Mechanochemical Solid-State Polymerization Research Articles

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−1. The Dx-based graft copolymers with hydrophobic segments formed nanoparticles with a particle size of 25–35 nm in an aqueous solution. The anti-pancreatic tumor drug 5-fluorouracil (5-FU) was covalently conjugated onto the hydrophobic segments of the amphiphilic Dx, and the nanoparticles were also prepared. The drug release profile from 5-FU-conjugated nanoparticles corresponded well to the Korsmeyer-Peppas model applied to drug release from matrix substrates, and was also immensely predicted by the Logistic and Gompertz curves. The 5-FU-conjugated nanoparticles showed cytotoxicity against the pancreatic adenocarcinoma cell lines (BxPC-3) that were not significantly inferior to the 5-FU positive group. Furthermore, the fluorescein-labeled nanoparticles internalized into BxPC-3 within 6 h and actively migrated into the cytosol. These results suggest that Dx-based graft copolymers with hydrophobic segments might be used to enhance therapeutic activity.

Mechanochemical solid-state vinyl polymerization with anionic initiator.

Mechanochemistry has been extended to various polymer syntheses to achieve efficiency, greenness, and new products. However, many fundamental polymerization reactions have not been explored, although anionic polymerization of vinyl compounds has been pursued under mechanochemical conditions. Two solid monomers, 4-biphenyl methacrylate and 4-vinyl biphenyl, representing methacrylate and styrenic classes, respectively, were reacted with secondary butyl lithium under high-speed ball-milling. The alkyl-anion-promoted polymerization process was established by excluding radical initiation and producing the expected polymers with good efficiency. However, the generally expected features of anionic polymerization, such as molecular weight control and narrow dispersity, were not observed. Analysis of the milling parameters, reaction monitoring, and microstructural analysis revealed that the mechanism of the mechanochemical process differs from that of conventional anionic polymerizations. The mechanical force fractured the newly formed polymer chains via anionic initiation and generated macroradicals, which participated in the polymerization process. The anionic process governs the initiation step and the radical process becomes dominant during the propagation step.

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. The in vitro hydrolysis behavior of the polymeric prodrug indicated that the release rate of drug from the polymeric prodrug was clearly dependent on the pH value of the hydrolysis solution. Moreover, sustained release of the drug at an almost constant rate for more than 10 hr was shown in both neutral and alkaline solutions. The results suggest that anhydride-based polymeric prodrugs could be potentially useful in colon targeted drug delivery systems.

Synthesis of o-aminophenol-m-phenylenediamine copolymer: an eco-friendly approach

Poly (o-aminophenol-co-m-phenylenediamine) P(oAP-mPDA) as a copolymer is successfully synthesized by mechanochemical solid state polymerization (MCSSP) as a green and simple method. The mechanochemical solid state polymerization is achieved by a developed Mortar Grinder RM200 without using any solvents during the preparation process. The copolymer was also prepared by traditional interfacial polymerization method (IP). A comparison between the resulting copolymers of the two methods is conducted by various analyses including, Fourier transform infrared spectra (FTIR), ultra violet, visible spectra (UV-Vis), X-ray diffraction (XRD), scanning electron microscope (SEM), and thermogravimetric analysis (TGA). The analyses revealed that there is a good agreement between the two copolymers synthesized by MCSSP and IP method. The energy band gap was determined and found to be 2.19 eV and 2.09 eV for the copolymer synthesized by MCSSP method and the IP method, respectively. The investigated copolymers are located in the semiconductor material range and displayed a good thermal stability.

Ecofriendly method to synthesize poly (o-aminophenol) based on solid state polymerization and fabrication of nanostructured semiconductor thin film

Poly (ortho-aminophenol) (POAP) has been successfully synthesized by mechanochemical solid state polymerization (MCSSP) as a green method which is simple, rapid, free hazard solvent, economically route and environmental friendly method. POAP has been synthesized by using developed Mortar Grinder RM200 without using solvents in the preparation process and has been compared with the POAP synthesized by interfacial polymerization method (IP) as traditional method. The comparison between the two techniques was carried out by justifying various analyses such as, Fourier transform infrared spectra, ultra violet visible spectra (UV–Vis), X-ray diffraction, thermogravimetric analysis, scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX). The analysis revealed that there is a good agreement between the MCSSP and IP method to synthesize POAP. POAP synthesized by MCSSP method has nearly the same high crystallinity of POAP synthesized by IP method. The energy band gap (Eg) was detected for POAP solution (DMF) synthesized by the two methods. Eg was found to be 1.74 eV and 1.95 eV for POAP synthesized by MCSSP and the IP method respectively. A thin film of POAP either synthesized by MCSSP or IP method was fabricated. Morphological and optical properties of the thin film have been investigated using SEM/EDX, AFM, and UV–Vis test. POAP thin film was located in the semiconductor materials range.

