Multifunctional Poly(ethylene glycol)s

In the rapidly evolving multidisciplinary field of polymer therapeutics, tailored polymer structures represent the key constituent to explore and harvest the potential of bioactive macromolecular hybrid structures. In light of the recent developments for anticancer drug conjugates, multifunctional polymers are becoming ever more relevant as drug carriers. However, the potentially best suited polymer, poly(ethylene glycol) (PEG), is unfavorable owing to its limited functionality. Therefore, multifunctional linear copolymers (mf‐PEGs) based on ethylene oxide (EO) and appropriate epoxide comonomers are attracting increased attention. Precisely engineered via living anionic polymerization and defined with state‐of‐the‐art characterization techniques—for example real‐time ¹H NMR spectroscopy monitoring of the EO polymerization kinetics—this emerging class of polymers embodies a powerful platform for bio‐ and drug conjugation.     

Temperature‐Responsive Graft Copolymers with Poly(propylene glycol) Side Chains

The phase behavior of graft copolymers in aqueous solution was investigated. The graft copolymers consist of poly(propylene glycol) (PPG) side chains and N,N‐dimethylacrylamide (dMA), N‐vinylimidazole (VIm), and N‐isopropylacrylamide (iPA), respectively, as backbones. Phase transition temperatures of the PPG copolymers increased with increasing the content of dMA and iPA as relatively more hydrophilic comonomers and with an increase in the degree of ionization of the incorporated VIm units.

Chemical structure of the graft copolymers     

聚乳酸-聚乙二醇嵌段共聚物晶行为研究

用1H NMR, SEC, XRD和DSC对聚乳酸(PLLA)-聚乙二醇(PEG)二嵌段共聚物进行了表征. 由于共聚物中两种组分比例的不同, 表现出某组分单独结晶或两种组分共同结晶. 用DSC和POM方法, 对两组分含量相当的共聚物进行了熔体结晶行为研究, 并采用Avrami方程进行了结晶动力学计算. 用Lauritzen-Hoffmann理论对PLLA-PEG结晶机理进行了分析. 在70~94 ℃范围内, 得到成核参数Kg(POM)=5.23×105 K2. 共聚物的Kg和链折叠自由能σe都比均聚物的文献报道值高, 表明PEG链段的存在影响了PLLA的结晶, 使得其成核较均聚物困难.     

Thermo-Responsive Hydrogels Based on Branched Poly(L-lactide)-poly(ethylene glycol) Copolymers

Summary: Branched poly(L -lactide)-poly(ethylene glycol) (PLLA-PEG) block copolymers were synthesized from trifunctional PLLA and amine functionalized methoxy poly(ethylene glycol)s. The copolymers in water formed hydrogels that showed thermo-responsive behavior. The hydrogels underwent a gel to sol transition with increasing temperature as determined with the vial tilting method and oscillatory rheology. For all copolymers, the transition temperature increased with increasing copolymer concentration. The transition temperature of corresponding branched copolymers also increased with increasing PEG molecular weight, and surprisingly decreased with increasing molecular weight of the PLLA branches. In general, the gel-sol transition is explained by disruption of micellar or aggregate interactions because of partial dehydration and shrinkage of the PEG chains. An increase in the molecular weight of the PLLA branches led to the formation of micelles and aggregates as observed with DLS at low concentrations. It is speculated that the non-uniform size distribution and possible crystallization of longer PLLA blocks may have a negative effect on the formation of micellar packing upon gelation, allowing the disruption of micellar or aggregate interactions to occur at lower temperatures. The transition temperature of the gels could be tuned closely to body temperature by varying the concentration of the solution or the molecular weight of the PEG block and the PLLA blocks, which implies that these polymers may be used as injectable systems for in-situ gel formation.     

Multifunctional Poly(N‐vinylcarbazole)‐Based Block Copolymers and their Nanofabrication and Photosensitizing Properties

The synthesis of poly(N‐vinylcarbazole)‐based block copolymers functionalized with rhenium diimine complexes or pendant terpyridine ligands is reported. The copolymers are synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization, and they exhibit interesting morphological properties as a result of the phase separation between different blocks. The rhenium complex polymer block may function as a photosensitizer, while the terpyridine‐containing polymer block can be used as the template for nanofabrication by selective deposition of zinc complexes.

