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Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
Kategorie: Wissenschaft und neue Technologien
Sprache: Englisch

Beschreibung

Authored by two experts working in this important field of research, the timely book covers the latest advances in the synthesis of cyclodextrins, their properties and important industrial applications. To this end, the authors describe covalent and non-covalent assemblies, cyclodextrin inclusion complexes, cyclodextrin polymers, and modified cyclodextrins, resulting in an up-to-date overview of cyclodextrin chemistry. An invaluable reference for organic and polymer chemists in academia as well as those researchers in industry working in polymer, supramolecular and pharmaceutical chemistry, as well as food, textile and cosmetic science.

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Leseprobe

Title Page

Acknowledgment

Introduction

References

Part I: Characteristic Features of CDs

Chapter 1: CD-Based Rotaxanes and Polyrotaxanes as Representative Supramolecules

Recent Reports

1.1 CD-Based Rotaxanes

1.2 CD-Based Polyrotaxanes

1.3 CD-Based Pseudopolyrotaxanes

Chapter 2: CD-Based Micelles, Vesicles, and Metal Nanoparticles

Recent Reports

2.1 CD-Based Micelles

2.2 CD-Based Vesicles

2.3 CD-Based Metal Nanoparticles

Chapter 3: CD Inclusion Complexes

Recent Reports

3.1 CD Inclusion Complexes with Monocarboxylic Aromatic Acids

3.2 The β- and γ-CD Inclusion Complexes with Selected Guest Components

Chapter 4: CD Dimers

Recent Reports

4.1 CD Dimers Bridged by Various Spacers

4.2 CD Dimers Bridged by Azobenzene Moiety and by Platinum (IV) Complex as Spacers

References

Part II: Polymeric CDs

Chapter 5: CD Multiarm Polymers

Recent Reports

5.1 Multiarm Polymers Containing a CD Core

5.2 Micelles and Multiarm CD Polymers Containing a POSS Core

Chapter 6: CD-Based Dendrimers

Recent Reports

6.1 Monomeric Dendrimers with a CD Core

6.2 Polymeric CD-Based Dendrimers

Chapter 7: CD-Based Polymeric Gels

Recent Reports

7.1 Polymeric Gels Built Exclusively from CD

7.2 Polymeric Gels Built from CD and selected Polymers

7.3 CD-Based Polymeric Gels as Nanosponges

7.4 CD-Based Gels Built with the use of ILs

References

Part III: CD Assemblies with Nanocarbons and Final Remarks Concerning CD Applications

Chapter 8: CD Assemblies with Nanocarbons

Recent reports

8.1 CD Assembles with Fullerenes

8.2 CD Assemblies with Nanotubes

8.3 CD Assemblies with Graphene

Chapter 9: CD Applications

Recent Reports

9.1 CD Medical Applications

9.2 CD Environmental Protection Applications

9.3 CD Industrial Applications

References

Conclusion

Index

End User License Agreement

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Guide

Table of Contents

Introduction

Part I

Begin Reading

List of Illustrations

Chapter 1: CD-Based Rotaxanes and Polyrotaxanes as Representative Supramolecules

Figure 1.1 Synthesis of compounds

and

Figure 1.2 Synthesis of dyes

4a,b.

Figure 1.3 Compounds

3, 4a,b, 5,

and

Figure 1.4 Synthesis of the compound

Figure 1.5 The grafting of propiolamide

onto Au@MSN surface.

Figure 1.6 Preparation of the complex

/α-CD.

Figure 1.7 Synthesis of Au@MSN-rotaxane.

Figure 1.8 The

trans

-to-

cis

photoisomerization of Au@MSN-rotaxane.

Figure 1.9 Synthesis of rotaxane

12.

Figure 1.10 Synthesis of the compound

14.

Figure 1.11 Polyrotaxanes

16a,b.

Figure 1.12 Synthesis of polyrotaxane

18.

Figure 1.13 Synthesis of polyrotaxane

20.

Figure 1.14 Formation of the flower polymeric micelle of

20.

Figure 1.15 Synthesis of polyrotaxane

21.

Figure 1.16 Synthesis of polyrotaxanes

30a,b

by the sonication followed by solid-state process.

Figure 1.17 Synthesis of polyrotaxanes

and

32,

and the synthesis of carboxylated α-CD, used for comparison purposes.

Figure 1.18 Synthesis of AF-545-labeled aminated polyrotaxane.

Figure 1.19 The AF-545-labeled PDMAEM and AF-545-labeled aminated pullulan.

Figure 1.20 Synthesis of the oligoazomethine permethylated polyrotaxane PR.

Figure 1.21 Schematic representation of polyrotaxane containing α-CD units functionalized by fluorescent tags and by lanthanide complexes.

Figure 1.22 Synthesis of mono-azido- and bis-azido-α-CDs

42a,b.

Figure 1.23 Synthesis of compound

functionalized by bodipy.

Figure 1.24 Synthesis of compounds

38, 39

monofunctionalized and of compounds

40, 41

bisfunctionalized by DOTA lanthanide complexes.

Figure 1.25 Synthesis of polyammonium

50.

Figure 1.26 Polyrotaxane

51.

Figure 1.27 Polyrotaxane

52.

Figure 1.28 Polyrotaxane

53.

Figure 1.29 Polyrotaxane

54.

Figure 1.30 Synthesis of PR 1500 Me-PU.

Figure 1.31 Synthesis of PR 4000 Me-PU, PR 6000Me-PU, and CDMe-PU.

Figure 1.32 Synthesis of pseudopolyrotaxane

57.

Figure 1.33 Formation of the CO and CC bonds between two phenyl groups.

Figure 1.34 Synthesis of tyramine-functionalized Pluronic F68/Tyr or F127/Tyr.

Figure 1.35 Schematic representation of physically cross-linked PPR hydrogel and of covalently cross-linked PR hydrogel.

Chapter 2: CD-Based Micelles, Vesicles, and Metal Nanoparticles

Figure 2.1 Synthesis of AA-6-PCL.

Figure 2.2 The β-CD/PCL polymeric micelle loaded by AA-6-PCL.

Figure 2.3 Synthesis of the copolymer PDMAEMA-

-AZOMa

58.

Figure 2.4 Synthesis of polymer β-CD-(PDMAEMA)

59.

Figure 2.5 The self-assembly/disassembly of polymeric micelle consisting of copolymer

(core) and polymer

(shell) by photoisomerization.

Figure 2.6 Synthesis of β-CD-en-grafted polyaspartic acid, that is, PASP-CD.

Figure 2.7 Synthesis of poly(d,l-lactide) bearing a cholesterol end, that is, PLA-chol.

Figure 2.8 The interaction of PASP-CD with PLA-chol leading to micelles formed by β-CD/cholesterol inclusion complexation.