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. Uptake of polymeric micelles containing fluorescein by HepG2 and HCT116 cells was also investigated. With both cell types, strong fluorescence was observed after a 12-h incubation, but the fluorescence weakened after 24 h of incubation. The fluorescein incorporated into the polymeric micelles was released into acidic organelles (endosome and/or lysosome), from which it diffused throughout the cell. The cytotoxicity of polymeric micelles containing 5-FU was evaluated against HepG2 cells using a CCK-8 assay. The results suggest that polymeric micelles containing 5-FU are more cytotoxic to HepG2 cells than free 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 5.7 and 5.6). Interestingly, micellization and demicellization occurred reversibly in this narrow pH range. Polymeric micelles incorporating 5-fluorouracil (5FU) were also prepared. Decreasing the pH of this polymeric micelle solution from 7 to 5.5 resulted in the rapid release of 5FU at pH 5.6; the drug was completely released within 30 min. These results suggest that deformation of the polymeric micelles caused the rapid release of 5FU.

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. Polymeric micelle formation was subsequently carried out with the copolymer by a dialysis method. To gain insight into the physicochemical properties of the polymeric micelle, dynamic light scattering (DLS) measurements were performed. A narrow distribution of diameters was observed in the polymeric micelle solution, and these micelles were disrupted by the addition of sodium dodecyl sulfate (SDS). It was also confirmed by DLS measurements that the polymeric micelles were spherical. These results suggested that the block copolymer synthesized by mechanochemical solid-state polymerization was as suitable for the preparation of polymeric micelles as materials obtained by living polymerization.

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. The resolution of the capillary filled with Con-M was apparently higher than with Con-RL. It is considered that higher resolution using the capillary filled with Con-M could be ascribed not only to the narrow molecular weight distribution but also to the difference of copolymer structure.

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. The molecular weight of the resulting polymeric prodrugs increased with increasing the content of Mgst or HCO. Prodrug hydrolysis was carried out in a heterogeneous system in phosphate buffer at pH 6.8 and 37 degrees C. The rate of drug release from the composite polymeric prodrug containing Mgst (Poly-Mgst) was faster than that from polymeric prodrug containing no pharmaceutical aids (Poly-Non), while hydrolysis of the composite polymeric prodrug containing HCO (Poly-HCO) was slower than Poly-Non. Scanning electron microscope (SEM) photos showed the surface of Poly-HCO was smoother than that of Poly-Non and Poly-Mgst. It was suggested that the slower drug release from Poly-HCO may be responsible for the smaller specific surface area than that of Poly-Non. It was also shown that the rate of drug release from the composite polymeric prodrugs decreases with increasing the content of Mgst or HCO. Hence, novel composite polymeric prodrugs with a variety of drug release rates can be prepared by mechanochemical solid-state polymerization in a totally dry process.

Development of Polymeric Prodrugs as a Therapeutic Agent for Alzheimers Disease by Mechanochemical Solid-State Polymerization

We carried out the mechanochemical solid-state polymerization of acrylamide and several kinds of vinyl monomer of bioactive compounds and reached several important conclusions from a series of such studies. The monomers prepared on the basis of the structural criteria derived from quantum chemical considerations underwent facile mechanochemical solidstate polymerizations to give corresponding polymeric prodrugs essentially quantitatively. Thus this method eliminates the need for any work-up of the reaction mixture. One of the most striking properties observed in such polymers is that the resulting polymeric prodrugs are of very low heterogeneity (narrow molecular weight distribution), which is of great value in pharmaceuticals for highly functionalized polymeric prodrugs. Therefore, the present reactions seem to be applicable to a wide variety of vinyl monomers of an important bioactive compound with different physicochemical properties and thus provide a novel and simple methodology for syntheses of polymeric prodrugs through a totally dry process. We have synthesized a novel polymeric prodrug possessing the derivative of 4-methylcatechol (4MC) as a side chain by mechanochemical solid-state polymerization. 1-Benzoyl-4-methylcatechol (Bz4MC) was selected as a hydrophobic compound of 4MC. It was suggested that Bz4MC was a potent stimulator on neurotrophic factor. The mechanochemical copolymerization of the methacryloyl derivative of Bz4MC and the water-soluble monomer proceeded to completion, and the polymeric prodrug produced possessed a narrow molecular weight distribution. These polymeric prodrugs were hydrolyzed to completion. The rate of hydrolysis can be controlled by the composition.