     

Multi‐Morphological Complex Aggregates Formed from Amphiphilic Poly(ethylene oxide)‐block‐Polydimethylsiloxane‐block‐Poly(ethylene oxide) Triblock Copolymers

Summary: Amphiphilic triblock copolymers (PEO_x‐b‐PDMS_y‐b‐PEO_x) with different block lengths were synthesized and multi‐morphological complex crew‐cut, star‐like, and short‐chain aggregates were prepared by self‐assembly of the given copolymers. The morphologies and dimensions of the aggregates can be well controlled by variation of the preparation conditions. TEM, SEM, FFR‐TEM, and LLS studies show the resulting morphologies range from LCMs, unilamellar or multilayer vesicles, LCVs, porous spheres to nanorods.

TEM images of the vesicles formed from PEO‐b‐PDMS‐b‐PEO.     

Development of Poly(ethylene glycol) Based Amphiphilic Copolymers for Controlled Release Delivery of Carbofuran

The formation of micelles in a solvent that is selective for one of the blocks is one of the most important and useful properties of block copolymers. We had synthesized copolymers of polyethylene glycol and various dimethyl esters, which self assemble into nano micellar aggregates in aqueous media. In the present work, we have utilized these nano micelles for the encapsulation of carbofuran, [2,3–dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate], a systemic insecticide-nematicide, for the development of controlled release formulation.     

Bioresorbable Hydrogels Prepared Through Stereocomplexation between Poly(L‐lactide) and Poly(D‐lactide) Blocks Attached to Poly(ethylene glycol)

Block copolymers were synthesized by ring‐opening polymerization of L ‐lactide or D ‐lactide in the presence of mono‐ or dihydroxyl poly(ethylene glycol), using zinc metal as catalyst. The resulting copolymers were characterized by various techniques, namely ¹H NMR spectroscopy, differential scanning calorimetry (DSC), X‐ray diffractometry, and Raman spectrometry. The composition of the copolymers was designed such that they were water soluble. Bioresorbable hydrogels were prepared from aqueous solutions containing both poly(L ‐lactide)/poly(ethylene glycol) and poly(D ‐lactide)/poly(ethylene glycol) block copolymers. Rheological studies confirmed the formation of hydrogels resulting from stereocomplexation between poly(L ‐lactide) and poly(D ‐lactide) blocks.

Ring‐opening polymerization of L (D )‐lactide in the presence of dihydroxyl PEG using zinc powder as catalyst.     

Poly(ethylene glycol)‐block‐Poly(glycidyl methacrylate) with Oligoamine Side Chains as Efficient Gene Vectors

Well‐defined diblock copolymers, poly(ethylene glycol)‐block‐poly(glycidyl methacrylate)s (PEG‐b‐PGMAs), with different poly(glycidyl methacrylate) (PGMA) chains, were prepared via atom transfer radical polymerization (ATRP) from the same macromolecular initiator 2‐bromoisobutyryl‐terminated poly(ethylene glycol) (PEG). Ethyldiamine (EDA), diethylenetriamine (DETA), triethylenetetramine (TETA), and polyethyleneimine (PEI) with an of 400 (PEI₄₀₀) were used to decorate PEG‐b‐PGMAs to get the cationic polymers PEG‐b‐PGMA‐ oligoamines. These cationic polymers possessed high buffer capability and could condense plasmid DNA (pDNA) into nanoscaled complexes of 125–530 nm. These complexes showed the positive zeta potential of 20–35 mV at N/P ratios of 10–50. Most of them exhibited very low cytotoxicity and good transfection efficiency in 293T cells. The presence of the serum medium did not decrease the transfection efficiency due to the steric stabilization of the PEG chains.

     

Multicomponent Polymers of Poly(Lactic Acid) Macromonomers with Methacrylate Terminal and Copolymers of Poly(2-Hydroxyethyl Methacrylate)

Abstract

Poly(lactic acid) macromonomers with methacrylate terminal functionality have been synthesized from the cyclic dimer of lactic acid (referred to as lactide) with 2-hydroxyethyl methacrylate (HEMA) as initiator and stannous 2-ethyl hexanoate as catalyst. The macromonomers were characterized with FT-IR, NMR, GPC, DSC, WAXS, and CD. The molecular weights of the macromonomers ranging from M _n 1425 to 19,169 are predictable from the lactide/HEMA ratio in the polymerization feeds. The properties of the macromonomers vary with the stereochemistry of the lactide and the composition. Circular dichroism measurements demonstrate that there is little racemization during polymerization.     

