Dextran-based nanoparticles with 5-FU-conjugated polymethacrylate segments for drug delivery: Synthesis of amphiphilic graft copolymers by mechanochemical solid-state polymerization and characterization.

Dextran (Dx) is a biodegradable and biocompatible polysaccharide, thus promising as a drug delivery carrier for tumor therapy. Herein, we applied mechanical energy to a high molecular weight Dx to control its molecular weight and simultaneously generate mechanoradicals. The solid-state polymerization of methacrylate- or methacrylamide derivatives initiated with Dx mechanoradicals showed polymer conversion of >95%, yielding Dx-based graft copolymers with molecular weights of approximately 30,000 g mol.

Characterization of a novel polymeric prodrug of an antibacterial agent synthesized by mechanochemical solid-state polymerization.

Polycrystalline methacryloyl monomers of the antibacterial drug nalidixic acid with an anhydride bond to the drug carboxyl group were prepared. The physicochemical properties of the synthesized vinyl monomer were characterized using X-ray powder diffraction, thermal analysis, and polarized light microscopy measurements. Mechanochemical solid-state polymerization of the resulting monomers was carried out to yield a novel polymeric prodrug.

Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen.

A detailed electron spin resonance (ESR) analysis of mechanically induced free radicals (mechanoradicals) formation of glucose-based polysaccharides, dextran (Dx) and glycogen (Gly) was performed in comparison with amylose mechanoradicals. The ESR spectra of the samples mechanically fractured at room temperature were multicomponent. The radical concentration of Dx and Gly mechanoradicals gradually decreased during vibratory milling after reaching the maximum value.

Development of Novel Polymeric Prodrugs Synthesized by Mechanochemical Solid-State Copolymerization of Hydroxyethylcellulose and Vinyl Monomers.

Novel polymeric prodrugs were synthesized by mechanochemical solid-state copolymerization of hydroxyethylcellulose and the methacryloyloxy derivative of 5-fluorouracil (5-FU). Copolymerization was about 94% complete after 4 h, and the polymeric prodrug was quantitatively obtained after 14 h of reaction. The number average molecular weight (Mn) and polydispersity (H) of the polymeric prodrug were 39000 g/mol and 6.

Novel pH-responsive polymeric micelles prepared through self-assembly of amphiphilic block copolymer with poly-4-vinylpyridine block synthesized by mechanochemical solid-state polymerization.

We fabricated polymeric micelles containing 5-fluorouracil (5-FU) or fluorescein using the amphiphilic block copolymer, poly-4-vinylpyridine-b-6-O-methacryloyl galactopyranose. Although the polymeric micelles were stable at pH 7.4, they readily decomposed at pH 5, resulting in near complete release of 5-FU.

Characterization of novel pH-sensitive polymeric micelles prepared by the self-assembly of amphiphilic block copolymer with poly-4-vinylpyridine block synthesized by mechanochemical solid-state polymerization.

We fabricated novel pH-sensitive polymeric micelles consisting of amphiphilic block copolymer containing pyridyl groups as side chains in the hydrophobic block. The number average particle diameter of the polymeric micelles at pH 7 was approximately 200 nm. A decrease in pH resulted in deformation of the polymeric micelles over a very narrow pH range (between pH 5.

Novel application of plasma treatment for pharmaceutical and biomedical engineering.

The nature of plasma-induced surface radicals formed on a variety of organic polymers has been studied by electron spin resonance (ESR), making it possible to provide a sound basis for future experimental design of polymer surface processing using plasma treatment. On the basis of the findings from such studies, several novel bio-applications in the field of drug- and biomedical- engineering have been developed. Applications for drug engineering include the preparation of reservoir-type drug delivery system (DDS) of sustained- and delayed-release, and floating drug delivery system (FDDS) possessing gastric retention capabilities, followed by preparation of "Patient-Tailored DDS".

Plasma-assisted immobilization of heparin onto low-density polyethylene surface.

In this study heparin was covalently immobilized onto LDPE-VEMAC sheet fabricated by the introduction of carboxyl groups to the surface of low-density polyethylene (LDPE) using a plasma technique. The plasma irradiation time influenced the density of carboxyl groups on the LDPE-VEMAC sheet. Heparin was immobilized on the LDPE-VEMAC sheet using a condensation reagent, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC).

Conventional synthesis of amphiphilic block copolymer utilized for polymeric micelle by mechanochemical solid-state polymerization.

The first example is presented here of an amiphiphilic block copolymer synthesized by mechanochemical solid-state polymerization and used to form polymeric micelles. A model amphiphilic block copolymer was synthesized first, possessing galactose as a hydrophilic side chain and theophylline as a hydrophobic side chain, by mechanochemical solid-state polymerization. The resulting copolymer had a narrow molecular weight distribution.

[Novel pharmaceutical and biomedical applications of plasma techniques].

