Polymers for Biomedicine E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 823

Veröffentlichungsjahr: 2017

Beschreibung

Highlighting dynamic developments in polymer synthesis, this book focuses on the chemical techniques to synthesize and characterize biomedically relevant polymers and macromolecules. * Aids researchers developing polymers and materials for biomedical applications * Describes biopolymers from a synthetic perspective, which other similar books do not do * Covers areas that include: cationically-charged macromolecules, pseudo-peptides, polydrugs and prodrugs, controlled radical polymerization, self-assembly, polycondensates, and polymers for surface modification

Leseprobe

Table of Contents

Cover

Title Page

List of Contributors

Part I: Pseudo‐Peptides, Polyamino Acids, and Polyoxazolines

1 Characterization of Polypeptides and Polypeptoides – Methods and Challenges

1.1 Introduction

1.2 Synthesis of Poly(peptide)s

1.3 Characterization of Poly(peptide)s

1.4 Gel Permeation Chromatography (GPC)

1.5 Infrared (IR) Spectroscopy

1.6 Nuclear Magnetic Resonance (NMR) Spectroscopy

1.7 Circular Dichroism (CD) Spectroscopy

1.8 Mass Spectrometry

1.9 Non‐Aqueous Capillary Electrophoresis (NACE)

1.10 Static Light Scattering (SLS)

1.11 Conclusion

References

2 Poly(2‐Oxazoline)

2.1 Introduction

2.2 Synthesis of Poly(2‐Oxazolines)

2.3 Functionalization of Poly(2‐Oxazolines) Chain Ends

2.4 Side Group Modification

2.5 Copolymers of 2‐Oxazolines

2.6 Poly(2‐oxazolines) as Carrier Systems for Medical Applications

2.7 Conclusion

References

3 Poly(2‐Oxazoline) Polymers – Synthesis, Characterization, and Applications in Development of POZ Therapeutics

3.1 Introduction

3.2 Synthesis

3.3 Characterization

3.4 Properties

3.5 Applications in Pharmaceutical Drug Development

3.6 Applications in Targeted Drug Delivery

3.7 Summary

Acknowledgments

References

4 Polypeptoid Polymers

4.1 Introduction

4.2 Synthesis of Polypeptoids by Controlled Polymerizations

4.3 Synthesis of Linear Polypeptoids

4.4 Synthesis of Cyclic Polypeptoids

4.5 Synthesis of Bottlebrush, Branched, and Star‐Shaped Polypeptoid Copolymers

4.6 Post‐Polymerization Modification of Polypeptoids

4.7 Fundamental Physicochemical Properties

4.8 Biomedically Relevant Properties (Degradability, Cytotoxicity, and Immunogenicity)

4.9 Cytotoxicity

4.10 Immunogenicity

References

Part II: Advanced Polycondensates

5 Polyanhydrides

5.1 Introduction

5.2 Background

5.3 Distinctive Features and Limitations

5.4 Polyanhydride Classification

5.5 Synthesis of Polyanhydrides

5.6 Characterization

5.7 Applications

References

6 New Routes to Tailor‐Made Polyesters

6.1 Introduction

6.2 Ring‐Opening Polymerization Approaches

6.3 Condensation Approach

6.4 Polyaddition and Other Recent Mechanisms

6.5 Conclusion

References

7 Polyphosphoesters

7.1 Introduction

7.2 PPEs: Synthesis

7.3 Polycondensation

7.4 Polyaddition

7.5 Ring‐Opening Polymerization (ROP)

7.6 ROP of Six‐Membered Cyclic Phosphates

7.7 Ring‐Opening Polymerization of Five‐Membered Cyclic Phosphates

7.8 Metathesis Polymerization of Unsaturated Phosphoesters

7.9 Degradation of PPEs

7.10 Conclusions

References

Part III: Cationically Charged Macromolecules

Chapter 8: Design and Synthesis of Amphiphilic Vinyl Copolymers with Antimicrobial Activity

8.1 Introduction

8.2 Amphiphilic Polymethacrylates as Synthetic Mimics of Antimicrobial Peptides

8.3 Other Classes of Antimicrobial Peptide‐Mimetic Polymers

8.4 Other Synthetic Approaches to the Development of Antimicrobial Polymers and Macromolecules

8.5 Summary and Future Perspectives

References

Chapter 9: Enhanced Polyethylenimine‐Based Delivery of Nucleic Acids

9.1 Introduction

9.2 Covalent Modification: Passive Functionality

9.3 Covalent Modification: Ligand‐Based, Active Targeting

9.4 Crosslinked PEI

9.5 Alternative Approaches

9.6 Selective Strategies

9.7 Hybrid Systems

9.8 Progress in the Clinical Development of PEI‐Based Systems

9.9 Conclusion

References

Chapter 10: Cationic Graft Copolymers for DNA Engineering

10.1 Introduction

10.2 Preparation of Cationic Comb‐Type Copolymers with Polysaccharide Grafts

10.3 Characterization of IPEC of Cationic Graft Copolymers with DNA

10.4 Characterization of Nucleic Acid Chaperone‐Like Activity of Cationic Comb‐Type Copolymers

10.5 Application of the Cationic Comb‐Type Copolymer to DNA Nanobiotechnology

10.6 Conclusion

Acknowledgments

References

Part IV: Biorelated Polymers by Controlled Radical Polymerization

11 Synthesis of (Bio)degradable Polymers by Controlled/“Living” Radical Polymerization

11.1 Introduction

11.2 Radical Polymerization for the Synthesis of (Bio)Degradable Polymers

11.3 CRP Methods for the Synthesis of (Bio)Degradable Polymers

11.4 Conclusions

References

Part V: Polydrugs and Polyprodrugs

Chapter 12: Polymerized Drugs – A Novel Approach to Controlled Release Systems

12.1 Introduction

12.2 Poly(Anhydride‐Esters)

12.3 Poly(Esters)

12.4 Green Chemistry

12.5 Conclusion

References

13 Structural Design and Synthesis of Polymer Prodrugs

13.1 Introduction

13.2 Structural Aspects of Polymer Carriers

13.3 Synthetic Routes

13.4 Drug Coupling Strategies

13.5 Elimination of Carriers

13.6 Conclusion

Acknowledgement

References

Part IV: Biocompatibilization of Surfaces

14 Polymeric Ultrathin Films for Surface Modifications

14.1 Methods for Preparation of Ultrathin Polymer Films

14.2 Examples in Medical Applications

14.3 Summary

References

15 Surface Functionalization of Biomaterials by Poly(2‐oxazoline)s

15.1 Introduction

15.2 Grafting‐To of End‐Functional Polyoxazolines

15.3 Photochemical Surface Grafting of Polyoxazolines

15.4 Poly‐(L‐lysine)‐g‐PMOXA Copolymer Films

15.5 Surface‐Initiated CROP

15.6 Conclusions

References

16 Biorelated Polymer Brushes by Surface Initiated Reversible Deactivation Radical Polymerization

16.1 Introduction

16.2 Brush Synthesis

16.3 Characterization of Polymer Brushes

16.4 Biomedical Application of Polymer Brushes

16.5 Perspectives and Summary

References

Part VII: Self‐Assembled Structures and Formulations

17 Synthesis of Amphiphilic Invertible Polymers for Biomedical Applications

17.1 Introduction

17.2 Synthesis of Amphiphilic Invertible Polymers

17.3 Micellization, Self‐Assembly, and Invertible Properties of AIPs

17.4 Self‐Assembly of AIPs in Water: Potential for Stimuli‐Responsive Drug Delivery

17.5 Conclusion

References

18 Bioadhesive Polymers for Drug Delivery

18.1 Introduction

18.2 Theories of Bioadhesion

18.3 Routes of Administration for Bio‐ and Mucoadhesive Drug Delivery Systems

18.4 Bio‐ and Mucoadhesive Polymers

18.5 Synthesis of Bio‐ and Mucoadhesive Polymers

18.6 Factors Affecting Mucoadhesion

18.7 Delivery Systems

18.8 Methods of Determining Mucoadhesion

18.9 Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Typical amide I frequencies of different secondary structures.

Table 1.2 Statistically derived chemical shifts in secondary structures.

Chapter 03

Table 3.1 Process steps used in the preparation of poly(2‐oxazoline).

Table 3.2 Properties of POZ, PEG, and polydextrans.

Chapter 06

Table 6.1 Common aliphatic polyesters by ROP.

Chapter 07

Table 7.1 Six‐membered cyclic phosphoesters used for ring‐opening polymerization.

Table 7.2 Five‐membered cyclic phosphates for the ring‐opening polymerization.

Chapter 10

Table 10.1 Preparation of PLL‐Dex graft copolymer.

Chapter 15

Table 15.1 Copolymer adlayers parameters for PLL‐g‐PMOXAs presenting different grafting densities α. PLL films and the bare Nb2O5 surface are also included.

Chapter 17

Table 17.1 Characteristics of the AIPE‐1 polyesters.

Table 17.2 Calculated hydrodynamic radius (in nm) of AIPEs‐1 in different solvents.

Table 17.3 Characteristics of the AIPE‐2 polyesters.

Table 17.4 Calculated hydrodynamic radius (in nm) of AIPEs‐2 in different solvents.

Table 17.5 Characteristics of the AIPUs.

Table 17.6 Calculated hydrodynamic radius (in nm) of AIPUs in different solvents.

Table 17.7 Critical micelle concentration of amphiphilic invertible polymers.

Table 17.8 Physical properties of blank and curcumin‐loaded AIPE micellar assemblies at polymer concentration of 1% (w/v).

Table 17.9 Phase transfer characteristics of curcumin‐loaded AIPE micellar assemblies at 1% concentration.