A Rocket‐Like Encapsulation and Delivery System with Two‐Stage Booster Layers: pH‐Responsive Poly(methacrylic acid)/Poly(ethylene glycol) Complex‐Coated Hollow Silica Vesicles

Rocket‐like vesicles formed are composed of poly(acrylic aicd) (PMAA )/poly(ethylene glycol) (PEG) complex coated hollow silica spheres, and the structure and composition of the vesicles are characterized using TGA, ¹H NMR, FTIR, and TEM. Although only one‐third of EG units of PEG brushes grafted to hollow silica spheres form the complex with PMAA via hydrogen bonding, the first “booster” layer composed of PMAA/PEG complex can provide secure encapsulation of model compound calcein blue under an acidic condition. The second “booster” layer composed of PEG brushes can be formed by changing acidic pH to 7.4 through the disassociation of the PMAA/PEG complex. A higher molecular weight PMAA exhibits a faster disassembly due to the formation of a looser PMAA/PEG complex on the surfaces of hollow silica spheres.

     

Synthesis and On‐Demand Gelation of Multifunctional Poly(ethylene glycol)‐Based Polymers

The synthesis of a novel photoreactive poly(ethylene glycol) (PEG)‐based polymer with caged carbonyl groups is reported. We further demonstrate its use for the on‐demand fabrication of hydrogels. For rapid gelation, a hydrazide‐functionalized PEG is used as the second component for the hydrogel preparation. The photoreactive PEG‐based polymer is designed for controlled cleavage of the protecting groups upon exposure to UV light releases free aldehyde moieties, which readily react with hydrazide groups in situ. This hydrogel system may find applications in controlled release drug delivery applications, when combined with in situ gelation. Furthermore, the possibility of forming gels specifically upon UV irradiation gives an opportunity for 3D fabrication of degradable scaffolds.

     

聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物的降解性能

以辛酸亚锡为引发剂,聚乙二醇大分子为共引发剂进行现交酯开环聚合,制备了系列聚乳酸（PLA）－聚乙二醇（PEG）－聚乳酸（PLA）三嵌段共聚物。从共聚物在生理盐水 中降解时特性粘度[η],质量和热行为的变化,考察了PEG分子量和丙交酯／PEG（摩尔比）对共聚物降解行为的影响,结果表明,PEG嵌段对共聚物的降解速率有重要影响,丙交酯／PEG一定时,PEG分子量越大,共聚物越容易降解,PEG嵌段长度一定时,丙交酯／PEG越大,共聚物降解速率越小。     

Amphiphilic block copolymers of high‐molecular‐weight poly(ethylene oxide) and either ε‐caprolactone or γ‐methyl‐ε‐caprolactone: Synthesis and characterization

Ethylene oxide (EO) has been block‐polymerized with both ε‐caprolactone (ε‐CL) and γ‐methyl‐ε‐caprolactone (MCL) through the combination of the anionic polymerization of EO and the ring‐opening polymerization (ROP) of ε‐CL and MCL. ω‐Hydroxyl poly(ethylene oxide) has been reacted with triethylaluminum (OH/Al = 1) and converted into a macroinitiator for ROP of ε‐CL and MCL. In toluene at room temperature, this polymerization leads to a bimodal molecular weight distribution as a result of monomer insertion in only some of the aluminum alkoxide bonds. However, in a more polar solvent (methylene chloride) added with 1 equiv of a Lewis base (pyridine), the expected diblock is formed selectively, and this indicates that aggregation of the active species in toluene is responsible for a macroinitiator efficiency of less than 1. A series of amphiphilic diblock copolymers with poly(ε‐caprolactone) (semicrystalline) and poly(γ‐methyl‐ε‐caprolactone) (amorphous) as the hydrophobic blocks have been prepared and characterized with size exclusion chromatography, ¹H NMR, IR, and wide‐angle X‐ray scattering. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 1132–1142, 2004     

Poly(ferrocenylsilane)‐block‐Polylactide Block Copolymers

A PFS/PLA block copolymer was studied to probe the effect of strong surface interactions on pattern formation in PFS block copolymer thin films. Successful synthesis of PFS‐b‐PLA was demonstrated. Thin films of these polymers show phase separation to form PFS microdomains in a PLA matrix, and ultrathin films (<5 nm) formed SINPATs on silicon and mica. The SINPATs consisted of strongly surface‐adsorbed PLA blocks on top of which the PFS blocks dewetted into sphere‐like features. The lateral spacing between these features was regular, and was typically much larger than the length scale associated with regular block copolymer phase separation.

