Sequential functionalization of janus‐type dendrimer‐like poly(ethylene oxide)s with camptothecin and folic acid

Janus‐type dendrimer‐like poly(ethylene oxide)s (PEOs) of 1st, 2nd, and 3rd generation carrying terminal hydroxyl functions on one side and cleavable ketal groups on the other were used as substrates to conjugate folic acid as a folate receptor and camptothecin (CPT) as a therapeutic drug in a sequential fashion. The conjugation of both FA and CPT was accomplished by “click chemistry” based on the 1,3 dipolar cycloaddition coupling reaction. First, the hydroxyl functions present at one face of Janus‐type dendrimer‐like PEOs were transformed into alkyne groups through a simple Williamson‐type etherification reaction. Next, the ketals carried by the other face of the dendrimer‐like PEOs were hydrolyzed, yielding twice as many hydroxyls which were subsequently subjected to an esterification reaction using 2‐bromopropionic bromide. Before substituting azides for the bromide of 2‐bromopropionate esters just generated in the presence of NaN₃, an azido‐containing amidified FA derivative was reacted through click chemistry with alkyne functions introduced on the other face of the dendrimer‐like PEOs. A purposely designed alkyne‐functionalized biomolecule derived from CPT was conjugated to the azido functions carried by the dendritic PEOs by a second “click reaction.” In this case, twice as many CPT as FA moieties were finally conjugated to the two faces of the Janus‐type dendrimer‐like PEOs, the numbers of folate and CPT introduced being 2 and 4, 4 and 8, and 8 and 16 for samples of 1st, 2nd, and 3rd generation, respectively (route A). An alternate route for functionalizing the dendrimer‐like PEO of 1st generation consisted, first, in conjugating the azido‐containing CPT onto the alkyne groups present on one face of the dendritic PEO scaffold. The alkyne‐functionalized FA was further introduced by click chemistry after the bromides of 2‐bromopropionate esters were chemically transformed into azido groups. The corresponding prodrug thus contains 2 CPT and 4 FA external moieties (route B). Every reaction step product was thoroughly characterized by ¹H NMR spectroscopy. A preliminary investigation into the water solution properties of these functionalized dendritic PEOs is also presented. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of dendrimer‐like copolymers based on the star[Polystyrene‐Poly(ethylene oxide)‐Poly(ethoxyethyl glycidyl ether)] terpolymers by click chemistry

The dendrimer‐like copolymers [PEEGE‐(PS/PEO)]_n (n ≥ 2) based on the star[Polystyrene‐Poly(ethylene oxide)‐Poly(ethoxyethyl glycidyl ether)] [star(PS‐PEO‐(PEEGE‐OH))] terpolymers were synthesized by click chemistry. First, the star‐shaped copolymers star[PS‐PEO‐(PEEGE‐Alkyne)] (also termed as [PEEGE‐(PS/PEO)]₁) were synthesized by the reaction of hydroxyl end group at PEEGE arm (on star[PS‐PEO‐(PEEGE‐OH)]) with propargyl bromide. Then, the small molecule 1,4‐diazidobutane (DAB) with two azide groups and pentaerythritol tetrakis (2‐azidoisobutyrate) (PTAB) with four azide groups were synthesized and reacted with [PEEGE‐(PS/PEO)]₁ by the click chemistry for dendrimer‐like [PEEGE‐(PS/PEO)]₂ and [PEEGE‐(PS/PEO)]₄, respectively. However, in the latter case, only the [PEEGE‐(PS/PEO)]₃ was formed as the main product because of the steric effect. The final dendrimer‐like [PEEGE‐(PS/PEO)]_n copolymers were characterized by SEC and ¹H‐NMR in detail. Comparing with the SEC of their precursor [PEEGE‐(PS/PEO)]₁, the curves of [PEEGE‐(PS/PEO)]₂ was shifted to the shorter elution time, while that of [PEEGE‐(PS/PEO)]_n (n ≥ 3) was shifted to the longer elution time, which was attributed to the different hydrodynamic volume derived from their separate structures and compositions in THF solution. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4800–4810, 2009     

Synthesis of Poly(ethylene oxide)s Bearing Functional Groups along the Chain

Well‐defined poly(ethylene oxide)s (PEOs) bearing reactive sites regularly distributed along the chain have been synthesized by the polycondensation of PEO containing a central tertiary amino group with dichloromethane, followed by quaternization with suitable reagents to obtain polyzwitterionic or cationic PEOs with alkyl, allyl, or fluorocarbon pendant groups. The pendant allyl groups have been converted into primary amino groups by reaction with 2‐aminoethanethiol hydrochloride to obtain polyamino‐functionalized PEO.