Figure 2.9 Synthesis of polycarbonates T and D.

Figure 2.10 Synthesis of polymeric micelles T/Mal-α-CD and D/Mal-α-CD.

Figure 2.11 Coenzyme Q10, that is, CoQ

Figure 2.12 NaTCA and GZK

γ-CD complexes.

Figure 2.13 Formation of water-soluble NaTCA/γ-CD or GZK

/γ-CD complexes and of water-soluble molecular captured micelles consisting of CoQ

surrounded by NaTCA or GZK

Figure 2.14 Synthesis of PEG/HDI/DM-β-CD polymers.

Figure 2.15 Synthesis of the M/β-CDP-based fluorescent TPA nanomicelle and its interaction with RGD peptide affording TPA bioprobe M/β-CDP/Ad-RGD able to bind with tumor cells.

Figure 2.16 Curcumin.

Figure 2.17 The β-CD derivatives: mono(6-

-hydroxypropyl)-β-CD (

), mono(6-

-Ts)-β-CD (

), and mono(6-deoxy-6-amino)-β-CD (

Figure 2.18 Formation of CD/CC vesicles.

Figure 2.19 The response of β-CD/CC vesicles to three external stimuli: sodium laurate, Cu

ion, and α-amylase.

Figure 2.20 The biamphiphilic ionic liquid (BAIL) C

mim

DSN

−

Figure 2.21 The self-assembly of β-CD with C

mim

DSN

−

leading to formation of the vesicle and of the hydrogel.

Figure 2.22 The photoreversible system consisting of α-CD-coated AuNPs and of the AZO ligand.

Figure 2.23 Synthesis of the thiolated α-CD

60.

Figure 2.24 The preparation of hybrid AuNP network aggregate.

Figure 2.25 The prepare of β-CD-grafted NPs, that is, CD-APS-NP.

Figure 2.26 Synthesis of the AuNP nanorattle.

Chapter 3: CD Inclusion Complexes

Figure 3.1 The β-CD/guest 1 : 1 inclusion complexes

68, 69,

and the β-CD/guest 2 : 1 inclusion complexes

70–74

with their guest components.

Figure 3.2 Amphotericin B.

Figure 3.3 The four orientations of inclusion complexes of AmB with γ-CD dimer; HP-γ-CD dimer, and hybrid γ-CD/HP-γ-CD dimer.

Figure 3.4 Synthesis of the host polymer

75.

Figure 3.5 The guest polymers

76–78

Figure 3.6 Synthesis of AIE compounds

79a–c.

Figure 3.7 The titration of

79c

by γ-CD leading to

79c

/γ-CD inclusion complex.

Figure 3.8 Isomeric anthracene-l-glutamate dendrons

and

83.

Figure 3.9 The assembly of

with γ-CD by method A (without irradiation) leading to inclusion complexes which are destroyed under surface pressure; the

molecules escaped from the γ-CD cavity form nanofibers.

Figure 3.10 The assembly of

with γ-CD by method B (under 365 nm irradiation) leading to inclusion complexes of

dimers in γ-CD cavity which form NPs.

Chapter 4: CD Dimers

Figure 4.1 Syntheses of monomer

and of dimer

87.

Figure 4.2 Syntheses of inclusion complexes

and

90.

Figure 4.3 Flavonols: myricetin, quercetin, and kaempferol.

Figure 4.4 Synthesis of the dimer

91.

Figure 4.5 Synthesis of isomeric 1.5- and 1.4-diols

94a

and

94b.

Figure 4.6 Synthesis of the γ-CD dimer

93.

Figure 4.7 The guest components

98–102

Figure 4.8 Compounds

103

and

104.

Figure 4.9 Interaction of

104

PDA with α-CD.

Figure 4.10 The dimeric fraction of β-CD.

Figure 4.11 Complexation of DA liposomes with β-CD dimer.

Figure 4.12 Synthesis of the γ-CD

dimer (the host component).

Figure 4.13 Synthesis of the PEGXS polymer.

Figure 4.14 Synthesis of the aniline tetramer AT.

Figure 4.15 Synthesis of the PEGXS-AT copolymer.

Figure 4.16 The assembly of host and guest components affording PEGXS-AT/γ-CD

hydrogel.

Figure 4.17 Synthesis of the dimer

107.

Figure 4.18 Syntheses of dimers

108

and

109.

Figure 4.19 Synthesis of the dimer

110.

Figure 4.20 Synthesis of the dimer

111.

Figure 4.21 Synthesis of the dimer

112.

Figure 4.22 Result of conformational analysis of the dimer

107

showing symmetrical conformation (100%).

Figure 4.23 Result of conformational analysis of the dimer

110

showing unsymmetrical conformation (77%).

Figure 4.24 Syntheses of spacers

119

and

121.

Figure 4.25 Syntheses of dimers

124, 125

with shorter spacer and dimers

126, 127

with a longer spacer.

Figure 4.26 Three conformations, (a)–(c), of

126.

Figure 4.27 Synthesis of the dimer

128

(the host).

Figure 4.28 The

cis

trans

photoisomerization of

128.

Figure 4.29 The ditopic adamantane

129

(the guest).

Figure 4.30 Synthesis of the β-CD dimer AZO-β-CD.

Figure 4.31 The self-assembly of the β-CD dimer AZO-β-CD.

Figure 4.32 Synthesis of the azobenzene-capped polycaprolactone AZO-PCL.

Figure 4.33 The AZO-β-CD/AZO-PCL assembly.

Figure 4.34 Synthesis of Pt-CD (the host).

Figure 4.35 Synthesis of TPyP-Ad (the guest).

Chapter 5: CD Multiarm Polymers

Figure 5.1 Synthesis of the triazol-CD monomer

Figure 5.2 Synthesis of multiarm polymer containing CD terminal groups PMACD, that is,

Figure 5.3 Synthesis of PEG2Ad.

Figure 5.4 The self-assembly of

with PEG2AD affording

/PEG2Ad NPs.

Figure 5.5 Synthesis of the first-generation multiarm polymer 7PEG/β-CD-G1, that is,

Figure 5.6 The fourth-generation multiarm polymer 7PEG/β-CD-G4, that is,

Figure 5.7 Synthesis of the 21-arm, star-shaped diblock copolymer PAA-

-PS.

Figure 5.8 Synthesis of 21-arm, diblock copolymer PS-

-P3HT.

Figure 5.9 Synthesis of the mono CD substituted isobutyl POSS, that is, mCPOSS.

Figure 5.10 Synthesis of the PEG-

-PDMAEMA-AZO polymer, that is, PPA.

Figure 5.11 Bisphenol A, that is, BPA.

Figure 5.12 Synthesis of POSS-(OH)

11.