     

Amphiphilic Block‐Graft Copolymers Poly(ethylene glycol)‐b‐(polycarbonates‐g‐palmitate) Prepared via the Combination of Ring‐Opening Polymerization and Click Chemistry

Amphiphilic block‐graft copolymers mPEG‐b‐P(DTC‐ADTC‐g‐Pal) were synthesized by ring‐opening polymerization of 2,2‐dimethyltrimethylene carbonate (DTC) and 2,2‐bis(azidomethyl)trimethylene carbonate (ADTC) with poly(ethylene glycol) monomethyl ether (mPEG) as an initiator, followed by the click reaction of propargyl palmitate and the pendant azido groups on the polymer chains. Stable micelle solutions of the amphiphilic block‐graft copolymers could be prepared by adding water to a THF solution of the polymer followed by the removal of the organic solvent by dialysis. Dynamic light scattering measurements showed that the micelles had a narrow size distribution. Transmission electron microscopy images displayed that the micelles were in spherical shape. The grafted structure could enhance the interaction of polymer chains with drug molecules and improve the drug‐loading capacity and entrapment efficiency. Further, the amphiphilic block‐graft copolymers mPEG‐b‐P(DTC‐ADTC‐g‐Pal) were low cytotoxic and had more sustained drug release behavior. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

High‐Fidelity End‐Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages

Commercial PEG‐amine is of unreliable quality, and conventional PEG functionalization relies on esterification and etherification steps, suffering from incomplete conversion, harsh reaction conditions, and functional‐group incompatibility. To solve these challenges, we propose an efficient strategy for PEG functionalization with carbamate linkages. By fine‐tuning terminal amine basicity, stable and high‐fidelity PEG‐amine with carbamate linkage was obtained, as seen from the clean MALDI‐TOF MS pattern. The carbamate strategy was further applied to the synthesis of high‐fidelity multi‐functionalized PEG with varying reactive groups. Compared to with an ester linkage, amphiphilic PEG‐PS block copolymers bearing carbamate junction linkage exhibits preferential self‐assembly tendency into vesicles. Moreover, nanoparticles of the latter demonstrate higher drug loading efficiency, encapsulation stability against enzymatic hydrolysis, and improved in vivo retention at the tumor region.     

Macromonomer Purification Strategy for Well‐Defined Polymer Amphiphiles Incorporating Poly(ethylene glycol) Monomethacrylate

Summary: Commercial hydroxy‐terminated poly(ethylene glycol) monomethacrylates (PEG‐MAs) contain poly(ethylene glycol) dimethacrylate, which leads to unfavorable gel formation on polymerization. Here, hydroxy‐terminated PEG‐MA is readily isolated using a dimethylsilyl resin chlorinated with 1,3‐dichloro‐5,5‐dimethylhydantoin. Solution polymerization of the isolated PEG‐MA by free radical routes gives a high‐molecular‐weight amphiphilic graft copolymer without cross‐linking. The resulting polymer is stable for long periods in ambient conditions with preservation of the hydroxy end groups of PEG.

Commercial hydroxy‐terminated PEG‐MA can be separated readily and completely from PEG dimethacrylate contaminant with chlorinated dimethylsilyl resin.     

Reverse Thermal Organogelation of Poly(ethylene glycol)‐Polypeptide Diblock Copolymers in Chloroform

Most organogel formation has been observed at low temperatures and the gel melts as the temperature increases. As an opposite case to traditional organogels, we report a reverse thermal gelation of methoxy‐aminopoly(ethylene glycol)‐homopolypeptide block‐copolymer chloroform solutions that undergo a sol‐to‐gel transition as the temperature increases. A series of methoxy‐aminopoly(ethylene glycol)‐homopolypeptide block copolymers showing reverse thermal gelation in chloroform was synthesized and we prove that the secondary structure of the polypeptide determines the morphology of the organogel.