Polyfunctional PEOs bearing different pendant groups.     

The Synthesis of Poly(ethylene oxide)-Block-Polybutylacrylate

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Shape Memory Properties in Poly(ethylene oxide)–Poly(ethylene terephthalate) Copolymers

Memory effects of several copolymers of poly(ethylene oxide) (PEO) and poly(ethylene terephthalate) (PET) were illustrated with photos, determined with shrinkage experiments and characterized by the recovery of samples to their original figures. Copolymers of appropriate composition could undertake an approximately full recovery which is tightly related to the annealing temperature at which shrinkage of samples occurs to some extent. Melting and recrystallization of PEO segments may be responsible for the memory effect. The memory properties of samples almost kept unchanged after many fatigue cycles (e.g. 15–20 cycles), which could make these copolymers useful in practical applications as novel shape memory materials. © 1997 John Wiley & Sons, Ltd.     

Solid‐State 1H NMR Studies of Degradable Poly(ethylene oxide) Based Hydrogels

Summary: Hydrogels, the elastic chains of which are constituted of a short central poly(1,3‐dioxolane) (PDXL) block surrounded by two hydrophilic poly(ethylene oxide) (PEO) blocks, were obtained by free radical homopolymerization of α,ω–methacryloyloxy PEO‐block‐1,3‐PDXL‐block‐PEO macromonomers. The central PDXL block is known to be sensitive to acidic degradation due to the presence of acetal groups. Once swollen to equilibrium, these hydrogels were characterized for their equilibrium swelling degree and their mechanical properties and network degradation studies were carried out.

Representation proposed for the breaking of a PEO‐block‐PDXL‐block‐PEO block copolymer.     

Study of the Crystallization Kinetics. Poly(ethylene oxide) and a blend of poly(ethylene oxide) and poly(bisphenol A-co-epichlorohydrin)

A kinetic study of the crystallization of poly(ethylene oxide) (PEO) and of a blend of PEO+poly(bisphenol A-co-epichlorohydrin) (PBE) was performed by using DSC in a non-isothermal program at constant cooling rates. The curves obtained were analyzed by the Kissinger, Ozawa and Friedman methods, with determination of the kinetic parameters in each case. As a consequence of the presence of PBE, the kinetic parameters were altered, leading to the conclusion that PBE has some influence on the crystallization of PEO, modifying its mechanism. This revised version was published online in July 2006 with corrections to the Cover Date.     

Macromolecular Architecture Based on Anionically Prepared Poly(ethylene oxide) Macromonomers

Synthesis of poly(ethylene oxide) (PEO) macromonomers carrying a methacyloyl group in one end, and N, N-dimethyl amino, thiophene, styryl and vinyl ether functional groups in the other end was desribed. The general synthetic strategy is based on the living anionic polymerization of ethylene oxide initiated with functional potassium alcoholates, followed by reaction with methacyloyl chloride. These macromonomers were further utilized in various macromolecular architectures through via concurrent or selective thermal free radical, oxidative and photoinitiated free radical and cationic polymerization methods. The use of this synthetic route to prepare graft copolymers possessing completly and perfectly alternating PEO side chains using charge-transfer-complex polymerization was also demonstrated.     

Peculiarities of Formation of Intermolecular Polycomplexes Based on Polyacrylamide,Poly(vinyl alcohol) and Poly(ethylene oxide)

The phenomenon of self-assembly of aggregates formed by relatively short chains of poly(vinyl alcohol) (PVA) on the long macromolecules of polyacrylamide (PAA) in aqueous medium are discussed. PVA and PAA form intermolecular polycomplexes (InterPC) of a constant composition independently on a ratio of polymer components. The complex formation between high-molecular-weight PAA and relatively low-molecular-weight poly(ethylene oxide) (PEO) are considered also. PEO with M ⩽ 4·10⁴ g.mol⁻¹ weakly interacts with PAA. The polymer-polymer interaction can be intensified when the part of amide groups (∼20 mol %) on PAA chain to transform into the carboxylic groups. InterPCs formed by PEO and initial or modified PAA have associative structure with friable packing of the polymer segments. They are stabilized by the hydrogen bond system.     

