Tetsuji Yamaoka

Comparison of Body Distribution of Poly(vinyl alcohol) with Other Water-soluble Polymers after Intravenous Administration

The body distribution of poly(vinyl alcohol) (PVA) with molecular weights (MW) from 14800 to 434000 Da was investigated after intravenous administration and compared with that of other water‐soluble polymers such as poly(ethylene glycol) (PEG), gelatin, dextran, and pullulan.

Body distribution profile of polysaccharides after intravenous administration

AbstractThe body distribution of pullulan and dextran, which are nonionic polysaccharides, was studied. After intravenous injection of 125I-labeled polysaccharides with different molecular weights, the half-life period in the blood circulation and the body distribution were pharmacokinetically investigated and compared with those of polyethylene glycol (PEG) and polyvinyl alcohol (PVA). Polysaccharides of higher molecular weights circulated in the bloodstream for a longer period than those of lower molecular weights. The half-life period of pullulan ranged from 15 to 90 min, changing remark-ably around molecular weight 30,000, and was shorter than that of dextran. Body distribution studies demonstrated that pullulan tended to accumulate in the liver to a greater extent than dextran, whereas PEG and PVA were hardly disposed there. This preferable accumulation of polysaccharides in the liver was observed over the whole molecular weight range studied. Eighty percent of pullulan with large molecular weights w...

Prolongation of the serum half-life period of superoxide dismutase by poly(ethylene glycol) modification

Abstract Superoxide dismutase (SOD) was chemically modified using poly(ethylene glycol) (PEG) with different molecular weights to prepare PEG–SOD conjugates with different extents of modification. The body distribution of the conjugates intravenously injected to mice was investigated to assess the influence of modification on the serum half-life period of SOD. The SOD modification with PEG was effective in lowering the elimination rate of SOD from the blood circulation without any change in the distribution pattern of organs other than the kidney. The molecular weight of PEG used for modification and the modification extent have a minimum effect on the half-life of the SOD. The half-life of the SOD and its PEG conjugates have a similar dependency on the apparent molecular weight as the PEG molecules. This indicates that the half-life of SOD and the PEG conjugates are mainly determined by their molecular size.

Synthesis and properties of malic acid-containing functional polymers.

Poly-L-lactides containing beta-alkyl alpha-malate-units were prepared by ring-opening copolymerizations of L-lactide with 3-(s)-[(benzyloxycarbonyl)methyl]- (BMD) and 3-(s)-[(dodecyloxycarbonyl)methyl]-1,4-dioxane-2,5-diones (DMD). The solution-cast films of these copolymers were alkali-treated to form a carboxyl-functionalized surface on which cell-binding Arg-Gly-Asp tripeptide (RGD) was immobilized with dicyclohexylcarbodiimide as coupling agent. For the copolymer of L-lactide and BMD the benzyl groups were removed by catalytic hydrogenolysis to obtain a fully carboxyl-functionalized copolymer (PLGM), and RGD was immobilized on the surface of its cast film. All the RGD-immobilized films thus prepared exhibited improved cell attachment compared with the original films. The cell attachment increased with increasing amount of immobilized RGD, which depended on the composition of the alpha-malate units in the copolymer. The RGD-immobilized PLGM films were degraded rapidly during the cell culture, while the RGD-immobilized films of the beta-alkyl alpha-malate-containing polymers survived the cell culture with little degradation. The rate of hydrolysis increased with increasing content of alpha-malate units for both series, depending on the structure of the protecting groups of the beta-carboxyl. These results suggest that the RGD-immobilized polymers could be a new class of functional bioresorbable polymer having improved cell-attachment and adjustable hydrolysis rate.

Body distribution of dextran derivatives with electric charges after intravenous administration

The body distribution of electrically charged dextran derivatives was investigated after intravenous administration of 125I-labeled dextrans. The effects of the charge density and molecular weight of dextran derivatives on their half-lives in the circulation and organ distribution were pharmacokinetically analyzed. The introduction of negative charges into the dextran molecule prolonged its half-life in the circulation. This trend became more marked with increasing molecular weight of the dextran, however, its half-life was reduced by derivatization with cationic diethylaminoethyl groups. The cationized dextran accumulated in the liver more significantly than the anionized and original dextrans. For example, approx. 10% substitution of dextran with the diethylaminoethyl group was sufficient to enhance the accumulation of dextran in the liver and spleen, but no effect of cationic derivatization was observed for the distribution in other tissues.

