Ryoichi Katakai

Controlled release of biomolecules from temperature-sensitive hydrogels prepared by radiation polymerization

Poly(acryloyl-L-proline methyl ester)-based hydrogels containing 1 and 5% of a crosslinking agent were studied as drug delivery systems. The drug loading properties were investigated by matrix incubation into solutions containing biomolecules with molecular weight ranging between 300 and 65,000 Da. The loading yield was found to depend on both the crosslinking degree and the molecular weight of the drug. In vitro release studies were carried out with both swollen and dry matrices loaded with gentamicin, isoniazid and insulin. Gentamicin and isoniazid were released by a bimodal Fickian diffusion with a remarkable burst that was found to depend on both matrix crosslinking degree and physical state. In vivo, the subcutaneous implantation into mice of the isoniazid loaded matrices allowed for an efficient drug release for 800 h. In vitro insulin was released from the swollen matrices for 1500 h by diffusional Fickian mechanism while the dry ones displayed a lag time followed by Fickian diffusion release. The subcutaneous implantation of the insulin-loaded matrices into diabetic mice induced a remarkable decrease in the glucose concentrations in blood. In particular, the dry 1% matrices were found to maintain a low glucose level for 700 h.

Biodegradable implant composites for local therapy

Abstract Implantable polymer-drug composites prepared by radiation polymerization have been applied to cancer therapy. Local chemotherapeutic treatment can be achieved by te use of implantable needles and buttons consisting of polymer and various anticancer agents. For example, the luteinizing hormone releasing hormone (LHRH) agonist-polymer needles have been successfully used for the hormone therapy of prostatic organ cancers. The effects of chemical structure on the in vivo degradation and controlled release were studied for biodegradable polymers of polypeptides, poly(α-hydroxy acids) and polydepsipeptides.

Characteristics of acrylic acid and N‐isopropylacrylamide binary monomers–grafted polyethylene film synthesized by photografting

Method for introducing grafted chains consisting of two types of monomer components, acrylic acid (AA) and N-isopropylacrylamide (NIPAAm), into low-density polyethylene (PE) film (thickness = 25 μm) was investigated by two photografting technique using xanthone photoinitiator at 60°C. In the first method (one-step method), AA and NIPAAm binary monomers were graftcopolymerized onto PE film. In the second method (two-step method), AA was first photografted onto PE film and then NIPAAm was further introduced into the AA-grafted PE film by a second-step photografting. Water absorbencies of the grafted films (one- and two-step samples) prepared by the one- and two-step methods, respectively, decreased in the order of AA-grafted film > one-step sample > two-step sample > NIPAAm-grafted film. The water absorbency steeply decreased at 20 to 40°C with increasing temperature when immersed in water at the temperatures (5–60°C) for 24 h. Thermosensitivity, which was defined as the ratio of water absorbencies of the grafted samples at 5 and 60°C, was higher for the one-step sample than the two-step one. The different extent of the water absorbency and the thermosensitivity between both samples is discussed in terms of location of grafted chains in the film substrate, which was determined by electron probe microanalysis and attenuated total reflection–infrared measurements, and monomer sequence distribution of the grafted chains.

Artificially intelligent hydrogels responding to external stimuli such as temperature and pH

Abstract Methacryloyl-D-alanine methyl ester (MA-D-AlaOMe) and methacryloyl-L-alanine methyl ester (MA-L-AlaOMe) were synthesized and polymerized by irradiation using γ-rays from a 60Co source, in order to investigate the effect of optical isomerism on the swelling of homopolymer hydrogels which changes in temperature in water. These hydrogels showed a typical thermo-response such as low-temperature-swelling and high-temperature-deswelling, but no difference in swelling between the two hydrogels could be regarded as significant. The stable swelling-deswelling kinetics on repeated use are characterized by very limited temperature ranges (0–40°C), and above this range (for example, when cycled between 10 and 70°C) the reversible thermo-response perfectly disappeared because of gel collapse. This defect could be overcome by copolymerization with other functional monomers and the resulting copolymers exhibited a reversible thermostability superior to those of homopolymers of MA-D-AlaOMe and MA-L-AlaOMe, depending strongly upon the type of copolymer and its composition. The hydrolysis products of these hydrogels gave a reversible-response not only for temperature but also for pH. The swelling-deswelling kinetics of non-hydrolyzed and hydrolyzed hydrogels were characterized with regard to porous structure formed in the hydrogel.

Synthesis of aromatic polyketones by using biphenylene monomers

Bisfunctional biphenylene monomers were designed, synthesized, and inspected as building blocks for aromatic polyketone synthesis. Starting from 2,2′-dimethoxybiphenylene (1), a highly activated acyl-acceptant biphenylene monomer affording high molecular weight polyketones, two types of biphenylene monomers were developed: 5,5′-bis(3[4]-chlorobenzoyl)-2,2′-dimethoxybiphenylenes (6) which readily gave the corresponding polyketones by nickel-catalyzed aromatic coupling polymerization and 2,2′-bis(trifluoromethyl)-4,4′-biphenylenedicarboxylic acid (27) which reacted with biphenylene 1 in P2O5CH3SO3H to give the corresponding fluorinated aromatic polyketone, selectively. The related model reactions for both monomer synthesis and polymerization were also investigated.