Chapter 18

Table 18.1 Anatomical differences of the mucus membrane adapted from Shaikh

et al.

Table 18.2 Chemical structures of some bioadhesive polymers used in drug delivery.

Table 18.3 Commercially‐produced cellulose ethers and the derivatizing reagent used to prepare them.

Table 18.4 Methods of studying mucoadhesion adapted from Junginer

et al

.

List of Illustrations

Chapter 01

Figure 1.1 Mechanisms of NCA polymerization: Normal amine mechanism (NAM) and activated monomer mechanism (AMM).

Figure 1.2 Initiation and propagation of metal catalyzed NCA polymerization.

Figure 1.3 Mechanism of trimethylsilyl‐mediated NCA polymerization.

Figure 1.4 Molecular structures of common GPC standards compared to polypeptides.

Figure 1.5 Kinetic plot from the amine initiated polymerization of poly(glutamic acid). Molecular weights were obtained from GPC data, calibrated with poly(glutamic acid) standards.

Figure 1.6 DMF GPC of a growing PLys(Z) chain showing the transition from random coil to α‐helix.

Figure 1.7 HFIP GPCs of PLys(Z), from right to left: P(Lys(Z)25, P(Lys(Z)50, P(Lys(Z)100, P(Lys(Z)200.

Figure 1.8 IR spectrum of mannose modified poly(glutamic acid) as well as its precursors, showing typical amide I and II bands of an α‐helical conformation.

Figure 1.9 IR spectrum of protected lysine, cysteine, and glutamic acid 20‐mers. The arrows indicate the amide I band.

Figure 1.10 Useful IR NCA peaks to control monomer conversion (Lys(Z) in DMF).

Figure 1.11 NMR of poly(

N

‐ε‐benzyloxycarbonyl‐L‐lysine) (PLys(Z)), degree of polymerization 420, initiator: neopentylamine.

Figure 1.12 Left: α‐proton in growing PLys(Z) chains changing from random coil to α‐helix.

Figure 1.13 CD spectrum of poly(lysine) in random coil (left), α‐helical (right, open symbols) and β‐sheet conformation (right, full symbols).

Figure 1.14 CD spectra of exactly defined

N

‐carbobenzoxy‐γ‐ethyl‐L‐glutamate oligomers showing a sharp transition from random coil to α‐helix at six repeating units.

Figure 1.15 CD spectrum of di(ethylene glycol)‐modified poly(serine) showing a coil to sheet transformation with increasing methanol content from A to E.

Figure 1.16 CD spectrum of coil to helix transition with increasing NaClO

4

concentration in polymer brushes with poly(lysine) side‐chains.

Figure 1.17 Poisson distribution of poly(Sarcosine) measured by MADI‐TOF.

Figure 1.18 MALDI‐TOF of PLys(Z) fractioned by HFIP GPC.

Figure 1.19 Endgroup analysis of Poyl(β‐benzyl‐L‐aspartate).

Figure 1.20 Capillary electrophoresis coupled to mass spectrometry for the identification of the peaks.

Figure 1.21 Zimm plot of SLS Data obtained from PGlu(OBn).

Chapter 02

Scheme 2.1 Schematic description of poly(2‐oxazolines) synthetic routes.

Scheme 2.2 Chain end functionalizations introduced at the α and ω terminals.

Scheme 2.3 Polymerization of poly(2‐oxazolines) using a bifunctional initiator.

Scheme 2.4 Reaction schemes for the cationic ring opening polymerization of 2‐oxazolines initiated by n‐octadecyl‐4‐chlorobenzene sulfonate (Top, a) and the preparation of poly(2‐oxazolines) derivatives (Bottom, b).

Scheme 2.5 Series of water‐soluble poly(2‐oxazolines).

Scheme 2.6 Poly(2‐oxazolines) with protected functional groups that allow post‐polymerization modification through the polymer side chains.

Scheme 2.7 Synthesis of the diblock copolymer hyaluronan‐block‐poly(2‐ethyl‐2‐oxazoline).

Scheme 2.8 Reaction schemes for the cationic ring opening polymerization of 2‐methyl‐2‐oxazoline initiated by N‐[2‐(p‐toluenesulfonyloxy)‐ethyl]‐phthalimide and the preparation of block copolymers of poly(2‐methyl‐2‐oxazoline) and protected poly(amino acids).

Scheme 2.9 Poly(N‐isopropylacrylamide‐ran‐methylstyrene)‐graft‐poly(2‐oxazolines).

Scheme 2.10 Synthetic route of poly(2‐oxazolines)‐graft‐pullulan.

Chapter 03

Figure 3.1 Chemical structures of methyl, ethyl, propyl, and butyl poly(2‐oxazoline) (POZ).

Figure 3.2 Chemistry of poly(2‐oxazoline) synthesis.

Figure 3.3 Setup, initiation, propagation, termination, and purification of a multifunctional POZ polymer.

Figure 3.4 Click chemistry to produce a POZ‐therapeutic: The production of a POZ‐therapeutic begins with attachment of an azide‐linker to a chemical handle on the drug of interest (see later example of SER‐214). The azide‐linker‐drug is then “clicked” onto the pendent POZ polymer of interest to produce a stable POZ‐conjugate. The release of the attached drug is controlled by the nature of the linker.

Figure 3.5 MALDI spectrum of PEOZ 10 K linear polymer.

Figure 3.6

1

H‐NMR spectrum of methyl‐PEOZ polymer (CDCl

3

as solvent).

Figure 3.7 POZ polymers made from (a) an uncontrolled process with PDI values >1.20 showing a high molecular weight (HMW) shoulder and peak tailing; and (b) a controlled process with PDI values of <1.05 that are suitable for drug development.

Figure 3.8 SER‐214 – Chemical synthesis and structure of SER‐214: SER‐214 Synthetic scheme, chemical structure and enzyme‐catalyzed release of Rotigotine. The

S

‐isomer of Rotigotine is attached to a propyl linker at the single phenolic hydroxyl, and then stably attached to the pendent groups of the POZ polymer employing azide‐linked and copper‐catalyzed click chemistry. When hydrolyzed, Rotigotine is released in its active form.

Figure 3.9 Hydrolysis of SER‐214 and release of Rotigotine in various plasma from different species – rat, dog, monkey, and human: Hydrolysis of Rotigotine in plasma from different species – rat, dog, monkey, and human. There is a marked difference in the release rates of Rotigotine in the different plasmas, with rapid release in rat (~11 h) and slow release in monkey and human (>3 days).

Figure 3.10 Good “On‐Time” in monkeys who receive either placebo polymer, L‐DOPA twice daily or SER‐214 as a single weekly injection: Monkeys were videotaped for 6 hours in an observation cage, and the “on‐time” was determined in a blinded review by a neurologist using a scoring system analogous to that used in humans. Good “On‐Time” is the total cumulative time during the 6‐hour observation period with a bradykinesia score of zero (the monkeys are moving around purposefully without any loss of balance) and without any evidence of dyskinesia (which is an involuntary movement). Vehicle control in this study was a 20 kDa POZ polymer with pendent propionic acid, no attached Rotigotine.

Figure 3.11 Plasma concentration of Rotigotine following weekly SC injections in normal

cynomolgus macaque

monkeys; data shown for Weeks 1, 5, 9, and 12, The dose administered SC was 58 mg SER‐214 per kg (SER‐214 contains approximately 12% by weight attached Rotigotine, thus this equates to approximately 7 mg equivalents Rotigotine/kg body weight).

Figure 3.12 General structure of a targeted POZ‐therapeutic: The polymer backbone is typically a 20 kDa POZ with multiple pendent groups (but as shown in Section 3.3 – this is programmable) to which is attached a cytotoxic linker:drug via click chemistry. The release of the attached drug is controlled by the nature of the linker attaching it to the polymer backbone. The targeting group can be either a small molecule or an antibody, antibody fragment or any other targeting ligand. In the following example the attached drug is irinotecan, a potent topoisomerase I inhibitor.

Figure 3.13 Folate‐targeted POZ‐irinotecan SER‐203 is capable of complete suppression of human cancers growing in nude mice that escape irinotecan as single‐agent therapy: Effect of vehicle, irinotecan, or folate‐targeted irinotecan on the growth of KB carcinoma in nude mice. Mice were explanted with a small aliquot of KB carcinoma cells grown initially in tissue culture. Once the nodules of tumors were well‐established (~100 mm in diameter) the mice were divided into separate cohorts of 10 mice each. One cohort received D5W as an infusion (control, line with circle), one cohort received two courses of irinotecan at 60 mg equivalents/kg every 4th day × 3 doses (irinotecan, line with diamonds, two courses of therapy) and the final cohort of mice received an initial course of irinotecan at 60 mg equivalents/kg every 4th day × 3 doses, followed by an infusion of SER‐203 at 60 mg equivalents irinotecan/kg every 4th day × 3 doses (SER‐203, line with triangles).

Figure 3.14 POZ polymer ADCs are capable of binding with high affinity to the target antigen on the surface of cancer cells: A 20 kDa POZ polymer with ~2 biotin molecules attached to the polymer backbone was stably attached to the single chain antibody (scFv‐Fc‐POZ:biotin, line with squares). Detection of binding was by ELISA (the plates were coated with the antigen for the scFv‐Fc) using standard colorimetric methods for binding of streptavidin coupled to horse radish peroxidase (HRP). Detection of scFv‐Fc (no attached polymer‐biotin, line with diamonds) was accomplished with anti‐HuFc‐IgG coupled to HRP.