Figure 5.13 Synthesis of the POSS/PCL/β-CD copolymer

14.

Chapter 6: CD-Based Dendrimers

Figure 6.1 The dendrimer

, containing β-CD core and β-CD arms.

Figure 6.2 Synthesis of

(for a core) and of

(for arms) of the dendrimer

Figure 6.3 The synthesis of the β-CD-based dendrimer

by two routes, A and B.

Figure 6.4 Naproxen and naltrexone drugs.

Figure 6.5 Synthesis of the bimodal fluorescence/MRI contrast agent

Figure 6.6 The Gd(III) chelates.

Figure 6.7 Synthesis of the dendrimeric host PAMAM-CD

Figure 6.8 Syntheses of β-CD PNIPAAm A and PAMAM (G 3.5 Ad) B and their self-assembly leading to an A/B system, affording nanorods.

Figure 6.9 Synthesis of the α-CD-based dendrimer (generation 3) modified by thioalkylated mannose, that is, Man-S-α-CDE (G3).

Figure 6.10 The α-CD-based dendrimer (generation 2) modified by fucose, that is, Fuc-S-α-CDE (G2).

Figure 6.11 Synthesis of the β-CD-based dendrimer consisting of the β-CD core and poly(l-lysine) dendrons, that is, dendrimer CD-PLLD

Figure 6.12 Monovalent iminosugar

and the β-CD-based 14-valent iminosugar

Figure 6.13 The β-CD-based 21-valent iminosugar

Figure 6.14 Synthesis of the azidodendron

Figure 6.15 Synthesis of the β-CD-based 21-valent iminosugar

Chapter 7: CD-Based Polymeric Gels

Figure 7.1 The role of DMF in the formation of the gel

from β-CD without the guest molecule.

Figure 7.2 Synthesis of the ferrocene-modified Pluronic F127, that is, Fc-F127-Fc

43.

Figure 7.3 Synthesis of the linear β-CD polymer

44.

Figure 7.4 Synthesis of β-CD gel.

Figure 7.5 Synthesis of Fc gel.

Figure 7.6 Synthesis of SSNa gel.

Figure 7.7 Synthesis of CDI cross-linked NS.

Figure 7.8 Synthesis of PMDA cross-linked NS.

Figure 7.9 Synthesis of HMDI cross-linked NS.

Figure 7.10 The results of increasing amount of the PMDA cross-linker with respect to CD in PMDA NSs.

Figure 7.11 Cross-linking of β-CD by PMDA at room temperature for 3 h leading to PMDA NSs.

Figure 7.12 EDTA dianhydride.

Figure 7.13 Erlotinib.

Figure 7.14 The ILS EMI TFSI and PMII.

Figure 7.15 Synthesis of the polymer

(the host).

Figure 7.16 Synthesis of Fc[BIM]TFSI

(the gemini guest).

Figure 7.17 The preparation of the

gel.

Figure 7.18 The reversible sol–gel transition of

gel, triggered by temperature and by electrochemical and chemical redox reactions.

Figure 7.19 Synthesis of the PIL gel PDV/A.

Chapter 8: CD Assemblies with Nanocarbons

Figure 8.1 Synthesis of the β-CD-C

conjugate bound by a hydrophilic diaminoethylene glycol spacer.

Figure 8.2 Synthesis of the CD-C

conjugate containing a peracetylated β-CD unit.

Figure 8.3 Synthesis of C

-PMOVE polymer.

Figure 8.4 Formation of C

-PMOVE aggregates and their dissociation upon treatment with γ-CD leading to 2 : 1 γ-CD/C

inclusion complexes.

Figure 8.5 The POPC, DMPC, and DPPC lipids, and the fluorescent label

Figure 8.6 Synthesis of the β-CD dimer

bridged by ethylenediamine.

Figure 8.7 Synthesis of

2 : 2 inclusion complex.

Figure 8.8 Spherical self-assembly of the

2 : 2 inclusion complex.

Figure 8.9 The γ-CD derivatives

and

and their syntheses.

Figure 8.10 The inclusion complexation of

with C

leading to

Figure 8.11 The inclusion complexation of γ-CDP with C

, affording (γ-CD)

Figure 8.12 The detection of singlet O

by EPR spectroscopy of TEMPO.

Figure 8.13 Synthesis of Pyr-β-CD.

Figure 8.14 The immobilization of Pyr-β-CD onto SWCNTs, affording β-CD-SWCNT.

Figure 8.15 Synthesis of adamantane-grafted polyethyleneimine, that is, PEI-Ad.

Figure 8.16 Preparation of the β-CD-SWCNT/PEI-Ad complex

Figure 8.17 The self-healing of the cut into pieces sample of

Figure 8.18 Formation of the β-CD/MWCNT hybrid material containing corrosion inhibitor BZ.

Figure 8.19 Synthesis of the β-CD dimer bridged by disulfide, that is,

Figure 8.20 Starlike block copolymer AE73.

Figure 8.21 The mechanism of BPA detection with the use of modified electrode, that is, β-CDP/EG/GCE.

Figure 8.22 Preparation of ADA-Ab

and ADA-Ab

conjugates.

Figure 8.23 Synthesis of ADA-Ab

/Cu@Ag/CD conjugate.

Figure 8.24 Preparation of the organic/inorganic hybrid CD/GN.

Figure 8.25 Preparation of CD/GN film with ADA-Ab

, that is,

Figure 8.26 Preparation of immunosensor

20.

Chapter 9: CD Applications

Figure 9.1 The structure of β-CDPP.

Figure 9.2 Synthesis of the BSA-CM-β-CD conjugates.

Figure 9.3 Synthesis of succinyl β-CD derivative SCD.

Figure 9.4 The octacationic photosensitizer

22.

Figure 9.5 The β-CD-labeled with NBFT, that is,

23,

and the β-CD oligomer labeled with RBITC, that is,

24.

Figure 9.6 Synthesis of

23.

Figure 9.7 Preparation of the supramolecular polymer Em-β-CD/PEI-β-CD, that is, E/P.

Figure 9.8 Surface functionalized with monomeric β-CD, for example,

27,

and surface functionalized with higher order dendrons, that is,

28.

Figure 9.9 Preparation of the surface functionalized with monomeric β-CD, that is,

27.

Figure 9.10 Preparation of the surface functionalized with the dendron

26.

Figure 9.11 Polycondensation of γ-CD with dicarboxylic acid dichlorides TPCl, IPCl, BPCl, and APCl leading to γ-CD polymers.

Figure 9.12 Preparation of SD/β-CD polymer and aniline adsorption by this polymer.

Figure 9.13 Preparation of the β-CD/chitosan assembly

36.

Figure 9.14 Permethrin

37.