Enzymatic Degradation of Poly(ethylene terephthalate): Rapid Hydrolyse using a Hydrolase from T. fusca

Summary: It is demonstrated that PET, which is usually regarded as ‘non‐biodegradable’, can effectively be depolymerized by a hydrolase from the actinomycete Thermobifida fusca. Erosion rates of 8 to 17 µm per week were obtained upon incubation at 55 °C. Lipases from Pseudomonas sp. and Candida antarctica did not degrade PET under comparable conditions. The influences of crystallinity, melting point, and glass transition temperature on the enzymatic attack on PET, PBT, and PHB are discussed.

Outline of the degradation of PET.     

Preparation of Clickable Poly(3‐hydroxyalkanoate) (PHA): Application to Poly(ethylene glycol) (PEG) Graft Copolymers Synthesis

A new synthesis of amphiphilic biodegradable copolymers consisting of hydrophobic poly(3‐hydroxyalkanoate) (PHA) backbone and hydrophilic poly(ethylene glycol) (PEG) units as side chains is described. Poly[(3‐hydroxyoctanoate)‐co‐(3‐hydroxyundecenoate)] (PHOU) was first methanolyzed and its unsaturated side chains were quantitatively oxidized to carboxylic acid. Esterification with propargyl alcohol led to an alkyne‐containing “clickable” PHA in 71% conversion. Its reactivity was successfully demonstrated by grafting azide‐terminated PEG chains of 550 and 5 000 g · mol⁻¹, respectively. All products were fully characterized using GPC, ¹H, and COSY NMR.

     

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.

     

Effect of aging on fractional crystallization of poly(ethylene oxide) component in poly(ethylene oxide)/poly(3‐hydroxybutyrate) blends

The effect of aging on the fractional crystallization of the poly(ethylene oxide) (PEO) component in the PEO/poly(3‐hydroxybutyrate) (PHB) blend has been investigated. The partial miscibility of the PEO/PHB blends with high PEO molecular weight (M_v = 2.0 × 10⁵ g/mol) was confirmed by differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis. The fractional crystallization behavior of the PEO component in the PEO/PHB blends with low PEO content (not more than 30 wt% of PEO), before and after aging under vacuum at 25 °C for 6 months, were compared by DSC, fourier transform infrared microscopic spectroscopy, small angle X‐ray diffraction, and scanning electron microscopy. It was confirmed that nearly all the PEO components remain trapped within interlamellar regions of PHB for the PEO/PHB blends before aging. Under this condition, the crystallization of PEO is basically induced by much less active heterogeneities or homogeneous nucleation at high supercoolings. While, after the same PEO/PHB samples were stored at 25 °C in vacuum for 6 months, a part of the PEO component was expelled from the interlamellar region of PHB. Under this condition, the expelled PEO forms many separate domains with bigger size and crystallizes at low supercoolings by active heterogeneous nucleation, whereas the crystallization of PEO in the interlamellar region is still mainly induced by less active heterogeneities or homogeneous nucleation at extreme supercoolings. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2665–2676, 2005     

Synthesis and characterization of poly(ethylene oxide)/polylactide/poly(ethylene oxide) triblock copolymer

Poly(ethylene oxide/polylactide/poly(ethylene oxide) (PEO/PL/PEO) triblock copolymers, in which each block is connected by an ester bond, were synthesized by a coupling reaction between PL and PEO. Hydroxyl‐terminated PLs with various molecular weights were synthesized and used as hard segments. Hydroxyl‐terminated PEOs were converted to the corresponding acid halides via their acid group and used as a soft segment. Triblock copolymers were identified by Fourier transform infrared spectroscopy, ¹H NMR, and gel permeation chromatography. Differential scanning calorimetry (DSC) and X‐ray diffractometry of PEO/PL/PEO triblock copolymers suggested that PL and PEO blocks were phase‐separated and that the crystallization behavior of the PL block was markedly affected by the presence of the PEO block. PEO/PL/PEO triblock copolymers with PEO 0.75k had two exothermic peaks (by DSC), and both peaks were related to the crystallization of PL. According to thermogravimetric analysis, PEO/PL/PEO triblock copolymer showed a higher thermal stability than PL or PEO. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2545–2555, 2002     