Figure 3.15 POZ‐polymer ADCs “armed” with POZ‐biotin of 5, 10, or 20 kDa do not appear to alter binding of the scFv‐Fc to cell lines which express the target antigen: Flow cytometry of scFv‐Fc‐POZ:biotin (gray line) versus scFv‐Fc (black line) in human B cell lymphoma cell line HBL‐2. Detection is via HRP‐strepavidin. Note that POZ polymers from 5 to 20 kDa appear to bind with high affinity to the antigen expressed on HBL‐2 cell lines. This is a “low density” antigen with ~2000 copies per cell.

Chapter 04

Figure 4.1 Structure of polypeptoids and polypeptides.

Scheme 4.1 Synthesis of N‐substituted N‐carboxyanhydride monomers.

Figure 4.2 Chemical structures of

N

‐substituted NCA (R‐NCA) and NTA monomers (R‐NTA) that have been synthesized.

Scheme 4.2 Primary amine‐initiated ROPs of R‐NCAs to afford the linear polypeptoid. (The solid sphere below signifies the solid support or surfaces bearing primary amine groups).

Figure 4.3 (a)

1

H NMR and (b) SEC chromatogram of pentablock copolypeptoids based on sarcosine and

N

‐ethyl glycine repeating unit and the structural assignment.

Scheme 4.3 TMG‐promoted ROPs of Bu‐NCAs using alcohol initiators to afford the linear PNBG polypeptoid.

Scheme 4.4 Ring‐opening polymerization of

N

‐substituted

N

‐carboxyanhydrides using alcohol initiators.

Scheme 4.5 ROPs of R‐NTAs using rare earth metal borohydrides or primary amine initiators to produce polypeptoids.

Figure 4.4 Synthesis and AFM topographic and amplitude images of the cyclic bottlebrush copolymers comprised of (

c

‐PNPgG

166

‐

r

‐PNBG

33

) backbone and PEG550 sidechains on mica (0001).

Scheme 4.6 NHC‐mediated ZROPs of R‐NCAs to afford cyclic PNBGs and post‐polymerization conversion of the cyclic PNBGs into the linear and NHC‐free cyclic polymeric analogs.

Scheme 4.7 DBU‐mediated ZROPs of Bu‐NCAs to afford cyclic PNBGs.

Figure 4.5 Synthesis and SEC chromatograms of the linear polypeptoid bottlebrush copolymers.

Scheme 4.8 Post‐polymerization modification of polypeptoids.

Figure 4.6 Thermal properties of polypeptoids in bulk.

Figure 4.7 (a) WAXS diffractograms (room temperature) and (b) DSC thermograms (2nd cooling cycle) of cyclic polypeptoids bearing various

n

‐alkyl sidechains; (c) plot of T

m1

and T

m2

or (d) the associated latent heat (∆H

m1

and ∆H

m2

) versus the number of carbons on the n‐alkyl sidechains.

Figure 4.8 (a): transmittance versus temperature for cyclic P(NEG

70

‐

r

‐NBG

47

) (,); cyclic P(NEG

65

‐

r

‐NBG

30

) (,) and cyclic P(NEG

101

‐

r

‐NBG

34

) (,) (polymer concentration = 1.0 mg∙mL

−1

; the filled and unfilled symbols designate the heating and cooling cycles respectively. (b) Plots of cloud point temperature (T

cp

) versus the molar fraction of NEG segment in the cyclic and linear P(NEG‐

r

‐NBG) random copolymers bearing different end groups and their respective linearly fit curves [cyclic NHC‐P(NEG‐

r

‐NBG) (,—), linear Bu‐P(NEG‐

r

‐NBG) (,—) and linear Bn‐P(NEG‐

r

‐NBG) (,—)].

Figure 4.9 Polypeptoid bottlebrush copolymers comprised of linear P(NEG‐

r

‐NBG) sidechains exhibited cloud point transitions that are dependent on the thermal history.

Scheme 4.9 Synthesis of redox‐responsive PNMG‐

b

‐PGlu(OtBu).

Figure 4.10 (a) DLS size distribution of the E

204

Pg

13

D

15

‐based NCLMs in water (‐‐) or DMF (‐‐) and the corresponding CCLMs in water (‐‐) or DMF (‐‐). The micellar solutions in water or DMF are kept at 0.5 mg∙mL

−1

or 0.05 mg∙mL

−1

, respectively in the DLS studies. (b) TEM micrograph of the CCLMs based on the E

204

Pg

13

D

15

block copolypeptoids (stained with uranyl acetate). (c) SEC chromatograms of the E

204

Pg

13

D

15

unimer (

—

) and the corresponding CCLMs before (

—

) and after DTT treatment (

—

) in DMF/0.1 M LiBr. (d) Plots of cumulative percentage DOX release over time from the CCLMs with DTT (10 mM) (‐‐) or without DTT presence (‐‐).

Scheme 4.10 Synthesis of redox‐responsive and core‐cleavable or non‐core‐cleavable micelles based on amphiphilic block copolypeptoids PNEG‐

b

‐P(NPgG‐

r

‐NDG).

Figure 4.11 Cryo‐TEM images obtained from dilute methanol solutions of the

c

‐PNMG

105

‐

b

‐PNDG

10

block copolypeptoid after 1 h (a), 2 h (b), and 15 d (c) in methanol and the linear counterpart (

l

‐PNMG

112

‐

b

‐PNDG

16

) (d: 1 h; e: 2 h; f: 15 d).

Figure 4.12 (a) Synthesis of linear ABC triblock copolypeptoids with various structures; (b) representative GPC traces showing the successful enchainment for the synthesis of the ABC triblock copolypeptoid (A

98

M

98

D

18

) and (c) all ABC triblock copolypeptoids.

Figure 4.13 (a) Optical images and schematics showing the reversible sol‐gel transition, (b) the plot of storage (G’) and loss modulus (G”) versus temperature for the aqueous solutions of A

98

M

98

DG

18

at different concentrations (1, 2.5 and 5 wt%); (c) cryo‐TEM image showing the micelles of the A

92

M

94

D

12

polymer in dilute aqueous solution; (d) cryo‐SEM image of the fractured A

92

M

94

D

12

(5 wt%) hydrogel interface.

Figure 4.14 Development of molar masses (a–c) (M

w

relative to original M

w

) of (a) polyethylene glycol (PEG), (b) poly(2‐ethyl‐2‐oxazoline) (POx) and (c) poly(

N

‐ethyl glycine) (POI) upon incubation with 0.5, 5, and 50 mM of H

2

O

2

and 50 mM of Cu(II)SO

4

at 37 °C as obtained from SEC elugrams. (d) Comparison of determined t

50%

(with respect to molar mass M

w

) of PEG, POx and POI plotted against 1/[H

2

O

2

]. Data (a–c) presented as means ± standard error means (SEM) (n = 3). Data were fitted with double exponential functions to guide for the eyes.

Figure 4.15 MTT cell viability assay of linear poly(

N

‐methyl glycine‐

b‐N

‐butyl glycine) random copolymer with different composition (P(Sar48‐

r

‐NBG26) P(Sar47‐

r

‐NBG30), P(Sar42‐

r

‐NBG36)) and polysarcosine at different concentrations.

Figure 4.16 (a) MTT assays to assess the cytotoxicity of CCLMs and ICCLMs based on E

204

Pg

13

D

15

block copolypeptoids. (b) The plots of percentage cell inhibition versus DOX concentration and (c) time‐resolved cytotoxicity at 40 µg∙mL

−1

equivalent DOX concentration for the DOX‐loaded CCLMs (), DOX‐loaded ICCLMs () and free DOX∙HCl (). HepG2 cells were used in the study.

Figure 4.17 (a) AlamarBlue analysis of the A

92

M

94

D

12

polymer solutions; (b) an optical microscopic image revealing the hASC morphology after acute exposure to the hydrogel extractives; (c) AlamarBlue analysis of the A

92

M

94

D

12

hydrogel (5 wt% in PBS) and (d) the DNA quantification using Quant‐iT™ PicoGreen assay at 3‐day incubation.

Figure 4.18 QPCR analysis of gene expression within the A

92

M

94

D

12

triblock copolypeptoid hydrogel matrix.

Chapter 05

Scheme 5.1 Synthesis of polyanhydride by melt polycondensation.

Scheme 5.2 Synthesis of polyanhydrides by melt condensation of trimethylsilyl dicarboxylates and diacid chlorides.

Scheme 5.3 Synthesis of ricinoleic acid based monomers.

Scheme 5.4 Synthesis of nonlinear fatty acid terminated poly (sebacic anhydride).

Scheme 5.5 Synthesis of polyanhydrides from diacid chloride and dicarboxylic acid.

Scheme 5.6 Synthesis of polyanhydrides by solution polymerization technique.

Scheme 5.7 Synthesis of polyanhydrides by ring‐opening polymerization.

Scheme 5.8 Imide‐diacid monomer prepared from aromatic acid anhydrides and α‐amino acids.

Scheme 5.9 Synthesis of poly(anhydride‐co‐imide) (poly(pyromellitylimidoalanine‐co‐bis (carboxyphenoxy)hexane) (PMA‐ala:CPH).

Chapter 06

Figure 6.1 Overview of synthetic routes for aliphatic polyesters.

Figure 6.2 Typical approaches for functionalization of aliphatic polyesters (PG = protecting group; FG, FG′ = functional group).

Figure 6.3 Metal‐catalyzed ring‐opening polymerization of lactones. (a) Anionic polymerization; (b) coordination insertion polymerization.

Figure 6.4 Examples of organocatalysts for ROP of cyclic esters.

Figure 6.5 Organocatalyzed ring‐opening polymerization of lactones. (a) Chain‐end/general base, B; (b) nucleophilic monomer activated; (c) concurrent monomer and chain‐end activation by thiourea‐amine (TU/A) catalyst; (d) activated monomer by acid (H‐A).