Figure 9.15 The adamantine-labeled fluorescein, that is,

and the adamantine-labeled rhodamine B, that is,

39.

Figure 9.16 Carvacrol

40.

Figure 9.17 The chiral phosphanes

and

42,

derived from α- and β-CD, respectively.

Figure 9.18 Reaction of

with [RhCl(CO)

]

leading to

43.

Figure 9.19 Reactions of phosphanes

and

with [Rh(acac)(CO)

affording rhodium monophosphane complexes

and

45.

Figure 9.20 The rhodium catalyzed hydroformylation of styrene using complexes

and

45.

Figure 9.21 Activation of the complex

with CO/H

mixture leading to the complex trans [Rh(CO)

], that is,

46.

Figure 9.22 Preparation of mesoporous TiO

List of Tables

Cyclodextrins

Properties and Applications

Wanda Sliwa and Tomasz Girek

The Authors

Prof. Wanda Sliwa

Jan Dlugosz University

Institute of Chemistry

Armii Krajowej 13/15

42-200 Czestochowa

Poland

Prof. Tomasz Girek

Jan Dlugosz University

Institute of Chemistry

Armii Krajowej 13/15

42-200 Czestochowa

Poland

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Acknowledgment

We express our especial gratefulness to Beata Girek, M.Sc. with many thanks for her help and attention in the preparation of the book.

Wanda Sliwa and Tomasz Girek

Introduction

Cyclodextrins (CDs) are conical, truncated macrocycles; the α-, β-, and γ-CD consist of six, seven, and eight α-d-glucose units, respectively. They are environmentally friendly and deserve attention for their valuable properties. CDs bind covalently or supramolecularly with other species to give a great number of products.

The CD molecule has a hydrophobic cavity and a hydrophilic outer part. CDs include various guest molecules, these properties being their characteristic feature; they are widely employed in numerous fields, for example, in biomedical applications as drug carriers, in food, cosmetics, textile, agricultural industries, in enantiomeric separations, and in other areas. The inclusion complexation of CDs involves the supramolecular self-assembly having a crucial role in the creation of nonconventional, intelligent, often self-healing novel materials.

The rapid development of CD investigations has its reflectance in many reports concerning this theme, and the number of books and reviews dealing with their modifications and applications is enormous. Therefore, the writing of an exhaustive monograph showing the present state of CD knowledge is impossible, and only characteristic examples are described.

The properties and applications of CDs are presented in selected books [1–5] and publications [6–17]. The CD polymers are described by our group in books [5], book chapters [18–20], and reviews [21]; the original works include polymerization of β-CD with maleic anhydride with thermogravimetric study of polymers [22], as well as polymerization of β-CD with succinic anhydride with thermogravimetric analysis of polymers [23], and the study of thermal stability of β-CD/metal complexes [24]. Also, reviews on CD-based rotaxanes [25] and on CD-based polyrotaxanes [26] should be noted.

CDs can be modified on the wide or narrow rim, or on both, for improvement of their properties; in the study of modified CDs, the investigation of amphiphilic CDs is very important. The amphiphilic CDs are obtained by chemical or enzymatic modification of CDs using phospholipidyl or peptidolipidyl groups or grafted hydrocarbon chains. These compounds form in an aqueous medium various supramolecular nanoassemblies such as micelles or vesicles [27, 28]; the self-assembled CD nanoparticles are promising in drug delivery application [29]. One should mention here the original work of our group concerning β-CD/protein conjugates as innovative drug systems [30].

The two classes of extended crystalline materials referred to as CD metal organic frameworks (CD-MOFs) and CD-Bamboo also deserve attention; they are based on CDs which are able to use the carbon dioxide to form metal-carbohydrate frameworks [31, 32].

CDs belong to macrocycles, and besides studies concerning them, investigations dealing with other compounds of a cavitand structure are also performed. As such, calixarenes [33–37], cucurbiturils [38–43], and pillararenes [44–48] are taken into account. Moreover, one should mention here assemblies of CDs with the widely used today nanocarbons, that is, fullerenes [49, 50], nanotubes [51, 52], graphene [53, 54], and carbon coils [55, 56].

Various modifications of CDs have been made to improve their properties, and many CD assemblies with other species have been investigated to design their novel valuable applications. In view of the enormous number of reports concerning CDs, it would be impossible to cover all of them; only some themes may be selected. This book is written with the aspect of CD employments in mind and does not pretend to include a large area of existing material. It is prepared rather to show the reader some characteristic features of these macrocycles and to describe their most important properties crucial for future applications; in this background, the syntheses and properties of CDs are presented.

The contents of the book are divided into three parts:

Part I, consisting of four chapters, includes characteristic features of CDs.

Part II, consisting of three chapters, deals with various kinds of polymeric CDs.

Part III, consists of two chapters, the former concerns CD assemblies with nanocarbons, and the latter one includes examples of CD applications.

Each chapter begins with a short introduction of recent reports concerning described compounds, followed by presentation of original works. In the text, the common abbreviations of considered species are used; in their absence, the numbers of compounds are introduced.

References

1 Jin, Z.-Y. (2013)

Cyclodextrin Chemistry: Preparation and Application

(ed. Z.-Y. Jin), World Scientific Publishing Co. Pte. Ltd., Singapore, 267 pp.

2 Bilensoy, E. (2011)

Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine: Current and Future Industrial Applications

(ed. E. Bilensoy), John Wiley & Sons, Inc., Hoboken, NJ, 395 pp.

3 Hu, J. (2010)

Cyclodextrins: Chemistry and Physics

(ed. J. Hu), Transworld Research Network, Trivandrum, 266 pp.

4 Dodziuk, H. (2008)

Cyclodextrins and Their Complexes

(ed. H. Dodziuk), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 489 pp.

5 Girek, T. and Sliwa, W. (2006)

Chemistry of Cyclodextrins

(eds T. Girek and W. Sliwa), Jan Dlugosz University of Czestochowa, Czestochowa, 162 pp.

6 Antoniuk, I., Wintgens, V., Volet, G., Nielsen, T.T., and Amiel, C. (2015)

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Part ICharacteristic Features of CDs

The wide development of CD studies results in the strongly increasing amount of reports, where the special features of CDs are shown. For example, for chromophoric dyes the modulation of their properties such as fluorescence characteristics and the prototropic behavior by inclusion complexation in CD has been investigated [1]. Moreover, the role of CD-based nanoparticles for targeted drug delivery in cancer therapy was described [2] and the pharmaceutical formulations containing CDs focusing on the solubilization of drugs were discussed [3]. The CD metal complexes are also reviewed [4] and the CD-functionalized monolithic capillary columns useful for chiral separations are described [5].

