Synthesis of theophylline–polyrotaxane conjugates and their drug release via supramolecular dissociation

Ooya, Tooru; Yui, Nobuhiko

doi:10.1016/s0168-3659(98)00163-1

Cited by 115 publications

(72 citation statements)

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“…Among these systems, DMSO is one of the most popular and the most investigated solvents for polyrotaxane. Aprotic and neutral DMSO readily dissolves PEG/CD polyrotaxane to yield a polyrotaxane solution in which many reactions and/or modifications have been made to date [10,[13][14][15][16]22]. However, many unrevealed properties seem to be potentially buried within this solution system.…”

Section: Introductionmentioning

confidence: 99%

“…The formation of the inclusion complex with CDs and various linear polymers via spontaneous self-assembly was thoroughly investigated by Harada et al [1,5,6], who successfully prepared polyrotaxane by binding bulky end groups (such as dinitrophenyl moieties) to the ends of pseudopolyrotaxane, i.e., the inclusion complex of CDs and PEG [7][8][9]. A wide variety of attractive concepts have been reported to date after the first finding by Harada, such as the preparation of a "molecular tube" by cross-linking adjacent CDs in single polyrotaxane followed by the dissociation of the included PEG [10], an insulated molecular wire comprising a conducting polymer and a molecular tube [11,12], a drug delivery system using polyrotaxane carrying drugs on the CD moiety [13], multivalent ligand system [14], the construction of an energy transfer system using polyrotaxane with photoluminescent side groups [15,16], a three-dimensionally cross-linked polyrotaxane network [17][18][19] and fiber formation by the wet spinning of a blend solution of polyrotaxane and cellulose [20].Since further applications of polyrotaxane than that mentioned above are anticipated in the future, the fundamental properties of polyrotaxane should be thoroughly characterized. Solution property is one of the most significant characteristics, which is necessary during processing and handling polyrotaxane when used in various applications.…”

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confidence: 99%

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Strongly thixotropic viscosity behavior of dimethylsulfoxide solution of polyrotaxane comprising α-cyclodextrin and low molecular weight poly(ethylene glycol)

Araki

Ito

2007

Polymer

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A strong thixotropic viscosity behavior was observed when polyrotaxane prepared from α-cyclodextrins (CDs) and poly(ethylene glycol) (PEG) with a molecular weight of 2000 was dissolved in dimethylsulfoxide (DMSO). A 10 wt% solution liquefied by vigorous shaking was rapidly gelated by standing --this sol-gel transition was reversible. The time for recovering the viscosity was dependent on the polyrotaxane concentration, i.e., a 10wt% solution regelated within 30 s, whereas several hours were required for the gelation of a 2.5wt% solution. The thixotropic nature of the solution was also confirmed by the clockwise hysteresis curve of the viscosity when the shear rate was increased and decreased. The gel permeation chromatography (GPC) measurement of the polyrotaxane in DMSO exhibited peaks in the high molecular weight region. The peak disappeared after the phenylcarbamoylation of polyrotaxane, suggesting that the peak was due to loose aggregations of polyrotaxane in DMSO. On the other hand, the DMSO solution of polyrotaxane prepared from CD and PEG with a molecular weight of 3350-whose inclusion ratio (51%) is slightly lower than that of PEG2000 polyrotaxane (72%)-neither demonstrated the abovementioned thixotropic viscosity nor the peak corresponding to the aggregations occurring during the GPC measurement. The thixotropic behavior was speculated to be caused by the combined contribution of intermolecular attractive hydrogen bonding and higher rigidity of polyrotaxane prepared from PEG 2000 than that of polyrotaxane prepared from PEG3350, presumably due to the higher inclusion ratio of the former than that of the latter. Key Word: Polyrotaxane, Thixotropy, intermolecular hydrogen bonding 2 INTRODUCTIONPolyrotaxane is a typical supramolecular material that possesses linear molecule threading through many cyclic molecules, which can freely slide or rotate over the linear molecule [1][2][3][4]. Great advances have been made in the investigation of polyrotaxane since the discovery of the formation of pseudopolyrotaxane by the spontaneous inclusion complexation of cyclodextrins (CDs) and linear polymers by Harada et al. [5][6][7][8][9]. The formation of the inclusion complex with CDs and various linear polymers via spontaneous self-assembly was thoroughly investigated by Harada et al. [1,5,6], who successfully prepared polyrotaxane by binding bulky end groups (such as dinitrophenyl moieties) to the ends of pseudopolyrotaxane, i.e., the inclusion complex of CDs and PEG [7][8][9]. A wide variety of attractive concepts have been reported to date after the first finding by Harada, such as the preparation of a "molecular tube" by cross-linking adjacent CDs in single polyrotaxane followed by the dissociation of the included PEG [10], an insulated molecular wire comprising a conducting polymer and a molecular tube [11,12], a drug delivery system using polyrotaxane carrying drugs on the CD moiety [13], multivalent ligand system [14], the construction of an energy transfer system using polyrotaxane with photoluminescent...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Strongly thixotropic viscosity behavior of dimethylsulfoxide solution of polyrotaxane comprising α-cyclodextrin and low molecular weight poly(ethylene glycol)

Araki

Ito

2007

Polymer

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confidence: 99%

Cyclodextrin Complexes of Polymers Bearing Adamantyl Groups: Host–Guest Interactions and the Effect of Spacers on Water Solubility