Mechanochemical solid-state polymerization (X): the influence of copolymer structure in copolymeric prodrugs on the nature of drug release.

From the standpoint of the mechanism of mechanochemical polymerization, two kinds of copolymeric prodrug, whose monomer sequence distribution (MSD) is different from each other, can be prepared by this polymerization under appropriate operational conditions: one is a random copolymer abundant in the longer block consisting of the same repeating units (multi-block copolymer), and the other is a block copolymer. To confirm the difference of MSD, the 13C-NMR spectra of poly(acrylamide-co-sodium acrylate) prepared by mechanochemical polymerization were measured and compared with the spectrum of that synthesized by a conventional radical-initiated solution polymerization, which produces the random copolymer normally. The results show that MSD in copolymers depends on the polymerization method (operational condition). We prepared three kinds of copolymeric prodrug consisting of acrylamide and vinyl monomer of 5-fluorouracil, whose MSD is different from one another. These copolymeric prodrugs had almost the same number average molecular weight, particle diameter and composition, and differed only in MSD. We compared the rate of drug release of these copolymeric prodrugs. The rate of drug release was the highest with the random copolymer, followed by the mechanochemically produced multi-block copolymer and the block copolymer. This result suggests that the rate of drug release depends on MSD of copolymeric prodrugs. These results are useful as they give a fundamental insight into the synthesis of copolymeric prodrugs having the desired rate of drug release.

Mechanochemical solid-state polymerization. VIII. Novel composite polymeric prodrugs prepared by mechanochemical polymerization in the presence of pharmaceutical aids.

We carried out the mechanochemical polymerization of methacryloyl derivatives of acetoaminophen and 5-fluorouracil in the presence of lactose. The reaction proceeded readily and the polymeric prodrugs were quantitatively produced. This method produces powdered polymeric prodrugs in which fine particles of lactose are homogeneously dispersed, since the reaction proceeds quantitatively through a totally dry process. It is difficult to prepare such a powdered polymeric prodrug by conventional solution polymerization. The rate of drug release of polymeric prodrugs increases with increasing content of lactose, as is shown to be true of the specific surface of polymeric prodrugs. These results suggest that lactose is homogeneously dispersed in powdered polymeric prodrugs. The present method seems applicable to a wide variety of pharmaceutical aids. If one takes the physiochemical property of pharmaceutical aids into consideration, novel polymeric prodrugs with a variety of drug release rates can be synthesized simultaneously with mixing.

Mechanochemical solid-state polymerization. IX. Theoretical analysis of rate of drug release from powdered polymeric prodrugs in a heterogeneous system.

We theoretically derived the rate equation of drug release from a simple model in a heterogeneous system. Four assumptions were used to simplify the model. Two kinds of rate equations for drug release derived from two possible limiting cases, that the rate-determining step is a diffusion or hydrolysis controlled process, can predict the experimental results up to 50% hydrolysis. However, the predictions at the later stage by these equations are insufficient. These results suggest that the process of drug release from powdered polymeric prodrugs in a heterogeneous system must be described by both diffusion and hydrolysis. The rate equation derived from a model considering both the diffusion and hydrolysis processes can successfully predict the experimental results for several kinds of polymeric prodrugs. It is also shown that the diffusion coefficient and rate constant for hydrolysis calculated from this equation thoroughly express the character of the comonomer. The rate equation derived from the model that considers both diffusion and hydrolysis is very useful to analyze drug release from various kinds of polymeric prodrugs in a heterogeneous system.