Figure 6.6 Various routes to functional PLA/PGA derivatives.

Figure 6.7 Synthesis of PLA/PGA derivatives from symmetric (a) and asymmetric (b) diester monomers.

Figure 6.8 Synthesis of PLA derivatives from spirolactide derivatives through exomethylenelactide

23

.

Figure 6.9 Synthesis of PGA derivatives from O‐carboxyanhydride of α‐hydroxy acids.

Figure 6.10 Synthesis of poly(ester amide)s from morpholine‐2,5‐diones with functional side chains.

Figure 6.11 Preparation of poly(propiolactone)s with side chains at β‐position and two possible ring‐opening pathways for the β‐lactones. (a) O‐carbonyl and (b) O‐alkyl scission.

Figure 6.12 Synthesis of poly(β‐malolactonate)s from different starting materials.

Figure 6.13 General procedure to produce poly(serine lactone).

Figure 6.14 Typical procedure to synthesize γ‐substituted poly(ε‐caprolactone)s.

Figure 6.15 Production of α‐, and ε‐substituted CL.

Figure 6.16 Various CL derivatives with substituents derived from natural products.

Figure 6.17 Synthetic routes to substituted valerolactones.

Figure 6.18 Oxidative lactonization of 1,5‐diols to provide β‐functionalized VL derivatives.

Figure 6.19 Synthesis of branched poly(

p

‐dioxanone) from glycerol.

Figure 6.20 Radical ring‐opening polymerization of 2‐methylene‐1,3‐dioxepane

101

.

Figure 6.21 Radical copolymerization of CKA

104

with functionalized methacrylates.

Figure 6.22 Comparison of the SSSP and ROP routes to PLLA.

Figure 6.23 Direct polycondensation approach to stereoblock PLA.

Figure 6.24 Poly(amino ester)s from amino acid by polycondensation.

Figure 6.25 Polyesters from naturally occurring tartaric acids.

Figure 6.26 Examples of backbone functionalization of polycondensates.

Figure 6.27 Condensation polyester of hydroxy acids with protected thiol side chain.

Figure 6.28 Polyesters by ring‐opening polyaddition.

Figure 6.29 Polyesters by step‐growth Michael addition.

Figure 6.30 Polyesters from a bicyclic dialkene by ADMET, and the hydrolyzed product.

Chapter 07

Figure 7.1 Chemical structures of some of the most important phosphorus containing biomolecules: general DNA and RNA sequences, responsible by genetic information transmission, and ATP and ADP, essential for the energetic flow in living systems.

Figure 7.2 The synthetic platform of poly(phosphoester)s highlighting the handles for the design of future materials.

Figure 7.3 Comparison between the structural motifs of natural occurring polymers (left), and synthetic polymers produced industrially with prominent examples (right).

Scheme 7.1 Overview on the synthetic pathways to PPEs (Z = O‐alkyl, O‐aryl, alkyl, Cl, H; R = alkyl, aryl).

Scheme 7.2 Reactions during the polycondensation of phosphorus dichlorides with diols.

Scheme 7.3 General scheme of the polytransesterfication.

Scheme 7.4 Post‐polymerization modification of poly(phosphite)s.

Scheme 7.5 Synthesis of amphiphilic graft copolymers (PPE‐

g

‐ethylene/diethylene glycol).

Scheme 7.6 General scheme of the Atherton–Todd reaction.

Scheme 7.7 Reaction pathway for the immobilization of mephalan onto poly(oxyethylene phosphite) under Atherton–Todd conditions.

Scheme 7.8 Formation of tetrahydrofuran during the polytransesterfication of phosphorus dialkyls with 1,4‐butanediol.

Scheme 7.9 Dealkylation during the polytransesterfication process.

Scheme 7.10 Synthesis of high molecular weight poly(phosphite)s by a two stage process.

Scheme 7.11 Polytransesterfication of diphenyl phosphite with diols.

Scheme 7.12 Direct polycondensation of phosphoric acid with ethylene glycol.

Scheme 7.13 Synthesis of PPEs by polyaddition of bisepoxides with phosphoric and phosphonic acid dichlorides.

Scheme 7.14 Synthesis of PPEs by polyaddition of ERL with ethylphosphoric acid.

Scheme 7.15 Ring‐opening polymerization of cyclic phosphoesters.

Scheme 7.16 Different synthetic pathways to cyclic phosphoester monomers.

Scheme 7.17 Mechanism of the cationic polymerization of 2‐methoxy‐2‐oxo‐1,3,2‐dioxaphosphorinane.

Scheme 7.18 Proposed mechanism for the propagation and chain transfer step within cationic polymerization of six‐membered cyclic phosphoesters [81,86].

Scheme 7.19 Branching during the cationic polymerization of 2‐methoxy‐2‐oxo‐1.2.3‐dioxaphosphorinane.

Scheme 7.20 Proposed mechanism of the anionic polymerization of six‐membered cyclic phosphoesters.

Scheme 7.21 Mechanism of the anionic ring‐opening polymerization of 2‐methoxy‐2‐oxo‐1,3,2‐dioxaphospholane initiated by aluminum triisopropanolate.

Scheme 7.22 Synthesis of the thermoresponsive copolymer PIPP‐

co

‐PEEP.

Scheme 7.23 Top: Synthesis of poly(D,L‐lactide‐co‐2‐ethoxy‐2‐oxo‐1,3,2‐dioxaphospholane) (PLA‐co‐PEEP). Bottom: Synthesis of poly(ε‐caprolactone‐

co

‐2‐ethoxy‐2‐oxo‐1,3,2‐dioxaphospholane) (PCL‐

co

‐PEEP).

Scheme 7.24 Mechanism of the ring‐opening polymerization of 2 alkoxy 2 oxo dioxaphospholanes initiated by stannous octoate.

Scheme 7.25 Schematic depiction of the transesterfication reactions of poly(phosphoester)s during ring‐opening polymerization.

Scheme 7.26 Activation‐mechanism of initiator and/or monomer by DBU, TBD, and TU/DBU.

Scheme 7.27 (a) General synthesis of cyclic phosphonate monomers; (b) polymerization of cyclic phosphonates initiated by 2‐(benzyloxy)ethanol and catalyzed by DBU at 0 °C in dichloromethane.

Figure 7.4 Two possible transesterfication reactions during AROP of poly(phosphonate)s.

Scheme 7.28 (a) Synthesis of cyclic phospholane amidate monomer and (b) Polymerization of MOEPA with TBD as catalyst and benzyl alcohol as initiator and subsequent cleavage of the side chain of PMOEPA.

Scheme 7.29 (a) Synthesis of 2‐((2,2‐dimethyl‐1,3‐dioxolan‐4‐yl)methoxy)‐1‐dioxaphospholane‐2‐oxide (GEP) and (b) polymerization of GEP with Sn(Oct)2 as catalyst and PCL as macroinitiator and subsequent cleavage of the pendant acetal.

Scheme 7.30 (a) Synthesis of ethylene glycol vinyl ether‐1,3,2‐dioxaphospholane‐2‐oxide (EVEP) and (b) post‐polymerization modification by three different reactions.

Scheme 7.31 Post‐polymerization modification of poly(2‐(but‐3‐yne‐1‐yloxy)‐ and 2‐(but‐3‐en‐1‐yloxy)‐2‐oxo‐1,3,2‐dioxaphospholane) (PBYP and PBeneP, Table 7.2 entry 22 and 27).

Scheme 7.32 (a) Synthesis of 2‐(2‐hdroxyethoxy)ethoxy‐2‐oxo‐1,3,2‐dioxaphospholane (HEEP) and (b) self‐condensing ring‐opening polymerization at 60 °C.

Figure 7.5

31

P NMR spectra of

hb

PHEEP for the calculation of DB.

Figure 7.6 Monomer structures for the acyclic diene (ADMET) and triene (ATMET) metathesis polycondensation.

Scheme 7.33 (a) Monomer synthesis for ADMET and ATMET polymerization and (b) following ruthenium catalyzed polymerization.

Scheme 7.34 HWE reaction with different aldehydes 6a–f yielding the corresponding chalcones 7a–f.

Scheme 7.35 (a) Synthetic approach to seven‐membered unsaturated cyclic phosphates and (b) homo‐ and copolymerization of different ROMP‐monomers.

Figure 7.7 Reaction constants for the different ester linkages within the polymer.

Scheme 7.36 Hydrolysis of poly(2‐methoxy‐1,3,2‐dioxaphospholane) under 1. acidic conditions and 2. basic conditions.

Chapter 08

Figure 8.1

Antimicrobial peptide and mode of action.

(a) α‐helical antimicrobial peptide LL‐37 with cationic (dark shaded) and hydrophobic (lighter shaded) residues segregated to opposite sides of the helix structure. (b) Proposed membrane‐disrupting mechanism of antimicrobial peptides.

Figure 8.2 Cationic and hydrophobic monomer units utilized for antimicrobial methacrylate random copolymers.

Figure 8.3

Synthesis of representative amphiphilic random methacrylate copolymers with cationic ammonium groups

[16]. AIBN: azobisisobutyronitrile, MMP: methyl 3‐mercaptopropionate, TFA: trifluoroacetic acid.

Figure 8.4 Mechanism of thiol chain transfer and re‐initiation.

Figure 8.5

Amphiphilic balance of copolymers and biological activities

. Optimized ratio of cationic and hydrophobic groups is critical for potent antimicrobial, non‐hemolytic polymers.