Poly(ethylene imine)‐graft‐poly(ethylene oxide) brush‐like copolymers: Preparation,thermal properties,and selective supramolecular inclusion complexation with α‐cyclodextrin

Poly(ethylene imine)‐graft‐poly(ethylene oxide) (PEI‐g‐PEO) copolymers were synthesized via Michael addition reaction between acryl‐terminated poly(ethylene oxide) methyl ether (PEO) and poly(ethylene imine) (PEI). The brush‐like copolymers were characterized by means of Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. It is found that the crystallinity of the PEO side chains in the copolymers remained unaffected by the PEI backbone whereas the crystal structure of PEO side chains was altered to some extent by the PEI backbone. The crystallization behavior of PEO blocks in the copolymers suggests that the bush‐shaped copolymers are microphase‐separated in the molten state. The PEO side chains of the copolymers were selectively complexed with α‐cyclodextrin (α‐CD) to afford hydrophobic side chains (i.e., PEO/α‐CD inclusion complexes). The X‐ray diffraction (XRD) shows that the inclusion complexes (ICs) of the PEO side chains displayed a channel‐type crystalline structure. It is identified that the stoichiometry of the inclusion complexation of the PEI‐g‐PEO with α‐CD is close to that of the control PEO with α‐CD. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 2296–2306, 2008     

Synthesis and Characterization of Star‐Shaped Diblock Poly(ε‐caprolactone)/Poly(ethylene oxide) Copolymers

Summary: Star‐shaped hydroxy‐terminated poly(ε‐caprolactone)s (ssPCL), with arms of different lengths, were obtained by ring‐opening polymerization (ROP) of ε‐caprolactone initiated by pentaerythritol, and were condensed with α‐methyl‐ω‐(3‐carboxypropionyloxy)‐poly(ethylene oxide)s ( = 550–5 000) to afford four‐armed PCL‐PEO star diblock copolymers (ssPCL‐PEO). The polymers were characterized by ¹H and ¹³C NMR spectroscopy and size‐exclusion chromatography (SEC). The melting behavior of ssPCLs was studied by differential scanning calorimetry (DSC). X‐ray diffraction and DSC techniques were used to investigate the crystalline phases of ssPCL‐PEOs.

The part of the synthesis of four‐armed star‐shaped diblock poly(ε‐caprolactone)‐poly(ethylene oxide) copolymers as described.     

Pathway‐Dependent Melting in a Low‐Molecular‐Weight Polyethylene‐block‐Poly(ethylene oxide) Diblock Copolymer

Summary: In a low‐molecular‐weight polyethylene‐block‐poly(ethylene oxide) (PE‐b‐PEO) diblock copolymer, two pathway‐dependent melting processes were observed: Upon slow heating, the PE lamellar crystals melted at ≈97 °C into a disordered state. However, when the temperature rapidly jumped to above the melting point (e.g., 100 °C), the PE lamellar crystals transformed directly into an ordered lamellar melt, followed by an isothermal conversion into a disordered melt. This isothermal order‐to‐disorder transition was explained by superheating of the PE crystals using a G‐T diagram.

A schematic G‐T diagram explaining the pathway‐dependent double melting for a crystalline polyethylene‐block‐poly(ethylene oxide) copolymer.     

Enforcing Effect of Double‐Fullerene End‐Capped Poly(ethylene oxide) on Mechanical Properties of Poly(L‐lactic acid)

Summary: The fracture strain for the composite of poly(L ‐lactic acid) (PLLA) and double‐fullerene end‐capped poly(ethylene oxide) (FPEOF) was observed about 100 times of PLLA with a high modulus for room‐temperature aged samples. The aggregates of fullerene of FPEOF ends give rise to the formation of physical network of poly(ethylene oxide), which forms a pseudo‐semi‐interpenetrating network with PLLA and renders the astonishing enforcing effect on the PLLA.

Strain‐stress curves of PLLA and PLLA/FPEO20F6 composite.