The plasma-induced surface radicals formed on a variety of organic polymers have been studied in detail using electron-spin resonance (ESR) coupled with systematic computer simulations. On the basis of the findings from such studies on the nature of radical formation and radical reactivity, we were able to open up several novel pharmaceutical and biomedical applications in plasma treatment. In this review, applications using plasma-irradiated organic polymers are described, which include: 1) preparation of double-compressed tablets applicable for reservoir-type drug-delivery systems (DDS) for sustained and delayed release, intragastric floating DDS (FDDS) for oral controlled-release dosage forms with gastric retention capabilities, and fabrication of functionalized composite powders applicable for controlled drug release with the mechanical application of plasma-irradiated polymer powder; 2) an approach to "patient-tailored DDS," administered by taking into account that the environment (pH, transit time, etc.

Preparation of floating drug delivery system by plasma technique.

A novel intragastric floating drug delivery system (FDDS) has been prepared by pulsed plasma-irradiation on the double-compressed tablet of 5-Fluorouracil (5-FU) as a core material with outer layer composed of a 68/17/15 weight ratio of Povidone (PVP), Eudragit RL (E-RL) and NaHCO3. The plasma heat flux caused the thermal decomposition of NaHCO3 to generate carbon dioxide and the resultant gases were trapped in bulk phase of outer layer, so that the tablets turned to have a lower density than the gastric contents and remained buoyant in simulated gastric fluid for a prolonged period of time. In addition, the release of 5-FU from the tablet is sustained by occurrence of plasma-induced crosslink reaction on the outer layer of tablet and the release rate of 5-FU can be well controlled by plasma operational conditions.

Synthesis of DNA conjugate by mechanochemical solid-state polymerization and its affinity separation of oligonucleotides having single-base difference by capillary electrophoresis.

In this communication, we discuss the characterization of DNA conjugate synthesized by mechanochemical polymerization, Con-M, on the separation of model oligo-DNA and its single nucleotide polymorphisms (SNPs) by affinity capillary electrophoresis, compared with that prepared by radical-initiated solution polymerization, Con-RL. The average molecular weight of Con-M was similar to that of Con-RL, although the molecular weight distribution of Con-M was narrower than that of Con-RL. Capillary electrophoresis of oligo-DNA was performed using the capillary filled with DNA conjugate.

Mechanochemical solid-state polymerization (XI): effect of water-insoluble pharmaceutical aids on drug release from mechanically synthesized polymeric prodrugs.

We discuss here the effect of water-insoluble pharmaceutical aids on the nature of drug release from composite polymeric prodrugs synthesized by mechanochemical solid-state polymerization. Magnesium stearate (Mgst) and hydrogen castor oil (HCO) were used as water-insoluble pharmaceutical aids. Composite polymeric prodrugs were synthesized by the mechanochemical solid-state polymerization of a vinyl monomer of 5-fluorouracil (I) in the presence of Mgst or HCO.

Novel and simple preparation method of matrix-type composite particles for controlled drug release by mechanical action.

Matrix-type composite particle for controlled drug release can readily be prepared through a totally dry process by simple anaerobic mechanical vibration of mechanoradical-containing ethylcellulose (EC) with theophylline powder due to occurrence of collision-induced radical-radical coupling reaction to form interparticle matrices, as well as the formation of interparticle network when solid-state vinyl monomer was further added.

[Riboflavin-radical formation by mechanochemical solid-state reaction using stainless steel vessel].

The mechanochemical reaction of free riboflavin (FR) due to vibratory ball milling was carried out in a stainless steel vessel at room temperature under anaerobic conditions. The ESR of the fractured sample showed a broad single-line spectrum. It is suggested that the solid-state single-electron transfer (SSET) reaction from the surface of the stainless steel vessel to FR proceeded during the vibratory milling, resulting in the formation of the corresponding anion radicals.

Nature of mechanoradical formation of substituted celluloses as studied by electron spin resonance.

Mechanically induced free radical (mechanoradical) formation of several substituted celluloses such as carboxylmethyl cellulose, chitin, and chitosan was studied based on electron-spin resonance (ESR) in comparison with those of plasma-induced radicals. Room temperature ESR spectra had multicomponent spectra and were different in pattern from each other. The mechanoradical concentration gradually decreased after reaching the maximum value in each substituted polysaccharide, accompanied by a decrease in molecular weight in the course of vibratory milling.

Synthesis of water-soluble polymeric prodrugs possessing 4-methylcatechol derivatives by mechanochemical solid-state copolymerization and nature of drug release.

In this study we synthesized the water-soluble polymeric prodrugs possessing a 4-methylcatechol (4MC) derivative as a side chain by mechanochemical solid-state copolymerization. 1-benzoyl-4-methylcatechol (Bz4MC) was selected as a model compound of 4MC, and its methacryloyl derivative (1) was synthesized. 6-O-methacryloyl-D-galactose (2) was also prepared as a water-soluble monomer.