THE STATE OF WATER IN THERMORESPONSIVE POLY(ACRYLOYL-L-PROLINE METHYL ESTER) HYDROGELS OBSERVED BY DSC AND 1H-NMR RELAXOMETRY

Hydrogels that reversibly swell or shrink in water with decreasing or increasing temperature, respectively, were obtained by γ ray-induced polymerization of acryloyl-l-proline methyl ester in the presence of different amounts of a crosslinking agent. The role of water in the hydrated polymers was investigated by DSC and 1H-NMR relaxometry. From the curves of fusion of water determined by the former it was possible to ascertain that the amount of both freezing and non freezing water decreased with increasing the crosslinker percentage and/or swelling temperature. Moreover, at the temperatures higher than 37°C, the water absorbed by the different hydrogels is mostly present as non freezing water. The 1H-NMR relaxometry study enabled the spin–spin and spin–lattice relaxation curves to be analyzed. It was possible to distinguish three “populations” of protons and identify two of them with protons of freezing and non freezing water determined by DCS.

Reversible on-off switch function of ion-track pores for thermo-responsive films based on copolymers consisting of diethyleneglycol-bis-allylcarbonate and acryloyl-L-proline methyl ester

Abstract Intelligent chemical valves responding to a slight change of temperature were created by the combination of ion beam-chemical etching technique and a novel material consisting of an ion track detector material diethyleneglycol-bis-allylcarbonate (CR-39) and a thermo-responsive gel acryloyl-L-proline methyl ester (A-ProOMe). The changes in size of ion-track pores in etched films were measured microscopically by repetition between 0 and 30°C at 24-h intervals for a 50 μm thick copoly(CR-39/A-ProOMe, 60 40 mol % ) film which was obtained by etching in aqueous 6M NaOH solution at 60°C after an 11.6 MeV/n 208Pb ion irradiation and, as a result, it was found that the pore size in the film obtained by etching for 10 min is reversibly changed from a perfectly closed pore at 0°C to a fully opened pore with a diameter of 0.30 μm at 30°C.

Light-scattering study of temperature-responsive poly(acryloyl-l-proline methyl ester)

Abstract Poly(acryloyl- l -proline methyl ester) (A-ProOMe) obtained by radiation-induced polymerization exhibited a lower critical solution temperature (LCST) at ca 14°C. Physical properties such as molecular weight ( M W ), particle radius of gyration ( 〈S 2 〉 1 2 ), and particle size distribution were investigated by static and dynamic light-scattering measurements as a function of temperature. The M W of poly (A-ProOMe), obtained by irradiating up to 30 kGy at 25°C, increased from 1,270,000 at 10°C to 56,100,000 at 20°C in water; on the other hand, the 〈S 2 〉 1 2 value decreased with rise in temperature, e.g. from 40.5 to 20.1 nm between 10 and 20°C. From the results of particle size distribution, it was concluded that polymers, dissolved in water below the LCST, aggregate to make globules above LCST.

Application of ion beams to synthesis of environmentally responsive track membranes

Abstract Heavy ion beams with energy in the order of 10 MeV/n were irradiated onto polyethylene terephthalate (PET) and polydiethyleneglycol-bis-allylcarbonate commercially known as CR-39 for producing organic porous membranes. The condition to obtain cylindrical pores was accounted for the relation of restricted energy loss, REL, from ion beams to the polymer films with relative etching rate, Q, in the region along ions trajectory versus non-irradiated region. Then the porous membranes were chemically modified by grafting such monomers as N-isopropylacrylamide and acryloyl-L-proline methyl ester onto the surface of pores to impart the characteristic of the hydrogel obtained from these polymers to the membrane. The pore size of the membrane changed from an open state to a completely closed state when environmental conditions such as temperature were changed. The permeation of water, choline, insulin and albumin through the membrane was controlled by temperature. An abrupt change of permeability was observed at the phase transition temperature of the hydrogel.

Functional polymeric microspheres synthesized by radiation polymerization

New functional microspheres consisting of diethylene glycol dimethacrylate (2G) and a methacryloyl monomer containing four amino acids, l-asparagynyl-l-alanyl-l-asparagynyll-proline methyl ester (MA-NANPOMe) were synthesized by radiation induced co-polymerization. These four amino acids were previously identified as a part of the immunodominant region of the circumsporozoite (CS) protein of Plasmodium falciparum. The use of this synthetic peptide as an antigen in immunoassay for malaria is promising: the microspheres exposed to the sera of malaria patients showed marked fluorescence, while the spheres contacted with sera of healthy donors showed no fluorescence.