Figure 8.6

Antimicrobial and hemolytic activities of cationic amphiphilic methacrylate copolymers

. (a) Chemical structure of methacrylate copolymers. The copolymers have R = methyl (C1), ethyl (C2), butyl (C4), or hexyl (C6) as a hydrophobic side chains. (b) Hydrophobic composition dependence. The average molecular weights of copolymers are in the range of 1600–2000. (c) Molecular weight dependence for the copolymers with butyl side chains (R = C4). The data are adapted from references [16,18].

Figure 8.7 Synthesis of amphiphilic copolymers containing tertiary or quaternary ammonium groups side chains [27].

Figure 8.8

Dansyl‐modified methacrylate copolymers.

(a) Synthesis of methacrylate copolymer with a florescent dansyl dye located singularly on the end of polymers. The monomers are polymerized in the presence of a chain transfer agent with a dansyl group [18]. (b) Polymer binding to a lipid bilayer (liposome). The dansyl groups are fluorescent upon the binding of polymers to the hydrophobic domains of lipid bilayer. (c) Confocal fluorescent image of giant unilamellar vesicle (POPC/POPG) incubated with the dansyl‐labeled copolymer.

Figure 8.9

Synthesis of cationic amphiphilic methacrylamide random copolymers

.

Figure 8.10

Self‐degrading amphiphilic polyester‐based acrylate copolymers

. (a) Copolymers possessing main‐chain ester linkages and pendent ammonium salts. (b) Antimicrobial and hemolytic activities of degradation products of Polymer

1

at pH 7.0. (c) Degradation mechanism of polymer chain via intramolecular amidation.

Figure 8.11

Synthesis of self‐degradable antimicrobial polymer by simultaneous chain‐ and step‐growth radical polymerization

. (a) Schematic presentation of simultaneous chain‐ and step‐growth radical polymerization of

t

‐butyl acrylate (

t

BA) and 3‐butenyl 2‐chloropropionate (1) using metal catalyst CuCl/1,1,4,7,10,10‐hexamethyltriethylenetetramine (HMTETA). (b) Cationic modification of polymers.

Figure 8.12

Cationic amphiphilic vinyl ether copolymers with random and block sequences

.

Figure 8.13 Synthesis of amphiphilic block PVEs by living cationic polymerization.

Figure 8.14

Antimicrobial and hemolytic activities of block and random amphiphilic vinyl ether copolymers

. (a) Bactericidal activity against

E. coli

of block and random copolymers. The BC

99.9

values defined as the lowest polymer concentration to cause 99.9% killing of

E. coli

is plotted against MP

IBVE

[22]. (b) Hemolytic activity of block and random copolymers with MP

IBVE

of ~50. (c) Schematic illustration of proposed antibacterial and hemolytic activities for block and random poly(vinyl ether)s.

Figure 8.15 Antimicrobial polymethacrylates prepared by RAFT polymerization [50–52].

Figure 8.16 Synthesis of norbornene copolymers via ROMP.

Figure 8.17 Synthesis of nylon‐3 copolymers via controlled chain growth ring‐opening polymerization [26,54,55].

Figure 8.18 Synthesis of antimicrobial carbonate terblock copolymers via organo‐catalyzed ring‐opening polymerization.

Chapter 09

Figure 9.1 General polymerization schemes of PEI.

Figure 9.2 Barriers to

in vivo

nucleic acid delivery.

Figure 9.3 Chemical transformation of the amino groups of PEI.

Figure 9.4 Acylation of PEI by acetic anhydride (top), succinic anhydride (middle), and ethyl acrylate (bottom).

Figure 9.5 Approaches to covalently modify PEI with macromolecules via small molecule linkers: (a) SPDP, (b) SMCC, (c) sulfo‐KMUS, (d) DSP, (e) EDC/NHS or DCC/NHS, (f) NaBH3CN.

Figure 9.6 Conjugation of PEI with folic acid through random DCC/EDC methods (top) or through aminolysis of specific glutamic ester derivatives (bottom).

Figure 9.7 Conjugation of PEI with galactose via lactobionic acid through lactobionolactone (top) and direct coupling to the acid (bottom).

Figure 9.8 Selected approaches to crosslink PEI using degradable small molecule linkers.

Figure 9.9 Routes to produce functionalized PEI without covalent modification, E = electrophile.

Figure 9.10 Differential protection of primary and secondary amines of branched PEI.

Figure 9.11 Loading of PEI/nucleic acid/PLGA hybrid systems. Encapsulation of complexes by PLGA (top) and surface‐coating of PLGA microspheres by complexes (bottom).

Chapter 10

Figure 10.1 Preparation of graft copolymers having polysaccharide side chains.

Figure 10.2 Preparation of PLL copolymers by a reductive amination reaction.

Figure 10.3 Dextran‐graft copolymers having various backbone structures, graft copolymers with polyallylamine (PAA), ε poly(L‐lysine) (ε PLL).

Figure 10.4 Chemical modifications of polymers: Graft copolymers with N, N, N‐trimethylated poly(L‐lysine) (MPLL), carbamoylpolyallylamine (CPAA) and guanidinated poly(L‐lysine) backbones.

Figure 10.5 Confocal laser scanning microscopic observation of inter‐polyelectrolyte complexes between T4 DNA and PLL‐g‐Dex copolymers with different Dex contents.

Figure 10.6 Conformational changes of a flow‐stretched DNA by PLL or PLL‐g‐Dex injections. Fluorescence images and kymographs acquired at 2 s/fram before (–) and after (+) polycation injection.

Figure 10.7 Cationic comb‐type copolymers, PLL‐g‐Dex, at nanomolar level concentration accelerates DNA hybridization rate over 200‐fold under physiologically relevant ionic conditions.

Figure 10.8 Nucleic acid chaperoning activity.

Figure 10.9 PLL‐g‐Dex activates conversion of metastable structures to the most stable quadruplex structures. Hetero quadruplexes consisting of DNA strands, TGGGGT (TG4T) and TGGGGGT (TG5T), were refolded to the most‐stable quadruplexes, [TG4T]4 and [TG5T]4 by incubating with PLL‐g‐Dex at 25 °C.

Figure 10.10 PLL‐g‐Dex increased MNAzyme activity under multiple‐turnover conditions.

Chapter 11

Figure 11.1 Examples of heterocyclic monomers and (bio)degradable products of their RROP. Y represents a functional group, while x and x’ are integers.

Scheme 11.1 CRP reactions for the synthesis of star (co)polymers. Note that the functional core in the “core‐first” approach can exist as a small molecule or (hyper)branched macromolecule.

Scheme 11.2 Various methods for the synthesis of graft (co)polymers.

Scheme 11.3 Radical polymerization reactions useful for the preparation of degradable (hyper)branched polymers containing cleavable functionalities at the branching points.

Scheme 11.4 Selected examples of (bio)degradable functionalities and their degradation products. The wavy lines represent polymer chains. Note that hydrolytically degraded mechanisms can also occur under basic conditions, resulting in the corresponding deprotonated products.

Scheme 11.5 Ring‐opening polymerizations of various cyclic esters using ionic methods and a cyclic ketene acetal undergoing RROP to form their respective polyesters.

Scheme 11.6 Nitroxide‐mediated controlled RROP of a cyclic ketene acetal.

Scheme 11.7 ATRP‐type controlled RROP of a cyclic ketene acetal.

Scheme 11.8 RAFT‐type controlled RROP of a cyclic ketene acetal mediated by a dithioester.

Scheme 11.9 RAFT‐type controlled copolymerization of a cyclic ketene acetal with vinyl acetate mediated by a xanthate.

Scheme 11.10 Traditional ROP of CL followed by modification of hydroxy end‐group with α‐bromoisobutyryl bromide for subsequent chain extension with

t

‐butyl acrylate via ATRP.

Scheme 11.11 Modification of well‐defined polySty with hydroxy groups for formation of polySty‐

g

‐polyCL graft copolymer via subsequent ROP of CL.

Scheme 11.12 Copolymerization of CL with α‐bromo‐CL and subsequent grafting of polySty from the pendant Br groups.

Scheme 11.13 Synthesis of polymer brushes with polyester backbones.

Scheme 11.14 Synthesis of graft copolymers with segmented and degradable side chains via combination of ATRP and ROP (Sn(EH)

2

 = tin(II) 2‐ethylhexanoate).

Scheme 11.15 Atom transfer radical polyaddition of a styrenic divinyl monomer and difunctional ATRP initiator with a degradable functionality to form a degradable polyester with pendant alkyl bromide groups.

Scheme 11.16 One‐pot synthesis of poly(CL‐

b

‐4‐vinyl benzyl chloride) using both ROP and RAFT polymerizations, followed by chain extension with DMAEMA.

Scheme 11.17 Polymerization of styrene using a polyurethanebased alkoxyamine macroinitiator.

Scheme 11.18 Synthesis of multiblock poly(Sty‐

b

‐tetrahydrofuran) using a combination of RAFT polymerization and polyaddition reactions.

Scheme 11.19 Synthesis of star copolymers with hydrolytically degradable acetal‐containing cores by chain extension of well‐defined block copolymers, prepared via RAFT polymerization, with a ketal‐functionalized crosslinker.

Scheme 11.20 Formation of stars with ketal‐functionalized crosslinked cores and post‐polymerization modifications.

Scheme 11.21 Formation of imine‐containing crosslinked structures via reaction of polymers with pendant amino groups with a difunctional aldehyde.

Scheme 11.22 Synthesis of copolymer with pendant hydrazide groups and subsequent model reaction with biotin to demonstrate formation of reversibly degradable hydrazone linkage.

Scheme 11.23 Reductive degradation of a polymer with a disulfide bond.

Figure 11.2 Dependence of f(H

+

) upon pH for the reduction of disulfides P

n

‐S

2

‐P

n

with various pK

a

values (shown at each curve) of the corresponding thiols P

n

‐SH. All reductions are carried out with a thiol RSH with pK

a

 = 7.