In Part I the characteristic features of CDs are presented with examples of rotaxanes and polyrotaxanes (Chapter 1), micelles and vesicles (Chapter 2), CD inclusion complexes (Chapter 3), and CD dimers (Chapter 4).

Chapter 1CD-Based Rotaxanes and Polyrotaxanes as Representative Supramolecules

Recent Reports

Rotaxanes

Structural analysis of rotaxanes consisting of alkylene backbone and α-CD or permethylated α-CD has been performed [6]; halogen bonding rotaxane to sense anions in water [7] and rotaxane for detection of toxic metals [8] also have been reported. Moreover, the [3]rotaxanes emitting blue light, which consist of alkynylpyrene and permethylated α-CD, were described [9]. One should mention here also a series of four reviews of our group concerning syntheses and properties of rotaxanes [10–13].

Pseudorotaxanes

Among pseudorotaxanes, the motion of the two rings in palindromic [3]pseudorotaxanes [14] and the photooxygenation of multiply threaded pseudorotaxanes have been investigated [15]. Also, the complexation of CD-based pseudorotaxanes with isoprenoid compounds, for example, with the reduced coenzyme Q10, and with squalene for improvement of the pharmaceutical properties of obtained CD-pseudorotaxane-like supramolecules was studied [16], as well as the fabrication of poly(ϵ-caprolactone)/α-CD pseudorotaxane nanofibers [17].

Polyrotaxanes

The first fast radical end-coupling synthesis of polydimethylsiloxane (PDMS)-γ- CD-based polyrotaxanes (PRs) [18] and the preparation of PRs by copper-free click chemistry [19] have been reported. Cationic Pluronic-based PR+s threaded with 2-hydroxypropyl-β-CD (HPCD) have been synthesized for pDNA delivery; they can be used as potent vectors for pDNA-based therapeutics [20].

Pseudopolyrotaxanes

Among studies concerning pseudopolyrotaxanes (PPRs), one should mention the report on PPRs consisting of poly( p-dioxanone) and CDs, which were obtained via heat–cool cycles; it was found that they have better thermal stability than their backbone [21].

In this chapter, selected examples of CD-based rotaxanes (Section 1.1), PRs with triblock and pentablock backbones (Section 1.2.1), and PRs with other backbones (Section 1.2.2), as well as PPRs (Section 1.3), are presented.

1.1 CD-Based Rotaxanes

Rotaxanes are often multifunctional due to the combination of their properties, for example, photochromic [22], photoconductive [23], or electronic [24], which is promising for their use in sensors, molecular switches, or molecular machines. The viologen-based rotaxanes containing azobenzene groups and CD rings are such examples [25]. These systems are an important class of dyes because of the properties of azobenzene moieties [26] and of the photoactivity and strong electron acceptor character of viologens [27]. They also deserve attention due to the presence of the azo group, showing solvatochromism and nonlinear optical (NLO) properties [28]. One should note that in rotaxanes the CD units can undergo controlling shuttling movements, induced by various stimuli, often by irradiation [25].

In the experiments [2]rotaxanes have been synthesized; their dumbbells consist of azobenzene and viologen moieties stoppered with pentacyanoferrate groups; they are threaded by α- and β-CD units [29]. The pentacyanoferrate stoppers act as strong electron donors; they are connected with the strong electron acceptor viologen, thus giving rise to an exceptionally intense solvatochromism. The work is a continuation of the previous study on ferrocyanide(II) complexes of 4,4'-bipyridines, serving for comparison of their solvatochromic properties to those of synthesized rotaxanes [30]. The starting compound of the process is the Zincke salt 1.

For the synthesis of compounds 2 and 3, first 2 has been obtained by an improved, earlier used procedure [25]. The synthesis of 2 proceeds in the solid state, (solvent-free Zincke reaction); for this purpose, 1, that is, the Zincke salt and p-azodianiline were dissolved in ethanol and heated in an open round bottom flask until the entire quantity of ethanol was removed. The remaining pasty mixture was heated under a condenser overnight in the absence of any solvent. The 2,4-dinitroaniline formed as a by-product on the upper part of the flask was removed by sublimation, and the solid mass was dissolved in MeOH and treated with Et2O to precipitate 2 as a red powder.

The aqueous solution of 2 formed by the reaction with the complex salt FeII(CN)5NH3 · 3H2O (solid) turned blue. Addition of EtOH precipitated the deep blue dumbbell 3 (Figure 1.1).

For the synthesis of dyes

4a,b,

the mixture of

with water was treated with α- or β-CD. In both cases the immediate dissolution of

occurred, indicating formation of pseudorotaxanes. Upon addition of Na

[Fe

(CN)

] · 3H

O, during the

in situ

stoppering, the color of both solutions turned deep blue. The reaction mixtures were stirred in the dark under an argon atmosphere at room temperature, and the subsequent addition of EtOH precipitated

4a,b

as blue powders (

Figure 1.2

Figure 1.1 Synthesis of compounds 2 and 3.

Figure 1.2 Synthesis of dyes 4a,b.

Figure 1.3 Compounds 3, 4a,b, 5, and 6.

Compounds 3 (i.e., dumbbell of 4a,b) and 5, (i.e., dumbbell of 6a,b) have the same precursor 2 [23, 25]. In 3 and 4a,b, the strong electron-donating cyanoferrate groups are stoppers; in 5 and 6, the strong electron-withdrawing 3,4-dinitrophenyl groups are stoppers. Intense charge transfer in 3 and 4a,b, as compared to 5 and 6, explains the intense solvatochromism of 3 and 4a,b and the only negligible solvatochromism of 5 and 6 [30] (Figure 1.3).

The dumbbell 3 and rotaxanes 4a,b are intensively solvatochromic. Solvatochromism involves the change in electronic spectra of a dye upon alteration of polarity of its solvent [31]; the changes in color often may be observed by the naked eye. Solvatochromic dyes receive growing attention today since they can be used as molecular sensors [32] and probes of solvent polarity. They became the basis of empirical parameters of solvent polarity, that is, of a Reichardt's dye and the corresponding polarity scale ET (30) [33], serving for a scale of dipolarity/polarizability and Lewis acidity of solvents [33].

The experimental results show that the introduction of α- or β-CD units into 3, affording 4a or 4b, does not decrease the solvatochromic character of 3; all three compounds 3 and 4a,b exhibit a very intense solvatochromism, even stronger than in the case of the Reichardt's betaine [33].

Dumbbell 3 and rotaxanes 4a,b are highly soluble in polar hydroxylic solvents, predominantly in water, since they form, by their nitrogen atoms of CN groups, strong hydrogen bonds with molecules of these solvents [30]. Solvatochromism of 3 and 4a,b was investigated in water/ethylene glycol binary mixtures. Water and ethylene glycol were chosen as two solvents not only because of their ability to dissolve 3 and 4a,b but also because of the high stability of 3 and 4a,b in these solvents and their mixtures. It was observed that 3 and 4b show similar susceptibilities to medium polarity changes (in the region between the polar solvents water and ethylene glycol).

