chemical compositions (CoFe2O4 and Fe3O4). The goal was to study the potential applications of these nanocomposites in the controlled release of doxorubicin (DOXO), a potent anticancer drug. The strength of the electrostatic interaction between the protonated nitrogen of the DOXO molecule and the ionized carboxylic groups of the hydrogel allowed effective control of the drug release rate in saline solutions. The embedded magnetic nanoparticles were an additional remote control of the drug release under the stimulus of an appropriate external alternating magnetic field (AMF). Data showed that the controlled release of DOXO proceeded for months and followed a diffusion-controlled release mechanism, while maintaining the amount of released drug within acceptable therapeutic windows. The amount of the released DOXO was found in all cases substantially higher than the "control" because the application of the AMF augments in stimulating the nanoparticles within the DOXO-loaded hydrogel. In vitro experiments have shown that the released DOXO is able to induce cell death to cervix adenocarcinoma cells (HeLa cells).

Biohydrogels with magnetic nanoparticles as crosslinker: characteristics and potential use for controlled antitumor drug-delivery.

Hybrid magnetic hydrogels are of interest for applications in biomedical science as controlled drug-delivery systems. We have developed a strategy to obtain novel hybrid hydrogels with magnetic nanoparticles (NPs) of CoFe(2)O(3) and Fe(3)O(4) as crosslinker agents of carboxymethylcellulose (CMC) or hyaluronic acid (HYAL) polymers and we have tested these systems for controlled doxorubicin release. The magnetic NPs are functionalized with (3-aminopropyl)trimethoxysilane (APTMS) in order to introduce amino groups on the surface. The amino coating is determined and quantified by standard Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy methods, and by cyclic voltammetry, a novel approach that permits us to look at the solution properties of the functionalized NPs. The gel formation involves the creation of an amide bond between the carboxylic groups of CMC or HYAL and the amine groups of functionalized NPs, which work as crosslinking agents of the polymer chains. The hybrid hydrogels are chemically and morphologically characterized. The rheological and the water uptake properties of the hydrogels are also investigated. Under the application of an alternating magnetic field, the CMC-HYAL hybrid hydrogel previously loaded with doxorubicin shows a drug release greater than that showed by the CMC-HYAL hydrogel crosslinked with 1,3-diaminopropane. In conclusion, the presence of magnetic NPs makes the synthesized hybrid hydrogels suitable for application as a drug-delivery system by means of alternating magnetic fields.

Vinyl polymers based on L-histidine residues. Part 2. Swelling and electric behavior of smart poly(ampholyte) hydrogels for biomedical applications.

Hydrogels based on the uncharged N-isopropylacrylamide and the ionic ampholyte N-acryloyl-L-histidine showed a reversible multiple-responsive volume change and volume phase transition behavior in aqueous solution. The phase transition phenomenon was induced by the temperature, the pH, the salt-type concentration, and the electric potential. The kind of cation (Na+, K+, Cs+, Mg2+, Ca2+, Sr2+) and anion (Cl-, ClO4-, NO3-, SO4(2-)) strongly influenced the critical concentration that improved the phase separation of the gels. The volume of the collapsed gel can be hundred times smaller than that of the swollen one. The oscillatory swelling of the gels in response to temperature and pH (4 and 9) changes was fast and reversible, while the contractile behavior in the electric field showed response only at pH 9, i.e., when the amount of negative charges on the L-histidine residues predominated. The electrically induced anisotropic gel deswelling was attributed to the syneresis of water from the gel. The nontoxicity against the RAW264 cell line and the low osmotic pressure exhibited by the swollen gels make these compounds useful scaffolds for human organs. The ability to load and release an ionizable drug molecular model (ferulic acid) from the hydrogels was shown also at different pH values.

Vinyl polymers based on L-histidine residues. Part 1. The thermodynamics of poly(ampholyte)s in the free and in the cross-linked gel form.

Amphiphilic vinyl polymers (in the free and cross-linked forms), carrying carboxyl and imidazole groups, were prepared by a radical polymerization of the purposely synthesized N-acryloyl-L-histidine. The protonation thermodynamic studies (at 25 degrees C in 0.15 M NaCl) showed high polyelectrolyte character of the soluble polymer. Unlike the linear decreasing trend of the basicity constant, over the whole range of alpha (degree of protonation), the enthalpy changes for the protonation of the imidazole nitrogen in the polymer showed a decreasing pattern only at alpha > 0.5. This was ascribed to the formation of hydrogen bonds between protonated and free neighboring monomer units. Viscometric data revealed a minimum hydrodynamic volume of the polymer at its isoelectric point (pH 5), whereas at higher or lower pHs, the macromolecule expanded greatly as a consequence of the charged sites formation. This produced a preferential solvation of the protonated imidazole and carboxylate ions, the latter being surrounded by more water molecules in the hydration shell. The peculiar hydration behavior was confirmed in the cross-linked polymer. The hydrogel showed an equilibrium degree of swelling (EDS), strongly dependent on pH, in a similar manner as viscometric data of the soluble polymer. A linear relationship between the reduced viscosity and the EDS was found. The polymer was non toxic against the RAW264 cell line.