メカノケミカル固相重合による新規ハイブリッド型高分子プロドラッグの構築とその薬物放出特性

Polymeric prodrugs having a basic side chain were synthesized by mechanochemical solid-state polymerization, and the nature of drug release of these polymeric prodrugs was investigated. Two kinds of methods, flow-through-cell and flask-shaking method, were used for hydrolysis of polymeric prodrugs. Drug release in flow-through-cell method can be considered to be a model experiment under in vivo condition, and the polymeric prodrugs synthesized in the present reactions eventually released the drugs quantitatively. It was also shown that the hydrolysis (drug release) profiles apparently follow a first-order kinetics. On the other hand, the drug release in flask-shaking method ceased before its completion due to lack of sink conditions. The flask-shaking method, however, was used in this study, since the 100% drug release time can be deduced by the rate constant of apparent first-order reaction calculated from the data of initial stage of drug release. The polymeric prodrugs having 5-fluorouracil (5-FU) and pyridyl group as a side chain were prepared by mechanochemical polymerization. The rate of drug release increased with an increase in the content of basic group in the copolymer. The plots of the rate constant as a function of the ratio of the basic monomer in copolymer exhibited exponential curves under the present experimental conditions. It was also shown that the rate of drug release is influenced by the nature of the basic group. The hybrid polymeric prodrugs were synthesized by mechanochemical polymerization of the methacryloyl derivatives of 5-FU and pyridoxamine which possesses a pyridyl group. Although pyridoxamine was not released from the hybrid polymeric prodrugs thus obtained, the rate of drug release of 5-FU can be controlled by the amount of the pyridoxamine in polymeric prodrug. These results provided the fundamental and significant information for the syntheses of novel hybrid polymeric prodrugs possessing a wide variety of drug as a side chain.

メカノケミカル固相重合を利用する新たなポリマープロドラッグの設計と開発

The chemotherapeutic utility of polymeric prodrugs has recently been the focus of intense research because of the possible reduction of undesirable side-effects and their utility as a sustained release system. We describe a novel polymeric prodrug preparation by mechanochemical solid state polymerization. The results include that solid vinyl monomers, methacryloyl derivatives of bioactive compounds, synthesized along the line of structural criteria derived from the quantum chemical considerations can undergo the mechanochemical polymerization to give the corresponding polymers essentially quantitatively. One of the most striking properties observed in such polymers is that the resulting polymeric prodrugs are of very low heterogeneity (narrow molecular weight distribution). Further, the molecular weight of the polymers can be controlled by the operational conditions. Thus, the mechanochemical solid-state polymerization provides a novel and simple methodology for syntheses of highly functionalized polymeric prodrugs through a totally dry process.

Mechanochemical Solid-State Polymerization. VII. The Nature of Hydrolysis of Novel Polymeric Prodrugs Prepared by Mechanochemical Copolymerization.

Hydrophilic polymeric prodrugs have been prepared by the mechanochemical copolymerization of methacryloyl derivatives of bioactive compounds with acrylamide, which is a hydrophilic conventional vinyl monomer. The polymeric prodrugs homogeneous in composition, since mechanochemical copolymerization is ideal copolymerization under the present experimental conditions. It is also shown that the polymeric prodrugs have a narrow molecular weight distribution.The alkaline hydrolysis of polymeric prodrugs prepared by mechanochemical copolymerization has been examined in a heterogeneous system. Though the degree of hydrolysis of polymeric prodrugs increases with increasing the content of hydrophilic monomer in the copolymer, there exists a limit to the degree of hydrolysis attainable due to the retardation by the carboxylic group produced as a side chain of the polymer hydrolyzate. The rate of hydrolysis depended largely on the structural feature of the polymer hydrolyzate; the use of carbamoyl derivatives of bioactive compounds is valuable for improving the nature of hydrolysis, since the amino group formed with the progress of hydrolysis does not cause any retardation of the nucleophilic reaction of the hydroxyl anion.

A new development of mechanochemical solid-state polymerization of vinyl monomers: prodrug syntheses and its detailed mechanistic study

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA new development of mechanochemical solid-state polymerization of vinyl monomers: prodrug syntheses and its detailed mechanistic studyMasayuki Kuzuya, Sinichi Kondo, and Akihiro NoguchiCite this: Macromolecules 1991, 24, 14, 4047–4053Publication Date (Print):July 1, 1991Publication History Published online1 May 2002Published inissue 1 July 1991https://doi.org/10.1021/ma00014a013RIGHTS & PERMISSIONSArticle Views289Altmetric-Citations30LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (877 KB) Get e-Alerts Get e-Alerts

The Nature of Hydrolysis of Novel Methacrystaloyl Polymeric Prodrugs Prepared by Mechanochemical Solid State Polymerization.

The Nature of Hydrolysis of Novel Methacrystaloyl Polymeric Prodrugs Prepared by Mechanochemical Solid State Polymerization.