Synthesis and properties of multiblock copolymers consisting of poly (L-lactic acid) and poly (oxypropylene-co-oxyethylene) prepared by direct polycondensation

A multiblock copoly(ester–ether) consisting of poly(l-lactic acid) (PLLA) and poly(oxypropylene-co-oxyethylene) (PN) was prepared and characterized. Preparation was done via the solution polycondensation of a thermal oligocondensate of l-lactic acid, a commercially available telechelic polyether (PN: Pluronic-F68), and dodecanedioic acid as a carboxyl/hydroxyl adjusting agent. When stannous oxide was used as the catalyst, the molecular weight of the resultant PLLA/PN block copolymers became very high (even with a high PN content) under optimized reaction conditions. The refluxing of diphenyl ether (solvent) at reduced pressure allowed the efficient removal of the condensed water from the reaction system and the feed-back of the intermediately formed l-lactide at the same time in order to successfully bring about a high degree of condensation. The copolymer films obtained by solution casting became more flexible with the increasing PN content as soft segments.

Body distribution of intravenously administered gelatin with different molecular weights

Abstract Radiolabelled gelatin with average molecular weights ( M w ) of 2700, 9700, 56 000 and 99 000 was intravenously administered to mice to study the change of body distribution with time. The half-life period of gelatin in the blood circulation ranged from 7.8 min for M w of 2700 to 315 min for M w of 99000. When compared at a similar M w , the half-life period of gelatin was always shorter than that of poly(ethylene glycol) and poly(vinyl alcohol) which were also water-soluble polymers but not ionically charged. The gelatin molecules intravenously administered were hardly accumulated in heart, lungs and spleen, but mostly in carcass and finally excreted from kidneys. Staying of low -M w gelatin in liver was not significant although the amount accumulated tended to increase with M w . The time course of gelatin accumulation in the carcass exhibited a peak within 20 min after intravenous administration except for gelatin with M w of 99000 which was much slowly accumulated to the carcass during the initial 3 h after injection. The excretion rate of gelatin to urine increased with M w , but 60% of gelatin was excreted from the body 400 min after intravenous injection even for the highest M w . Moreover, pharmacokinetic analysis demonstrated that the tissue clearance of gelatin was higher than that of other polymers although the excretion clearance was similar, irrespective of the polymer type and M w . This indicates that gelatin tends to be distributed more dominantly from the plasma to tissues than other polymers, leading to a shorter half-life period in the circulation.

Blood Clearance and Organ Distribution of Intravenously Administered Polystyrene Microspheres of Different Sizes

hen considering effective delivery of drugs to the site of action by W polymeric drugs carriers, it is essential to learn the biological fate of the polymeric carriers themselves after administration into the body. To this end, numerous investigations have been reported on the organ distribution of polymer microspheres: polystyrene [1-6], polycyanoacrylate [7-10], serum albumin [11-14], starch [15,16], acrylic polymers [17,18], and poly(glycolic acid) microspheres [19]. In addition, liposomes [20] and carbon particles [21] were examined as drug carriers. It has been suggested that the general fate of foreign particles in the body depends on their size and surface properties. For instance, it was demonstrated that microspheres with diameter larger than about 7 ,m tended to be trapped in the lungs while smaller ones were located in the liver or spleen [2]. Moreover, the effect of the surface properties on the body distribution of microspheres has been observed [22-24]. It was demonstrated that coating the microspheres with surfactants, which

Radiolabeling of polystyrene by γ-ray irradiation in the presence of Na 125I solution

Abstract The radiolabeling of polystyrene microsphere and film was carried out by γ-ray irradiation under immersion in Na 125I aqueous solution. It was found that radiolysis of Na 125I aqueous solution occurred upon γ-ray irradiation to form I2 molecules, which formed charge transfer complex with polystyrene. The complex formation was confirmed with UV and vis spectrophotometry. The spectrum of polystyrene film irradiated in the presence of NaI aqueous solution was similar to that of the polystyrene film forming charge transfer complex with I2 molecules in gas phase andits λmax value was almost the same as that of the complex between I2 and benzene, indicating that produced I2 molecules form CT complex with benzene ring of the polystyrene by γ-ray irradiation. The stability of the complex was studied in phosphate buffered saline solution, alcohol and mouse peritoneal cavity.