Immobilization of aminothiols on poly(oxyethylene H‐phosphonate)s and poly(oxyethylene phosphate)s—An approach to polymeric protective agents for radiotherapy of cancer

This study describes the synthesis and characterization of polymer complexes constructed from the radioprotective agent S‐2(3‐aminopropylamino) ethylphosphorothioic acid dihydrate (amifostine or WR‐2721), applied in the radiation cancer treatment, and biodegradable poly(oxyethylene H‐phosphonate), poly(hydroxyoxyethylene phosphate), or poly(methyloxyethylene phosphate). The immobilization of another radioprotector, used in cancer radiotherapy, 1‐(3‐aminopropyl)aminoethanethiol (WR‐1065) on the same polymers is also achieved through a covalent bond (Atherton‐Todd reaction coupling), ionic bond, and physical complexation, respectively. The structure of the complexes formed is elucidated by ¹H‐ ¹³C‐, ³¹P NMR and FTIR spectroscopy. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1349–1363, 2007     

Synthesis of poly(oxyethylene phosphonate)s bearing oxirane groups in the side chain

The interaction between poly(oxyethylene phosphonate)s and 1,2-epoxy-7-octene has been investigated. It has been established that in the presence of benzoyl peroxide there proceeds a selective addition of the P( )H group to the C()C double bond. Poly(oxyethylene phosphonate)s bearing oxirane groups in the side chain have been synthesized. The new polymers can be used as polymer carriers of drugs. © 1997 John Wiley & Sons, Inc.     

Synthesis and hydrolytic degradation of stereoregular aromatic poly(ester amide)s derived from D‐xylose

Stereoregular poly(ester amide)s (PEAs) were prepared by the polycondensation method using naturally occurring D ‐xylose and aromatic diacids as the starting materials. The polymers were characterized by elemental analysis, GPC, IR, and ¹H‐ and ¹³C NMR spectroscopies. Thermal and X‐ray diffraction studies revealed them to be mainly amorphous. The polymers are hydrophilic and their degradation studies were carried out at 37 and 80 °C in buffered salt solution at pH 8. The degradation study was monitored by mass loss, GPC, IR, and NMR spectroscopies. The hydrolytic degradation of these PEAs occurred rapidly by hydrolysis of the ester functions to a final compound, which maintained the amide functions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Synthesis and properties of multiblock copolymers consisting of poly(L‐lactic acid) and poly(oxypropylene‐ co‐oxyethylene) prepared by direct polycondensation

A multiblock copoly(ester–ether) consisting of poly(l ‐lactic acid) (PLLA) and poly(oxypropylene‐co‐oxyethylene) (PN) was prepared and characterized. Preparation was done via the solution polycondensation of a thermal oligocondensate of l ‐lactic acid, a commercially available telechelic polyether (PN: Pluronic‐F68), and dodecanedioic acid as a carboxyl/hydroxyl adjusting agent. When stannous oxide was used as the catalyst, the molecular weight of the resultant PLLA/PN block copolymers became very high (even with a high PN content) under optimized reaction conditions. The refluxing of diphenyl ether (solvent) at reduced pressure allowed the efficient removal of the condensed water from the reaction system and the feed‐back of the intermediately formed l ‐lactide at the same time in order to successfully bring about a high degree of condensation. The copolymer films obtained by solution casting became more flexible with the increasing PN content as soft segments. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1513–1521, 1999     

Synthesis,characterization, and biodegradation of copolymers of unsaturated and saturated poly(ester amide)s