It is known that azo dyes can undergo photochemical trans/cis isomerization; due to this property, the azo dyes are promising for design of photoresponsive compounds and materials of a wide range of applications [26, 34]. However, in 3 and 4a,b, the presence of the stopper groups FeII(CN)5 renders these compounds photochemically unstable. The irradiation of pentacyanoferrate(II) complexes results in the loss of the FeII(CN)5 groups [35]. But, on the other side, one should point out that these groups render these compounds strongly solvatochromic. It is noteworthy that 3 and 4a,b are very stable in solution when they are not irradiated.

Today, the light-responsive drug delivery systems are intensively studied since they may enhance drug delivery efficiency and minimize side effects. It is known that light stimuli can easily be exerted with high precision at specific sites. There have been reports of several light-responsive drug carriers, upon irradiation undergoing cleavage of chemical bonds [36] or conformational changes, for example, cis–trans photoisomerization of azobenzene [37]. In these systems, UV or visible light is usually used as a trigger. However, due to the “water window” (700–1400 nm), the tissue penetration of UV and visible light is limited, resulting in inefficient deep-tissue drug delivery [38]. Therefore, to overcome this difficulty, the near-infrared (NIR)-responsive drug delivery systems are employed. NIR irradiation has high transmittance and attenuated cytotoxicity in living tissues and is of interest in noninvasive cancer therapy.

Thus was developed the NIR-responsive nanosystem for anticancer drug delivery [39]; it consists of the photo-switchable α-CD-based azobenzene rotaxane, immobilized onto an Au nanorod-mesoporous silica core–shell hybrid where the Au nanorods are silica covered.

The Au nanorods (core), which are widely used as a photothermal agent [40], serve as the energy converter to activate the isomerization of the azobenzene moiety. The mesoporous silica (shell) serves as a drug-storage reservoir [41] and as the substrate for postmodification by the rotaxane [42]. The rotaxane immobilized on the silica layer, formed of a thread containing the azobenzene group and α-CD encapsulating the trans-azobenzene, acts as a capping agent to control the drug loading and release.

The experiments concerning the design of the NIR-responsive nanosystem involve following procedures A–D.

For

the preparation of Au mesoporous silica-covered nanorods (Au@MSN),

four steps are necessary:

In the first step, the ultrasmall Au seeds were prepared by reduction of HAuCl4 using NaBH4 in aqueous environment. For this purpose, the HAuCl4 aqueous solution was mixed with cetyltrimethyl ammonium bromide (CTAB) aqueous solution. Then this mixture was treated with ice-cold NaBH4 aqueous solution, and the ultrasmall Au seeds were formed immediately.

In the second step, the growth solution for Au nanorods was prepared; it is a mixture of CTAB, HAuCl4, AgNO3, H2SO4, and ascorbic acid solutions, added sequentially. The growth was initiated by treating this mixture with the above-obtained seed solution and was carried out at 30 °C for 6 h. The prepared Au nanorods were washed with water to remove the excessive CTAB, and then they were extracted by centrifugation and concentrated to 10 mg Au ml−1.

In the third step, the mesoporous silica coating was performed via a template method. First, the concentrated Au nanorods solution (1 ml) was redispersed in aqueous CTAB solution (0.01 M, 100 ml) and the mixture was stirred for 15 min. The mixture was treated with ammonia water in order to adjust the solution pH to be slightly basic and then tetraethoxysilane (TEOS) was added. The temperature of the mixture was kept at 30 °C, and the reaction was carried out for 24 h. The Au nanorods coated with silica were extracted by centrifugation.

In the fourth step to remove the CTAB template, the prepared Au nanorods coated with silica were dispersed in ethanol (40 ml) containing hydrochloric acid (5 ml), and the mixture was stirred at 40 °C. After centrifugation and dehydration, the Au nanorods coated with mesoporous silica (Au@MSN) were obtained.

For the synthesis of

containing azido group

, the reaction of azocompound

with bis(2-chloroethyl)ether in DMF in the presence of K

and KI in DMF was performed by stirring at 100 °C for 12 h. After filtration the solvent was removed under a reduced pressure to give compound

The DMF solution of

was heated with NaN

and stirred at 70 °C under nitrogen for 12 h. After filtration and removal of the solvent, compound

was obtained (

Figure 1.4

For grafting of propiolamide

onto Au@MSN surface affording Au@MSN- alkyne,

the anhydrous Au@MSN homogenously suspended in toluene was treated with

and refluxed at 120 °C for 24 h. The product was extracted by centrifugation and dehydrated under vacuum at room temperature to give Au@MSN-alkyne (

Figure 1.5

For the synthesis of Au@MSN-rotaxane,

first the complex

/α-CD, containing azido group had to be obtained. To this end,

was stirred with α-CD in water at room temperature under nitrogen for 2 h affording the complex

/α-CD (

Figure 1.6

Figure 1.4 Synthesis of the compound 7.

Figure 1.5 The grafting of propiolamide 10 onto Au@MSN surface.

Figure 1.6 Preparation of the complex 7/α-CD.

Then the mixed solutions of Au@MSN-alkyne and of the complex 7/α-CD in water were treated with CuSO4 · 5H2O and sodium ascorbate, and under click reaction conditions were stirred at room temperature for 3 days. After centrifugation the Au@MSN-rotaxane was obtained (Figure 1.7).

Figure 1.7 Synthesis of Au@MSN-rotaxane.

In order to investigate the NIR-triggered drug release from Au@MSN-rotaxane serving as a nanocarrier, the fluorophore fluorescein isothiocyanate (FITC) was used as a model drug. Initially, the Au@MSN-rotaxane was loaded with FITC cargo molecules via diffusion at 40 °C, then the cargo-loaded nanocarrier was UV irradiated; in this process, the trans to cis isomerization occurs, along with the closure of silica mesopores and the robust encapsulation of FITC. The UV irradiation enables trans to cis photoisomerization of azobenzene; therefore, α-CD moves toward the nanopore orifice for the closure of nanopores [43].

The UV irradiation can induce the trans-to-cis photoisomerization of azobenzene, and the cis-azobenzene can undergo a thermal relaxation process to return to trans conformation. The α-CD can efficiently encapsulate trans-azobenzene, but not cis-azobenzene; in this way, the UV-/heat-controlled movement of α-CD unit in the rotaxane exists.

Upon UV irradiation of Au@MSN rotaxane, the trans-to-cis photoisomerization of azobenzene occurs, while under NIR irradiation the cis-azobenzene returns to its trans conformation, and the cargo release occurs, that is, the cargo release is performed under NIR irradiation [44] (Figure 1.8).