Figure 11.3 Examples of a disulfide‐containing ATRP initiator (a), disulfide‐containing divinyl monomer (b), and disulfide‐containing inimer (c).

Scheme 11.24 Use of hydroxyl‐terminated, disulfide‐containing ATRP initiator for ROP of glycolide and subsequent ATRP of oligo(ethylene glycol) monomethyl ether methacrylate.

Scheme 11.25 Synthesis of highly branched polymers with hydrolysable (ester) or reductively degradable (disulfide) groups at the branching points by copolymerization of monovynyl monomers and crosslinkers in the presence of CBr

4

and their use as macroinitiators for ATRP [177,178].

Scheme 11.26 Possible structures of polymers derived from an inimer with a degradable functionality and proposed products of their complete degradation.

Scheme 11.27 Synthesis of uniform hyperbranched polymers via SCVP ATRP in microemulsions.

Scheme 11.28 Synthesis of miktoarm star copolymers with (bio)degradable cores and their degradation products upon reduction with tributylphosphine (Bu

3

P).

Scheme 11.29 Use of alkyne‐terminated disulfide‐containing spacers for “click” chemistry formation of brush copolymers with (bio)degradable arm connections.

Scheme 11.30 Synthesis of multiblock copolymers segmented by disulfide groups via end‐group modification of prepolymers synthesized by RAFT polymerization.

Scheme 11.31 Synthesis of miktoarm stars with degradable crosslinked cores.

Chapter 12

Figure 12.1 Drug incorporation to (a) pendant group and (b) polymer backbone.

Scheme 12.1 Proposed anhydride exchange mechanism during melt condensation polymerization.

Scheme 12.2 Traditional three‐step synthesis of SA‐sebacic diacid vs optimized SA‐sebacic diacid synthesis.

Scheme 12.3 Synthesis of antiseptic‐based PAEs.

Scheme 12.4 Phosgene‐mediated polyanhydride synthesis via a dehydrochlorination mechanism as hypothesized by Domb.

Scheme 12.5 (a) Synthesis of HCA‐based PAEs and polymer precursors. (b) Hypothesized mechanism of Knoevenagel Condensation with Doebner Modification.

Scheme 12.6 Mechanism of the conversion of 3,6,9‐trioxaundecanedioic diacid to tetraglycolyl dichloride utilizing thionyl chloride where

26

undergoes nucleophilic addition to thionyl chloride, generating a tetrahedral intermediate that subsequently collapses to eliminate a chloride ion. Chloride then attacks the carbonyl carbon (

28

) and the resulting tetrahedral intermediate

29

collapses, producing sulfur dioxide gas and an additional chloride. The chloride finally deprotonates

30

to acquire

31

and HCl. This process continues to generate the second acyl chloride, acquiring product.

Figure 12.2 DPPH radical scavenging assay of SGA (adipic) and VA (adipic) PAE day 30‐degradation media compared to identical concentrations of free bioactives. Studies performed in triplicate and statistically similar.

Scheme 12.7 Cyclic ring‐opening of EDTA dianhydride by respective phenols to acquire diacids (7.3), which were subsequently polymerized by triphosgene mediated coupling.

Figure 12.3 Kirby–Bauer disk diffusion assay results for (i)

E. coli

and (ii)

S

.

aureus

, revealing zones of inhibition for (a) negative control (1:1 PBS:DMSO), (b) extracted eugenol, (c) free eugenol, (d) extracted thymol, (e) free thymol, (f) extracted carvacrol, (g) free carvacrol, and (h) free EDTA.

Scheme 12.8 Synthesis of 5‐ASA‐based PAE via melt‐condensation polymerization and polymer precursors.

Scheme 12.9 Hypothesized TMSEA‐mediated solution polymerization of Mandelic acid.

Scheme 12.10 (a) Synthesis of poly(tetraibuprofen mannitol succinate) PAE and PAE precursors. (b) Mechanism of TBDMS protection of mannitol primary alcohol through activated

N‐t‐

butyldimethylsiylimidazole silylating agent. An additional TBDMS protecting group will subsequently protect the second primary alcohol of mannitol via the same mechanism.

Scheme 12.11 Synthesis of cross‐linked salicylic acid based polyester (SAP).

Scheme 12.12 Synthesis of NSAID containing biodegradable polyesters.

Scheme 12.13 Poly/oligo(trolox) synthesis via carbodiimide coupling and competing oxygen → nitrogen migration that can effectively hinder polyesterification.

Scheme 12.14 Synthesis, characterization and hydrolysis of PVO (

a

) Synthesis of acetal‐protected, diol‐containing vanillin prodrug, (

b

) Synthesis and subsequent degradation of PVO.

Figure 12.4 Comparison of traditional (a) and (b) one‐pot approach.

Scheme 12.15 Synthesis of poly(ibuprofen‐L‐malate) and polymer precursors.

Chapter 13

Figure 13.1 Schematic description of Kopeček‘s model of polymer prodrug based on the simplified Helmut Ringsdorf’s model.

Figure 13.2 Schematic description of synthesis of HMW polymer carriers suitable for passively targeted prodrug systems containing biodegradable linkages facilitating their elimination from the organism.

Figure 13.3 Scheme of the synthesis of the HMW enzymatically or reductively degradable graft PHPMA conjugates with Dox bound by pH‐sensitive hydrazone bond.

Figure 13.4 Scheme of the synthesis of the HMW enzymatically degradable multi‐block PEG conjugate with Dox bound by pH‐sensitive hydrazone bond.

Figure 13.5 Scheme of the synthesis of the HMW enzymatically degradable multi‐block PHPMA conjugate with gemcitabine bound by enzymatically degradable GFLG spacer.

Figure 13.6 Scheme of the synthesis of the HMW reductively degradable star‐like PHPMA conjugate with Dox bound by pH‐sensitive hydrazone bond.

Figure 13.7

In vivo

effect of polymer–Dox conjugates with pH‐triggered activation of drug on the growth of T cell lymphoma EL‐4 (a) and survival of mice (b) at a dose 1 × 15 mg Dox (eq.)/kg (—star‐like conjugate,

M

w

 = 260,000 g/mol,

Ð

 = 1.9, 10.2 wt.% Dox; —— grafted conjugate,

M

w

 = 130,000 g/mol,

Ð

 = 3.5, 9.6 wt.% Dox; ‐ ‐ ‐ linear conjugate,

M

w

 = 35,000 g/mol,

Ð

 = 1.9, 9.9 wt.% Dox; ‐ ‐ ‐ untreated controls). Tumor growth: mean tumor volume is plotted; V = a*b

2

/2, where a = longer diameter, b = shorter diameter. Arrow marks administration of the treatment.

Figure 13.8 Scheme of the synthesis of heterotelechelic PHPMA containing reactive terminal groups; i.e., TT for aminolytic reactions and azide groups for azide‐alkyne click reactions, and

tert‐

butyloxycarbonyl (Boc) group‐protected hydrazide groups distributed along the polymer chain enabling attachment of drug by hydrazone bond after deprotection.

Figure 13.9 Schematic structure of the PHPMA‐Dox conjugates differing in the structure of biodegradable spacer: enzymatically degradable glycyl‐DL‐phenylalanyl‐L‐leucyl‐glycyl spacer (

1

) and pH‐sensitive

cis‐

aconityl (

2

) and hydrazone (

3

) spacers (a). The drug release from the conjugates incubated at 37°C in phosphate buffers at pH 7.4 (▲‐ ‐ ‐

2

;

●‐ ‐ ‐ 3

) and pH 5.0 (∇

— 1

▲

— 2

;

●— 3

) (b). (The conjugate

1

was incubated in the presence of 0.5 μM cathepsin B. The conjugates

2

and

3

contained glycyl‐glycyl spacer as

R

.

Figure 13.10 Scheme of the synthesis of linear PHPMA conjugates by polymerization of polymerizable Dox derivative (a) or by post‐polymerization reaction with Dox.HCl (b) or a PTX oxoderivative (c).

Figure 13.11 Drug model (fluorescent dye DY‐676) distribution in human colon carcinoma‐bearing nude mice after injection of star‐like PHPMA containing different spacers – 4‐(2‐oxopropyl)benzoyl (OPB), 4‐isopropyl‐4‐oxobutanoyl (IPB), and 4‐oxo‐4‐(2‐pyridyl)butanoyl (PYR) spacers.

Figure 13.12 Gel permeation chromatograms of reductively degradable star‐like PHPMA fluorescently labeled by DY‐615 (

—

) and its degradation products after 6 h‐ (

—

), 12 h‐ (‐ ‐ ‐), and 24 h‐incubation (∙∙∙∙∙) with EL4 T‐cells. Fluorescently labeled linear PHPMA (‐ ‐ ‐) was used as control.

Chapter 14

Figure 14.1 Schematic of a self‐assembled monolayer and the molecules necessary for that.

Figure 14.2 Possible hypothetical adhesion, oxidation and crosslinking reaction pathways for peptidyl DOPA and DOPA ortho‐quinone residues.

Figure 14.3 Possible catechol‐TiO

2

‐interactions. The bridging, dissociative bidentate structure of two Ti‐atoms on the right side is the most favorable according to theoretical calculations [27,28].

Figure 14.4 Tripeptide conjugated with a tertiary bromide, able to polymserize at high pH on metal oxide, metallic, and polymeric substrates to form a thin ATRP initiator layer.

Figure 14.5 Schematic of a self‐assembled monolayer and the molecules necessary for that.

Figure 14.6 Synthesis of monolayers of polystyrene terminally attached to SiO

x

surfaces by using a self‐assembled monolayer of AIBN like azo compound with a chlorosilane headgroup.