A new family of biodegradable copolymers of unsaturated poly(ester amide)s (UPEAs) and saturated poly(ester amide)s (SPEAs) based on L ‐phenylalanine, aliphatic dicarboxylic acids, and aliphatic dialcohols was synthesized by solution polycondensation and characterized. These unsaturated/saturated poly(ester amide) copolymers (USPEAs) were obtained in fairly good yields with N,N‐dimethylacetamide as the solvent. The molecular weights (M_n and M_w) of the USPEAs measured by GPC ranged from 15 to 60 kg/mol with a molecular weight distribution of 1.07–1.63. The chemical structures of the USPEAs were confirmed by both IR and NMR spectra. The USPEA copolymers had glass transition temperatures lower than that of pure UPEA but higher than that of pure SPEA. An increase in the unsaturated component in the USPEA copolymers led to an increase in their glass transition temperatures. The solubility of the copolymers was good in N,N‐dimethylacetamide and dimethyl sulfoxide but poor in water, acetone, methanol, and ethyl acetate. The preliminary in vitro biodegradation properties of the USPEA copolymers were investigated in both pure phosphate buffered saline (PBS) buffer and α‐chymotrypsin solutions. The copolymers showed significantly faster weight loss in an enzyme solution than in a pure PBS buffer. Upon the adjustment of the unsaturated‐to‐saturated diester monomer feed ratio, the obtained USPEA copolymers could have controlled chemical and physical properties, such as glass transition temperatures, solubility, and biodegradability, which could easily extend their applications to biomedical and pharmaceutical areas. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 1595–1606, 2007     

Synthesis of amphiphilic poly(para‐phenylene)s by Suzuki polycondensation

1,4‐Dibromobenzenes carrying nonpolar hexoxy and polar oligo(ethylene glycol) side chains were subjected to Suzuki polycondensation with a benzene‐1,4‐bisboronic acid ester to produce high‐molar‐mass poly(para‐phenylene)s. The molar masses were determined with size exclusion chromatography with conventional polystyrene and universal calibration. These novel amphiphilically equipped rigid‐rod polymers have the potential to segregate lengthwise into polar and nonpolar domains, a property that has only rarely been described, and promise to exhibit novel interesting supramolecular properties. The oligo(ethylene gylcol) side chains terminate with a silyl‐protected alcohol group, and its deprotection on the polymer was proven to proceed quantitatively. This not only led to a further polarity increase but allows us to attach even more polar (e.g., charged) units in future projects. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2879–2889, 2003     

Acid‐base properties of poly(amidoamine)s

Polyamidoamines (PAAs) represent a family of degradable polymers carrying tert‐amine groups in the polymer backbone, which behave as polyelectrolytes in aqueous solutions. Many relevant properties of PAAs, including the ability to interact with components of the biological environments, such as nucleic acids, proteins, and living cells, are strongly dependent on their acid‐base properties, hence on their ionization state in different biological districts. In this article, the protonation constants of a series of PAAs have been precisely determined by electrochemical techniques in order to build up a homogeneous library containing both the protonation constants and the average distribution of the charged species, hence the net average charge as a function of pH. Moreover, correlations between chemical and cytotoxicity, have been attempted. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2009     

Microwave‐Assisted Single‐Step Synthesis of Poly(alkylene hydrogen phosphonate)s by Transesterification of Dimethyl Hydrogen Phosphonate with Poly(ethylene glycol)

Summary: Poly(alkylene hydrogen phosphonate)s with a number‐average molecular weight of about 3 000 Da were obtained by a transesterification of dimethyl hydrogen phosphonate with poly(ethylene glycol) (PEG 400) under microwave irradiation with a very short reaction time (55 min) relative to that of classical thermal heating (9 h). The structure of the resulting polymer was confirmed by ¹H, ³¹P, and ¹³C NMR spectroscopy. The molecular weight was determined by ¹H, ³¹P{H} NMR spectroscopy, MALDI‐TOF, and GPC.

The transesterification of dimethyl hydrogen phosphonate with poly(ethylene glycol).     

Synthesis and characterization of novel biodegradable unsaturated poly(ester amide)s

A series of novel biodegradable unsaturated poly(ester amide)s (UPEAs) were synthesized through the solution polycondensation of two unsaturated monomers, di‐p‐nitrophenyl fumarate and L ‐phenylalanine 2‐butene‐1,4‐diol diester p‐toluene sulfonate, and four other saturated monomers in different combinations. The UPEAs were obtained in fairly good yields with N,N‐dimethylacetamide (DMA) as the solvent. The number‐average and weight‐average molecular weights of the UPEAs, measured by gel permeation chromatography, ranged from 10 to 30 kg/mol, they had a rather narrow molecular weight distribution of 1.40. The chemical structures of the novel biodegradable UPEAs were confirmed by both IR and NMR spectra. The UPEAs had higher glass‐transition temperatures than saturated PEAs of similar structures, and their glass‐transition temperatures were affected more by the CC double bond located in the diamide part than by those in the diester part. The solubility of the polymers was poor in water but better in DMA and dimethyl sulfoxide. With the availability of these inherent CC double bonds in the UPEA backbones, these UPEAs have the functionality of CC bonds, such as photochemical reactivity or the ability to react with or be modified by other bioactive or other environmentally sensitive compounds, and this can easily extend their applications to biomedical and pharmaceutical areas. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1463–1477, 2005     