Figure 1.8 The trans-to-cis photoisomerization of Au@MSN-rotaxane.

It was established that the UV/NIR reversibility between two azobenzene conformations maintained even after five cycles. These results confirm that NIR irradiation can efficiently trigger the cis-to-trans isomerization of azobenzene for controlled drug release.

In vivo drug release was carried out on zebrafish embryo models using the anticancer drug doxorubicin (DOX), itself having a strong red fluorescence, which facilitated confocal laser microscopy observation [45]. It was found that DOX release from the nanocarrier in zebrafish embryo models could be controlled remotely under NIR irradiation; a significant drug spreading to the adjacent tissues was established. The above study is a successful example of NIR-controlled drug release in vivo.

Oligoynes, that is, carbon-rich compounds containing conjugated triple bonds, are intensively studied due to their application possibilities; they show NLO properties [46] and have been recently used as molecular precursors for the preparation of carbon nanomaterials at room temperature [47–49]. It is also noteworthy that spectroscopic studies of oligoynes may be considered as an approach toward the properties of the carbon allotrope carbyne (CC)n [50, 51]. Although the stabilization of oligoynes by encapsulation via rotaxane formation is known [52], few examples have been reported [24, 53].

In the study of oligoynes, it was found that the amphiphilic nature of the TMS-protected triyne, 11 can be of use in the facile preparation of the CD-based hexayne [3]rotaxane 12 by simple reaction of 11 with α-CD in water [54].

The synthesis of rotaxane 12 begins with the deprotection of 11 by MeONa in an ether/methanol mixture (4 : 1), followed by Amberlite (H+), which results in the deacetylation and simultaneous desilylation leading to the amphiphile 13. The formed 13 was not isolated, but subjected in situ to the oxidative homocoupling with α-CD in water by the addition of CuBr2 and TMEDA to give hexayne [3]rotaxane 12 (Figure 1.9). It was established that the 12 isomer with a tail-to-tail arrangement of α-CD units is formed exclusively.

Figure 1.9 Synthesis of rotaxane 12.

For comparison purposes, the dumbbell 14 of rotaxane 12 was obtained. The synthesis begins with the desilylation of 11 by cesium fluoride and simultaneous homocoupling by Cu(OAc)2, leading to hexayne 15, which upon deacetylation with NaOMe/MeOH affords the dumbbell 14 (Figure 1.10).

Figure 1.10 Synthesis of the compound 14.

It was found that the encapsulation of 14 by CD units stabilizes the resulting rotaxane 12 against UV irradiation, while sole 14 does not show stability against UV irradiation. The effective prevention of 14 by formation of rotaxane 12 against photodegradation or polymerization is promising for preparation of shielded molecular wires of the 12 type.

1.2 CD-Based Polyrotaxanes

1.2.1 CD-Based Polyrotaxanes with Triblock and Pentablock Backbones

The biocompatibility of biomolecules for implantation is closely related to collagen adsorption and subsequent fibrillization on implants. Important steps for the body to adapt to the biomaterials for implantation are the initial adsorption rearrangement and infiltration of collagen fibrils onto the biomaterials [55]. The inadequate interaction of collagen with the implant may lead to its rejection.

The control of collagen adsorption and fibrillization was investigated using surface mobility, that is, molecular mobility on the surface. The surface mobility represents the dynamic motion of molecules under hydrated conditions. The dynamic motion of the surface molecules is an important parameter in the regulation of nonspecific biological responses [56–58]. Therefore, the protein molecules, or the cells, continuously move on the surface until they achieve a thermodynamic equilibrium for their final conformation.

In the experiments, the relations between surface mobility, fibrillogenesis of collagen molecules, and the inflammatory response have been investigated in vitro and in vivo [59]. The study concerned in vitro adsorption and fibrillogenesis of collagen on a surface with dynamic properties and how this surface influences the inflammatory response in vivo. The investigation of collagen–surface interactions is related to the control of wound healing where collagen adsorption, fibrillization, deposition, and maturation occur.

Polyrotaxanes (PRs) 16a,b consisting of the ABA-type block copolymers as backbones, threaded along poly(ethylene glycol) (PEG) by mobile α-CD units α-CD and MeO-α-CD, respectively, and end capped by hydrophobic terminal groups were used to prepare mobile surfaces with representative dynamic properties (Figure 1.11).

Figure 1.11 Polyrotaxanes 16a,b.

PRs 16a,b are convenient models to establish specific biorelevant interactions involving collagen adsorption and fibrillization, with surface mobility as one of the functional parameters. The surface dynamism represented by 16a,b has shown that differences in protein adsorption and fibroblast morphology may occur [56, 57]. The difference in mobility of α-CD unit within the PEG chain is a crucial parameter in the regulation of a nonspecific biological response.

It was found that increasing the mobility of the polymer on the surface resulted in the formation of the soft collagen layer. The collagens in this layer rearrange, leading to the formation of thicker collagen fibrils by lateral aggregation, that is, by their maturation. The obtained results show that the surface mobility on an implant is important for wound healing.

With the use of PRs 16a,b it was found that a loop structure was formed on the surface. This allowed to determine the role of molecular mobility on collagen adsorption and fibrillogenesis, and to see how it affects the healing process. The presence of methoxy groups in 16b promoted the adsorption of collagen onto the surface. Although the mobility of the polymer surface did not influence the amount of proteins adsorbed, it influenced the formation of a soft-dissipative layer of collagen on the surface. The collagen in this layer had reaggregated to form thicker fibrils aligned in a specific direction. This affected in vivo responses, where the high molecular mobility facilitated by 16b induced faster molecular rearrangement leading to the formation of a new collagen layer at the implant–tissue interface. The obtained results suggest that wound healing can be controlled by modulation of the surface property of implants, and that the surface mobility plays an important role in this process.

Today, the CD-based PRs have been widely investigated in various areas, including biomedical applications [60]. PRs consisting of ABA triblock copolymers threaded by α-CD units have been synthesized; they form flower polymeric micelles (PMs), which are promising for delivery of anticancer drugs [61]. Such copolymers may be obtained via atom transfer radical polymerization (ATRP); however, it is difficult to regulate the number of threading CDs in the synthesized PRs. It is known that the number of threading CD units in PRs is an important factor determining their properties; therefore, another synthetic procedure was necessary.

To this end, in the performed study the reversible addition-fragmentation chain transfer (RAFT) polymerization was used; in this procedure the PR-based macro-chain transfer agent, that is, macro-CTA is involved. This method enables the regulation of both the molecular weight of the polymer chain and the number of threading CD units in PR segments. Moreover, the formation of self-assembled supramolecular flower micelles consisting of a core of hydrophobic polymers surrounded by hydrophilic loops of PRs was studied and the possibility of their use as a drug delivery carrier was shown.