2007

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Polymer-inclusion complexes (PICs) with cyclodextrins (CDs) show a broad structural variety [1][2][3][4] and are of interest for many different applications, for example, drug delivery systems [5] and stimuli-responsive hydrogels. [6, 7] We have demonstrated that the lower critical solution temperature (LCST) of N-isopropylacrylamide(NIPAAM)-based copolymers bearing adamantyl groups can be influenced through complexation of the adamantyl moieties by cyclodextrins (CDs). [8,9] Recently, we reported on the synthesis of a PIC consisting of randomly methylated b-CD and a polymethacrylamide which showed a reversible phase transition in aqueous solution as a result of a dissociation/ complexation process.[10] Unfortunately, this system was not optimal in terms of chemical stability and the guest moiety used. We report herein on the pseudo-LCST behavior of PICs consisting of poly(adamantylacrylamide)s and Me-b-CD. In contrast to the previously reported system, the newly synthesized polyacrylamides are expected to be much more stable against hydrolysis. Additionally, the incorporated adamantyl moieties are well suited for inclusion into b-CD. With this optimized system we will demonstrate the influence of spacer groups and concentration on the phase-transition process.It is known that Me-b-CD-complexed hydrophobic monomers can be polymerized in water by means of a free-radical mechanism by use of water-soluble azo or redox initiators. [11] In most cases, the Me-b-CDs slip off the growing macroradicals which leads to precipitation of the polymeric material. In contrast, polymerization of Me-b-CD-complexed 1-adamantylacrylamide (1 a) and 6-acryloylaminohexanoic acid 1-adamantylamide (3 a) resulting the formation of the water-soluble polymer/Me-b-CD-complexes 2 a and 4 a, respectively (Scheme 1). The polymerization was carried out in water at 25 8C using 1 mol % of the redox initiator system K 2 S 2 O 8 /Na 2 S 2 O 5 .The molecular weights of the purified Me-b-CD-free polymers 2 and 4 were determined by MALDI-TOF mass spectrometry (Figure 1). Interestingly, the obtained polymer/ Me-b-CD complexes 2 a and 4 a show thermosensitive solubility properties in water that strongly depend on the distance between the Me-b-CD-complexed adamantyl groups and the polymer backbone. Figure 2 shows the transmittance of an aqueous solution of 2 a as a function of temperature. The measurement was performed at a concentration of 100 g L À1 using a heating/ cooling rate of 1 K min À1 . It can be seen that in the heating run the transmittance of the solution drops from 100 to 0 % within a temperature range of about 1-2 8C around the cloud point of 44.6 8C. This effect is caused by the dissociation of the polymer/Me-b-CD complex 2 a and the precipitation of the uncomplexed, more hydrophobic polymer; the Me-b-CD molecules remain in the aqueous solution. During the cooling run the transmittance did not return back to the starting level. However, after the solution had been stirred for several days at 5 8C, it became transparent again, indicating...

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“…Theophylline-polyrotaxane conjugates were synthesized by coupling theophylline with a-CD that threaded onto PEG chain capped with L-Phe [75]. Theophylline-7-acetic acid was activated by coupling with 4-nitrophenol, and the N-aminoethyl-theophylline-7-acetoamide was obtained after reacting with ethylenediamine.…”

Section: Biodegradable Conjugated Polyrotaxanes For Drug Deliverymentioning

confidence: 99%

Supramolecular Polymers Based on Cyclodextrins for Drug and Gene Delivery

Zhao

2010

Biofunctionalization of Polymers and Their Applications

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Supramolecular polymers based on cyclodextrins (CDs) have inspired interesting and rapid developments as novel biomaterials in a broad range of drug and gene delivery applications, due to their low cytotoxicity, controllable size, and unique architecture. This review will summarize the potential applications of polyrotaxanes in the field of drug delivery and gene delivery. Generally, cyclodextrin-based biodegradable polypseudorotaxane hydrogels could be used as a promising injectable drug delivery system for sustained and controlled drug release. Temperature-responsive, pH-sensitive, and controllable hydrolyzable polyrotaxane hydrogels have attracted much attention because of their controllable properties, and the self-assembly micelles formed by amphiphilic copolymer threaded with CDs could be used as a carrier for controlled and sustained drug release. Polyrotaxanes with drug or ligand conjugated CDs threaded on a polymer chain with a biodegradable end group could be useful for controlled and multivalent targeted delivery. In the field of gene delivery, cationic polyrotaxanes consisting of multiple OEI-grafted CDs threaded on a block copolymer chain are attractive non-viral gene carries due to the strong DNA-binding ability, low cytotoxicity, and high gene delivery capability. Furthermore, cytocleavable end-caps were introduced in the polyrotaxane systems in order to ensure efficient endosomal escape for intracellular trafficking of DNA. The development of the supramolecular approach using CD-containing polyrotaxanes is expected to provide a new paradigm for biomaterials.

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Synthesis of theophylline–polyrotaxane conjugates and their drug release via supramolecular dissociation

Cited by 115 publications

References 33 publications

Strongly thixotropic viscosity behavior of dimethylsulfoxide solution of polyrotaxane comprising α-cyclodextrin and low molecular weight poly(ethylene glycol)

Strongly thixotropic viscosity behavior of dimethylsulfoxide solution of polyrotaxane comprising α-cyclodextrin and low molecular weight poly(ethylene glycol)

Cyclodextrin Complexes of Polymers Bearing Adamantyl Groups: Host–Guest Interactions and the Effect of Spacers on Water Solubility

Supramolecular Polymers Based on Cyclodextrins for Drug and Gene Delivery

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