Melt‐processable poly(oxyphenylalkanoate): Synthesis,properties, and in vitro degradation of poly(4‐oxyphenylacetate)

The homopolyester of 4‐hydroxyphenylacetic acid (HPAA) was synthesized by one‐pot, slurry‐melt, and acidolysis melt polymerization techniques and was characterized by its inherent viscosity and IR and NMR spectra. Differential scanning calorimetry (DSC), polarizing light microscopy (PLM), and wide‐angle X‐ray diffraction (WAXD) studies of the homopolymer were carried out for its thermal and phase behavior. The results indicated that the yield and molecular weight of the polymer depended on the method of preparation; moreover, the acidolysis melt polymerization of the pure acetoxy derivative of HPAA was the best method for the preparation of high molecular weight poly(4‐oxyphenylacetate) (polyHPAA) without side reactions. DSC and PLM studies also showed that the thermal and optical properties depended largely on the polymerization conditions and inherent viscosity values. PolyHPAA did not show a clear texture typical of liquid‐crystalline polymers, whereas after cooling from the melt, structures similar to spherulitic crystals were observed. WAXD patterns showed a crystalline nature. The in vitro degradability of the polymer was also studied via the water absorption in buffer solutions of pH 7 and 10 at 30 and 60 °C; this was followed by Fourier transform infrared, inherent viscosity, DSC, thermogravimetric analysis, WAXD, and scanning electron microscopy techniques. Unlike Vectra®, which showed no degradation, polyHPAA showed an increase in hydrolytic degradation from 5.0 and 6.0% at 30 °C to 12.5 and 15.0% at 60 °C after 350 h in buffer solutions of pH 7 and 10, respectively. The results indicated a possible biomedical prosthetic application of poly(oxyphenylalkanoate)s such as polyHPAA with better crystallinity coupled with degradability as a substitute for poly(hydroxyalkanoates). © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2430–2443, 2001     

Poly(ester anhydride)s prepared by the insertion of ricinoleic acid into poly(sebacic acid)

New degradable poly(ester anhydride)s were prepared by the melt polycondensation of diacid oligomers of poly(sebacic acid) (PSA) transesterified with ricinoleic acid. The transesterification of PSA with ricinoleic acid to form oligomers was conducted via a melt bulk reaction between a high molecular weight PSA and ricinoleic acid. A systematic study on the synthesis, characterization, degradation in vitro, drug release, and stability of these polymers was performed. Polymers with weight‐average molecular weights of 2000–60,000 and melting temperatures of 24–77 °C were obtained for PSA containing 20–90% (w/w) ricinoleic acid. NMR and IR analyses indicated the formation of ester bonds along the polyanhydride backbone. These new degradable copolymers have potential use as drug carriers. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1059–1069, 2003     

Copolyesters of hydroxyphenylalkanoic acids: Synthesis,properties, and in vitro degradation of poly(4‐oxybenzoate‐co‐4‐oxyphenylacetate)