The experiments begin with the synthesis of the PR-based macro-CTA, 17, followed by the synthesis of the PR consisting of triblock copolymer, threaded by α-CD units, that is, 18.

For the synthesis of PR-based macro-CTA,

17,

first the aqueous solution of α,ω-bisphenylalanyl PEG was treated with the saturated aqueous solution of α-CD. After the freeze drying, the pseudopolyrotaxane

was obtained as a powder. The reaction of

with 4-cyanopentanoic acid dithiobenzoate (CPDTB) and 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) afforded the precipitate, which was dissolved in DMSO. The received solution was freeze dried to give the PR-based macro-CTA,

17.

For the synthesis of polyrotaxane, which contains triblock copolymer, that is,

18,

first

17,

benzyl methacrylate, and 4,4'-azobis(4-cyanopentanoic acid) (V-501) were dissolved in DMSO; then this solution was bubbled with nitrogen for deoxygenation. The reaction mixture was stirred at 70 °C for 24 h, and then the obtained polymer was purified by dialysis against DMSO, followed by water. The recovered solution was freeze dried to yield

(

Figure 1.12

Figure 1.12 Synthesis of polyrotaxane 18.

The number of threading α-CD units in 17 can be controlled by varying the α-CD/19 ratio and the reaction time, as in the previous study [62]. Therefore, the synthetic method used in this work may be applied to prepare a variety of PRs which contain triblock copolymers.

It is known that the amphiphilic block copolymers (composed of hydrophobic and hydrophilic polymers) self-assemble into PMs with a shell of hydrophilic polymers. The PRs which contain triblock copolymers also form PMs [63].

The preparation of supramolecular PMs consisting of a hydrophobic polymer core and hydrophilic PR shell was attempted using 18. However, the PR is not soluble in aqueous solution due to the intra- and intermolecular hydrogen bonding among threading α-CD units; therefore, the 18 precipitates in aqueous solution. To increase the solubility of the PR segments of 18 in aqueous media, the hydrophilic hydroxyethyl (HE) groups were introduced into the α-CD units of 18 to give 18 modified by HE groups denoted as 20 [64].

For the synthesis of 18 modified by HE groups, 20, the DMSO solution of 18 and 1,1′-carbonyldiimidazole (CDI) was stirred at room temperature for 24 h. Then 2-hydroxylethylamine (HEA) was added and the reaction mixture was stirred at room temperature for a further 24 h. The formed polymer was purified by dialysis against water for 3 days and the recovered solution after freeze drying yielded 20 (Figure 1.13). The number of introduced HE groups, determined by 1H NMR, was sufficient to solubilize PR segments in aqueous solution [64].

The ABA-type triblock copolymers with central hydrophilic segments form by self-assembly the PMs consisting of a core of hydrophobic segments surrounded by a shell of loops of hydrophilic segments.

For the preparation of PMs

, the DMSO solution of

was dialyzed against water. The transmission electron microscopy (TEM) results have shown that

formed in aqueous solution uniform spherical PMs that were 15.3 ± 1.9 nm in diameter. In this way were obtained the PMs, named the flower PMs since they have the shape of a flower with hydrophilic segments resembling petals (

Figure 1.14

Figure 1.13 Synthesis of polyrotaxane 20.

Figure 1.14 Formation of the flower polymeric micelle of 20.

In the investigation of the ability of flower PMs to act as drug carriers, the loading of the hydrophobic anticancer drug, paclitaxel, was performed. It was found that the flower PMs can incorporate paclitaxel in their core, and therefore are promising for use in the delivery of anticancer drugs to targeted tumor tissues. This property is valuable for their application in the medical field.

PNIPAAm, that is, poly(N-isopropylacrylamide) has an interesting thermoresponse property due to its lower critical solution temperature (LCST) at around 32 °C in aqueous solution. Below the LCST, PNIPAAm is hydrophilic and has extended chains; but when temperature increases up to 32 °C, it becomes hydrophobic and phase-separated. Chemical modification of PNIPAAm may alter the LCST value. For example, the grafting of a hydrophilic polymer onto PNIPAAm usually enhances its LCST. The LCST is strongly increased due to the coverage of γ-CD units hindering the thermally responsive aggregation of the PNPAAm blocks.

PNIPAAm is used as end-capping polymeric blocks in the preparation of CD-based PRs; it not only inhibits the dethreading of α-and β-CDs but also imparts the thermoresponsive behavior to PRs [65–67].

In the experiments, the PR 21 containing PR PNPAAM-b-Pluronic F68-s-PNIPAAM pentablock copolymer “backbone” threaded by γ-CD units and terminated by β-CD units has been synthesized [68]. Before the synthesis of PR 21, first the two following processes, that is, synthesis of the azido-terminated copolymer 22 and synthesis of propargylamine-β-CD 23 were performed.

For the synthesis of azido-terminated copolymer

22,

the DMF solution of Br-terminated copolymer

was treated with NaN

in DMF and stirred at room temperature for 30 h. After dialysis against water with the use of a cellulose membrane, the azido-terminated copolymer

was obtained [69, 70].

For the synthesis of propargylamine-

-CD

23,

the reaction of mono-tosyl-β-CD with propargylamine in DMF was performed at 70 °C for 24 h, and then the reaction mixture was treated repeatedly with cold acetone. The precipitates were subsequently dissolved in water/methanol mixture and poured into acetone for the removal of unreacted propargylamine. After drying at 50 °C in a vacuum oven, the propargylamine-β-CD

was obtained.

Synthesis of PR

proceeded via aqueous click chemistry. The azido-terminated copolymer

and aqueous solution of γ-CD were stirred at room temperature for 24 h to give PPR

(nonisolated). Then the obtained suspension of

underwent

in situ

the click reaction with propargylamine-β-CD,

in the presence of CuSO

·5H

O and sodium ascorbate. The reaction temperature was maintained at 25 °C for 24 h, the crude product was dialyzed against water, dissolved in DMF, and precipitated with anhydrous ether to give PR

terminated by β-CD units (

Figure 1.15

Figure 1.15 Synthesis of polyrotaxane 21.

It was observed that the higher the feed molar ratio of NIPAAm is, the PNIPAAm blocks become longer and therefore the molar ratio of γ-CD is lower because it is difficult for γ-CD units to include and slip over the longer PNIPAAM blocks to form PPRs. One should note that the molar ratio of γ-CD units is more than stoichiometric; this means that the γ-CDs not only form inclusion complexes with the flank PNIPAAM blocks but also slip over to the central poly(propylene glycol) (PPG) block of Pluronic F68.

After the click reaction with propargylamine-β-CD 23

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