Figure 14.7 A schematic representation of the general surface modification strategy presented in ref. 42, consisting of four steps. (1) Plasma treatment, (2) AEMA‐graft polymerization and (3) coating with gelatin by physisorption or by (4) covalent immobilization.

Figure 14.8 Strategy for grafting from by redox polymerization of N‐isopropylacrylamide.

Figure 14.9 Schematic of the photochemical grafting onto using a benzophenone derivative.

Figure 14.10 Influence of the chain dimensions, i.e. the bulk radii of gyration,

R

g

, on the maximum film thickness for photochemically attached polystyrene layers on benzophenone monolayers.

Figure 14.11 Schematic of the different possible reaction taking place after the initial photoreaction of aryl azides, R can be a polymer or a side chain of a polymer

Figure 14.12 Synthetic route to prepare a Triblock copolymer with a middle block bearing vinylsilane groups which can be used to bind the block‐copolymer to hydrogen terminated polysiloxane.

Figure 14.13 Polymers with trimethoxysilane groups for grafting onto glass and silicon dioxide [54] and polymers with phosphonate groups for grafting onto titanium substrates.

Figure 14.14 Coating scheme for polymers with phosphonate groups for grafting onto titanium substrates.

Figure 14.15 Polymers with catechol groups for grafting‐onto on glass.

Figure 14.16 Polymers with benzophenone [47] or arylazide groups [61] for a photo‐chemically induced grafting from.

Figure 14.17 Copolymer that forms coatings by electrostatic interaction on negatively charged substrates and makes the substrate protein resistant.

Figure 14.18 Schematic illustration of cell sheet engineering using temperature sensitive polyNIPAM layers.

Figure 14.19 Plot of the growth score for mesenchymal progenitor stem cells (C3H10T1/2) on different polymer layers bound to glass substrates using the grafting onto method with benzophenone bearing SAMs versus the advancing contact angle of the respective polymer layer. The data indicate that a contact angle higher than 45° is a necessary but not a sufficient condition for a high cell growth score.

Figure 14.20 Schematic of the activation of an APTES SAM with 3‐(maleimido)propionic acid N‐hydroxysuccinimide ester and subsequent binding of a cyclic peptide with an SH‐group via a thio‐ene‐reaction.

Figure 14.21 Self‐assembly of 12‐carboxydodecyl phosphonic acid, activation as N‐hydroxysuccimide ester and reaction with amino groups for binding a protein.

Figure 14.22 Schematic presentation of the process of film production: films directly after coating and for a crosslinked and a non‐crosslinked polymer film.

Figure 14.23 Hydrolysis and condensation of 3‐(trimethoxysilyl)‐propyldimethyloctadecyl ammonium chloride with surfaces containing reactive functional groups.

Figure 14.24 Polymer surface modifier (PSM) concept where A and B are complementary side chains that generate an amphiphilic, biomimetic soft block, and the implementation as polyurethane with a soft block having trifluoromethyl and dimethylbutyldodecyl ammonium as A and B side chains.

Figure 14.25 Schematic of the derivatization of a surface with cationic poly(n‐hexyl vinylpyridinium) polymers via an aminopropyltriethoxysilane monolayer.

Figure 14.26 Schematic of some mechanism proposed for the attack of antimicrobial peptides or polymers on bacterial membranes.

Figure 14.27 Schematic illustration of the proposed actions of telechelic antimicrobial polymers with satellite function (alkyl–PMOX–DDA) binding to a phospholipid membrane. (a) no aggregation of the end groups and insertion in different positions of the membrane; (b) aggregation of the end groups and insertion in close proximity.

Figure 14.28 Self‐binding antibacterial copolymers (a) prepared by copolymerization of DMMEP and VP and subsequent quaternization with hexyl bromide.

Figure 14.29 A smart polymer coating repeatedly switches between the attacking function (CB‐Ring, to kill bacteria under dry conditions) and defending function (CB‐OH, to release and resist bacteria under wet conditions). CB‐Ring can be hydrolyzed to CB‐OH in neutral or basic aqueous solutions and can be regenerated by dipping CB‐OH in acidic media.

Chapter 15

Figure 15.1 Surface‐functionalization by grafting‐to (a) and grafting‐from (b) approaches.

Figure 15.2 (a) The chemical structures of PEG, PMOXA and PEtOXA. (b) The CROP process, featuring initiation by electrophiles, propagation by opening of the oxazolinium ring and isomerization, and termination by a suitable nucleophile. The synthesis of α,ω‐heterobifunctional PAOXA presenting R

1

and R

3

chain‐end groups is especially highlighted.

Figure 15.3 Silane‐, catechol‐, and thiol‐bearing PAOXA adsorbates for the functionalization of silicon oxide, metal oxide, and gold surfaces, respectively.

Figure 15.4 (a) Functionalization of ZnO NCs by PMOXA‐nitrodopamine adsorbates. Atomic force microscopy (AFM) tapping‐mode micrograph (b) and transmission electron micrograph (c) displaying PMOXA‐stabilized ZnO NCs (d) ZnO NCs/PMOXA aqueous suspensions after 6 months of storage, no signs of aggregation or precipitation are observed.

Figure 15.5 (a) Synthesis of linear PMOXA‐OH and multi‐arm star‐copolymer PEI‐g‐PMOXA. (b) Fabrication of PMOXA/PDA films exploiting PDA as grafting promoter layer.

Figure 15.6 Adsorption of five different proteins on differently functionalized Au surfaces as measured by surface plasmon resonance (SPR) spectroscopy.

Figure 15.7 PiPrOXA‐b‐PesterOXA copolymers were applied for the functionalization of PGMA‐coated surfaces to yield dense PiPrOXA brush interfaces.

Figure 15.8 PMOXA‐MA‐r‐PGMA bottle‐brush copolymers are capable of reacting with the silicon oxide surface through the reaction between the epoxy groups of the GMA units and the silanol functions at the substrate.

Figure 15.9 PMOXA‐MA‐r‐PGMA copolymers presenting higher content of GMA comonomer formed thicker films on silicon oxide surfaces (i). Nevertheless, the best antifouling and antimicrobial properties were displayed by copolymers presenting the highest concentration of PMOXA segments. (ii) Optical micrographs of stained

E. Coli

adhering on (a) the pristine, unfunctionalized silicon oxide, (b) PMOXA‐MA(1)‐r‐PGMA(3), (c) PMOXA(1)‐MA‐r‐PGMA(1), and (d) PMOXA(1)‐MA‐r‐PGMA(0.33).

Figure 15.10 Surface functionalization by PAOXA adsorbates exploiting click reactions (a) between alkyne‐PMOXA and PS‐N

3

,(b) Conjugation between PEtOXA‐NH

2

and cyanuric chloride‐bearing TEL assemblies.

Figure 15.11 Benzophenone‐mediate photografting of PEtOXA on functionalized silicon oxide and glass surfaces.

Figure 15.12 PFPA‐mediated grafting of PEtOXA. Three examples of PFPA‐based grafting promoters are shown: disulfide‐, silane‐, and poly(allylamine)‐based.

Figure 15.13 PLL‐g‐PEG (a) and PLL‐g‐PMOXA (b) graft‐copolymers for the functionalization of negatively charged, inorganic, and organic surfaces.

Figure 15.14 Comparison of (a) the adsorbed copolymer mass and (b) the adsorbed serum mass, as a function of the grafting density (α) for PLL‐g‐PEG (side polymer chains: 2 and 5 kDa) and PLL‐g‐PMOXA (side polymer chains: 4 and 8 kDa). The adsorption of all the copolymer types was carried out on Nb

2

O

5

surfaces. α = 0 corresponds to pure PLL.

Figure 15.15 Schematic representation of the different copolymer adlayers, PLL films and bare niobia. The positive charges on the PLL backbone and the overall surface potential are indicated qualitatively, reflecting the sum of the negative charges at the substrate, the charge density of the PLL backbone (positive) and the copolymer surface coverage. (a) PLL; (b) PLL‐g‐PMOXA(0.09); (c) PLL‐g‐PMOXA(0.33); (d) PLL‐g‐MOXA(0.56); and (e) Bare niobia.

Figure 15.16 (a) Optical micrographs of bare niobia, PLL, PLL‐g‐PEG(0.29) and PLL‐g‐PMOXA(0.22)‐modified Nb

2

O

5

after a 20 min of exposure to

E. coli

at 37 °C. (b) A quantitative reduction in bacterial adhesion for both PLL‐g‐PEG and PLL‐g‐PMOXA adlayers in comparison to the bare niobia substrate was recorded.

Figure 15.17 Serum adsorbed mass as a function of EG and MOXA surface density calculated for four different copolymer adlayers: PLL‐g‐PEG (2 kDa) (open circle), PLL‐g‐PEG (5 kDa) (open triangle), PLL‐g‐PMOXA (4 kDa) (filled circle), and PLL‐g‐PMOXA (8 kDa) (filled triangle).

Figure 15.18 Remaining thickness measured by ellipsometry for the different copolymer films following the stability test in a) 10 mM H

2

O

2

and b)10 mM HEPES + 150 mM NaCI.

Figure 15.19 Remaining copolymer mass measured by OWLS for the different copolymer films after 5 hours of incubation in 10 mM HEPES + 150 mM NaCl + 10 mM H

2

O

2

(gray bars). Serum adsorption test was performed following the stability study (black bars).