Hydrolytically degradable copolyesters of the naturally occurring monomer 4‐hydroxyphenylacetic acid (HPAA) with 4‐hydroxybenzoic acid (HBA) were synthesized for the first time by the acidolysis melt polymerization of their acetoxy derivatives. The HPAA/HBA copolyesters prepared by acidolysis melt polycondensation had higher yields and molecular weights than those obtained by a one‐pot method. The high‐temperature solvent Dowtherm® improved the color of the polyester. Although catalysts did not affect the inherent viscosity and yield of the polymer, they did reduce the polymerization time. A higher degree of polymerization was achieved with postpolymerization and annealing techniques. Copolyesters prepared in different molar ratios were analyzed by elemental analysis, IR, NMR, and inherent viscosity and were further characterized for their thermal and phase properties by thermogravimetric analysis, differential scanning calorimetry, wide‐angle X‐ray diffraction, and polarized light microscopy. The composition of the copolyesters affected the yield, solubility, and inherent viscosity. The NMR data indicated comparatively high randomization for the copolyester obtained by acidolysis melt polymerization. The 60/40 HPAA/HBA copolyester formed a birefringent melt with a grainy texture above 175 °C with isotropization at 297 °C and thermal stability above 350 °C. The occurrence of birefringence with a grainy texture in the melt indicates a layered smectic phase; this was supported by wide‐angle X‐ray diffraction powder patterns. The in vitro hydrolytic degradability of the copolyester was studied by the measurement of the water absorption of the film samples in buffer solutions of pH 7 and 10 at 30 and 60 °C. The copolyester showed considerable hydrolytic degradation, enough to be called biodegradable, compared with the commercial polyester Vectra®, thereby demonstrating prospects for syntheses of copolyesters with tailor‐made degradability. The degradation of the copolyester was identified by Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, and scanning electron microscopy. These polyesters with controlled crystallinity and degradability should be considered for possible applications in biomedical areas (e.g., bone fixation devices in fracture treatment) in which high strength with biodegradability is an essential requirement. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 693–705, 2001     

Synthesis and characterization of phthalazinone containing poly(arylene ether)s via a novel N–C coupling reaction

High‐molecular‐weight poly(phthalazinone)s with very high glass‐transition temperatures (T_g's) were synthesized via a novel N–C coupling reaction. New bisphthalazinone monomers ( 7a–e ) were synthesized from 2‐(4‐chlorobenzoyl) phthalic acid in two steps. Poly(phthalazinone)s, having inherent viscosities in the range of 0.34–0.91 dL/g, were prepared by the reaction of the bis(phthalazinone) monomers with an activated aryl halide in a dipolar aprotic solvent in the presence of potassium carbonate. The poly(phthalazinone)s exhibited T_g's greater than 230 °C. polymer 8b synthesized from diphenyl biphenol and bis(4‐flurophenyl) sulfone demonstrated the highest T_g of 297 °C. Thermal stabilities of the poly(phthalazinone)s were determined by thermogravimetric analysis. All the poly(phthalazinone)s showed a similar pattern of decomposition with no weight loss below 450 °C in nitrogen. The temperatures of 5% weight loss were observed to be about 500 °C. The poly(phthalazinone)s containing 4,4′‐isopropylidenediphenol and 4,4′‐(hexafluoroisopropylidene) diphenol and diphenyl ether linkage were soluble in chlorinated solvents such as chloroform. Other poly‐(phthalazinone)s were soluble in dipolar aprotic solvents such as N,N′‐dimethylacetamide. The soluble poly(phthalazinone)s can be cast as flexible films from solution. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2481–2490, 2003     

Biodegradable Coumaric Acid‐Based Poly(anhydride‐ester) Synthesis and Subsequent Controlled Release

To overcome drug delivery issues associated with its short half‐life in vivo, p‐coumaric acid (pCA), a naturally occurring bioactive, has been chemically incorporated into a poly(anhydride‐ester) backbone through solution polymerization. Nuclear magnetic resonance and Fourier transform infrared spectroscopies indicated that pCA was successfully incorporated without noticeable alterations in structural integrity. The polymer's weight‐average molecular weight and thermal properties were determined, exhibiting a molecular weight of over 26 000 Da and a glass transition temperature of 57 °C. In addition, in vitro hydrolytic release studies demonstrated pCA release over 30 d with maintained antioxidant activity, demonstrating the polymer's potential as a controlled release system.

     

Novel thermally stable poly(amine hydrazide)s and poly(amine‐1,3,4‐oxadiazole)s for luminescent and electrochromic materials

We describe the preparation, characterization, and luminescence of four novel electrochromic aromatic poly(amine hydrazide)s containing main‐chain triphenylamine units with or without a para‐substituted N,N‐diphenylamino group on the pendent phenyl ring. These polymers were prepared from either 4,4′‐dicarboxy‐4″‐N,N‐diphenylaminotriphenylamine or 4,4′‐dicarboxytriphenylamine and the respective aromatic dihydrazide monomers via a direct phosphorylation polycondensation reaction. All the poly(amine hydrazide)s were amorphous and readily soluble in many common organic solvents and could be solution‐cast into transparent and flexible films with good mechanical properties. These poly(amine hydrazide)s exhibited strong ultraviolet–visible absorption bands at 346–348 nm in N‐methyl‐2‐pyrrolidone (NMP) solutions. Their photoluminescence spectra in NMP solutions or as cast films showed maximum bands around 508–544 and 448–487 nm in the green and blue region for the two series of polymers. The hole‐transporting and electrochromic properties were examined by electrochemical and spectroelectrochemical methods. All obtained poly(amine hydrazide)s and poly(amine‐1,3,4‐oxadiazole)s exhibited two reversible oxidation redox couples at 0.8 and 1.24 V vs. Ag/AgCl in acetonitrile solution and revealed excellent stability of electrochromic characteristics, changing color from original pale yellow to green and then to blue at electrode potentials of 0.87 and 1.24 V, respectively. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 3245–3256, 2005     

Synthesis and characterization of star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties

Star oligo/poly(2,2‐dimethyltrimethylene carbonate)s containing cholic acid moieties were synthesized through the ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate (DTC) initiated by cholic acid with hydroxyl groups. Through the control of the feed ratio of the initiator cholic acid to the monomer DTC, a series of star oligomers/polymers with different molecular weights were obtained. The star oligomers/polymers were characterized with Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, combined size exclusion chromatography/multi‐angle laser light scattering analysis, wide‐angle X‐ray scattering, polarizing light microscopy, and differential scanning calorimetry. Compared with linear poly(2,2‐dimethyltrimethylene carbonate), these star oligo/poly(2,2‐dimethyltrimethylene carbonate)s had much faster hydrolytic degradation rates. With one of the star oligomers/polymers, a microsphere drug‐delivery system of a submicrometer size was fabricated with a very convenient ultrasonic dispersion method that did not involve toxic organic solvents. The in vitro drug release was studied. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6688‐6696, 2006     

Synthesis and characterization of poly (styrene-co-vinyl phosphonate) ionomers

Poly(styrene-co-diethyl vinylphosphonate) copolymers were synthesized by free radical copolymerization. The ester groups of the copolymers were hydrolyzed to phosphonic acid groups, and the sodium and zinc salts ionomers were obtained by neutralization. The structure and the thermal and viscoelastic properties of the copolymers and ionomers were characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy, differential scanning calorimetry, dynamic mechanical analysis, and small-angle X-ray scattering. The phosphonate ester lowered the glass transition temperature (T_g) of polystyrene. The free acid derivatives and metal phosphonates increased T_g and produced a rubbery plateau region in the viscoelastic properties due to the formation of a physical network. The acid and salt ionomers exhibited microphase-separated morphologies and were thermorheologically complex. The phosphonic acid derivatives absorbed relatively little water, even for materials with ion-exchange capacities greater than 1.0 mEq/g, and were not conductive, which made them unsuitable for application as proton exchange membranes. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3628–3641, 2004     

Conjugates of Antibody‐Targeted PEG Multiblock Polymers with Doxorubicin in Cancer Therapy

The synthesis and physico‐chemical characterisation of biodegradable multiblock polymer drug carriers based on poly(ethylene glycol) (PEG) are described. The blocks of PEG ( = 2 000) are interconnected by an enzymatically degradable tripeptide derivative consisting of one Lys and two Glu residues. An anticancer drug, doxorubicin (Dox), was attached to the polymer carrier by a Gly‐Phe‐Leu‐Gly tetrapeptide spacer, which is also susceptible to degradation by lysosomal enzymes. A targeting polyclonal antibody was covalently linked to the polymer‐Dox conjugate by the aminolytic reaction of reactive sulfosuccinimidyl ester groups of the polymer with the protein. The resulting antibody‐polymer‐drug conjugates were characterised by SEC, UV/VIS spectrophotometry and amino acid analysis. Although the studied polymers show only a moderate antiproliferative activity against concanavalin A‐stimulated murine splenocytes and a murine T‐cell EL 4 lymphoma in vitro, they exhibited significant antitumour efficiency against murine T‐cell EL 4 lymphoma in vivo.