Figure 15.20 Synthesis of bottle‐brushes featuring PAOXA side chains and poly(methacrylamide) backbones. Poly(2‐isopropenyl‐2‐oxazoline) (PIPOx) was first synthesized either by free radical or living anionic polymerization. Reaction of the so‐synthesized backbone with methyl triflate (MeOTf) produces the macroinitiator salt (PIPOxR/A), which can initiate CROP in the presence of different 2‐alkyl‐2‐oxazolines species (e.g., 2‐methyl‐2‐oxaoline MOXA, 2‐ethyl‐2‐oxazoline EtOXA and 2‐isopropyl‐2‐oxazoline, iPrOXA).

Figure 15.21 Fibronectin (FN) adsorption on poly(2‐oxazoline) BBBs as a function of BBB architecture and composition, measured by fluorescence microscopy following 1 hour of culture. (a) BBBs presenting PMOXA, PEtOXA, and poly‐2(n‐propyl‐2‐oxazoline) (PnPrOXA) side chains with side chains of similar length. (b) BBBs with PMOXA side chains presenting different end groups. (c) BBBs with PMOXA side chains presenting variable length.

Chapter 16

Scheme 16.1 Approaches to polymer thin film synthesis via: physisorption, grafting onto, and grafting from [5,6].

Figure 16.1 Conformations of surface grafted polymers, transitioning from “mushroom” regime to “brush” regime with increasing grafting density.

Scheme 16.2 Basic description of the three RDRP methods mostly used for surface initiated polymerization.

Scheme 16.3 Representative surface initiator immobilization strategies.

Scheme 16.4 SI‐NMP of styrene, reported by Husseman et al.

Scheme 16.5 SI‐ATRP of styrene as reported by Matyjaszweski et al.

Scheme 16.6 Schematic illustration of the use of [Cu

I

]/[Cu

II

] gradients, generated by (a) tilting the angle of the substrate relative to the working electrodeor (b) by the use of a bipolar electrode

Scheme 16.7 Photo‐mediated SI‐ATRP using iridium photo‐redox catalysts or

N

‐phenyl phenothiazine (metal free approach) (a) [40,41]; and schematics illustrating the synthesis of patterned brushes, gradient brushes, and brush copolymers via photo‐mediated SI‐ATRP, using organic based or iridium photo redox catalysts (b–d).

Scheme 16.8 Approaches towards SI‐RAFT mediated polymerization, azo‐initiator tethered surfaces (a), and from RAFT agent functionalized surfaces, via the R‐group approach (b), and the Z‐group approach (c).

Figure 16.2 Number average molecular weight of PMMA brushes, prepared via SI‐ATRP at four different Cu

(II)

/C

(I)

ratios, plotted as a function of the dry brush thickness (

h

p

). The insert shows the variation of grafting density with Cu

(II)

/C

(I)

ratio.

Scheme 16.9 Schematic illustrating examples of strategies for degrafting of polymer brushes.

Figure 16.3 Brush Thickness of PMMA grafts prepared by SI‐ATRP (top),

M

n

(middle) and

Ð

(PDI, bottom), after degrafting, as a function of time. The shape coding corresponds to four different Cu

(II)

/C

(I)

ratios used for the polymerizations.

Scheme 16.10 Schematic illustrating the variation of surface initiator “concentration” by immobilizing mixtures of “active” ATRP initiators and “inactive” ATRP initiators, and the functionalization of the subsequent brushes (top); the figure illustrates the influence of grafting density and brush height on the post‐polymerization modification of PHEMA brushes with

D

‐leucine.

Figure 16.4 Examples of monomers used to prepare polymer brushes for immobilizing biomolecules [2,83,88].

Scheme 16.11 Synthetic approaches towards COOH functional polymer brushes.

Scheme 16.12 Illustration of the activation of –COOH functional polymer brush, and subsequent immobilization of a bioactive compound.

Scheme 16.13 Illustration of the direct bio‐functionalization of PGMA brushes (ii) or their activation with allylamine or propargylamine for subsequent bio‐functionalization via thiol‐ene chemistry [100,102].

Scheme 16.14 Illustration of the activation of OH functional polymer brush, and subsequent immobilization of bioactive compound.

Scheme 16.15 DNA biosensing based on polymer brushes, illustrating the probe immobilization and hybridization events.

Scheme 16.16 Schematic illustration of end‐group modification of (a) SI‐ATRP made polymers, and subsequent CuAAC modification

Scheme 16.17 Carboxylates polymer brushes, grown inside a membrane pore, functionalized with a nitroloacetate‐metal (Ni

2+

) complex for specific binding to histidine tagged proteins.

Scheme 16.18 Cartoon illustrating the non‐covalent capture of DNA using polymer brushes.

Scheme 16.19 Schematic illustrating examples of, dual purpose, smart polymer brushes based on (a) the cationic and antimicrobial

N

,

N

‐dimethyl‐2‐morpholine, the antifouling zwitterionic carboxy betaine form(b) PTMAEMA brushes, which kill bacteria on contact, before releasing, assisted by electrostatic effectsand (c) nanopatterned PNIPAM and QAS surfaces

Chapter 17

Figure 17.1 A principal scheme of AIP structure and environment‐dependent formation of AIP micelles and micellar nanoassemblies.

Figure 17.2 Synthesis of amphiphilic invertible polyesters (AIPEs‐1) based on poly(ethylene glycol) and aliphatic dicarboxylic acids.

Figure 17.3 FTIR (a) and

1

H NMR (b) spectra of the amphiphilic invertible polyester D10: (a): 1145–1110 cm

−1

: valence (stretching) vibration of ester and ether C–O bonds, 1730 cm

−1

stretching vibration of carbonyl group, 2900 cm

−1

valence vibration, 1450 cm

−1

deformation vibration and 730 cm

−1

pendulum vibration of –(CH

2

)

n

– groups. (b): see structure for peak assignment.

Figure 17.4 Specific viscosity of the AIPE‐1 solutions in solvents differing by polarity (

C

 = 0.01 g/mL).

Figure 17.5 Synthesis of the PEG‐PTHF based amphiphilic invertible polyesters (AIPEs‐2).

Figure 17.6 FTIR spectra of (1) PTHF

250

, (2) carboxyl terminated prepolymer based on PTHF

250

, and (3) amphiphilic invertible polyester PEG

1000

PTHF

250

.

Figure 17.7

1

H NMR spectrum of the polyester PEG

300

PTHF

250

.

Figure 17.8 Specific viscosity of the AIPE‐2 solutions in solvents differing by polarity (

C

 = 0.01 g/mL).

Figure 17.9 Synthesis of amphiphilic invertible polyurethanes with an alternating (a) and a random (b) distribution of the hydrophilic and hydrophobic fragments along the polymer backbone.

Figure 17.10 FTIR spectra of (1) PTHF

650

, (2) isocyanate terminated PTHF

650

, and (3) amphiphilic polyurethane PEG

1000

‐

alt

‐PTHF

650

.

Figure 17.11

1

H NMR spectrum of the AIPU PEG

1000

‐

alt

‐PTHF

650

in CDCl

3

.

Figure 17.12 Surface tension isotherms of the AIPEs‐1 (a) and AIPEs‐2 (b) aqueous solutions.

Figure 17.13 Expanded regions of

1

H NMR spectra of the polyester S6 in different solvents.

Figure 17.14 AIP macromolecules in solvents differing by polarity: (a) expanded, (b) inverse micelle with a hydrophilic interior and a hydrophobic exterior, and (c) micelle with a hydrophobic interior and a hydrophilic exterior.

Figure 17.15 Expanded regions of

1

H NMR spectra of S6 recorded in D

2

O at different concentrations.

Figure 17.16 The size of blank and curcumin‐loaded AIPE micellar assemblies as determined by dynamic light scattering: (1) D10, (2) curcumin–D10, (3) PEG

600

PTHF

650

, and (4) curcumin–PEG

600

PTHF

650

.

Figure 17.17 Chemical stability of curcumin in AIPE micellar assemblies in the aqueous medium with time.

Figure 17.18 Representative UV‐vis spectra of curcumin in (1) aqueous phase before the transfer, (2) 1‐octanol, and (3) aqueous phase after the transfer from water to 1‐octanol. Inset: appearance of water‐octanol mixture before (left‐side tube) and after (right‐side tube) the transfer of curcumin from water (bottom phase) to 1‐octanol (top phase).

Figure 17.19 Possible mechanisms of AIPE‐mediated curcumin delivery from water to 1‐octanol.

Figure 17.20 Cell viability of HEK 293 cells treated with various concentrations of blank AIPE micellar assemblies.

Figure 17.21 Cytotoxicity of curcumin‐loaded AIPE micellar assemblies on T47D breast carcinoma cells after 18, 42, and 66 h incubation.

Chapter 18

Figure 18.1 Schematic representation of the surface roughness of a soft tissue.

Figure 18.2 A liquid bioadhesive spreading over a typical soft tissue surface.

Figure 18.3 Schematic representation of the diffusion theory of bioadhesion. Dark gray polymer layer and light gray mucus layer before contact (a); upon contact (b); the interface becomes diffuse after contact for a period of time (c).

Figure 18.4 Poly(ethylene glycol) synthesis and reaction mechanisms.

Figure 18.5 Poly(vinyl alcohol) synthesis.

Figure 18.6 Poly(vinylpyrrolidone) synthesis mechanisms in aqueous and organic solution.

Figure 18.7 Preparation of poly(acrylic acid) by hydrolysis of poly(acrylate).

Figure 18.8 Mechanism of radical polymerization for acrylic monomers.

Figure 18.9 Scheme detailing the deacetylation process of chitin to form chitosan.

Figure 18.10 Cellulose etherification.

Figure 18.11 Homogenous mucoadhesive tablet (a) and bilayer mucoadhesive patch (b).

Figure 18.12 Texture Profile Analyser in bioadhesion test mode.

Figure 18.13 Simplified representation of the test set‐up used to determine peel strength of bioadhesive films.

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