Folic Acid Modified Polymeric Micelles for Intravesical Instilled Chemotherapy

In this study,a targeting micellar drug delivery system was developed for intravesical instilled chemotherapy of bladder cancer.The amphiphilic diblock copolymer poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEO) with functional amino group (NH2) at the end of PEO block was synthesized.Then the copolymer was conjugated with folic acid (FA) and fluorescein isothiocyannate (FITC) via the PEO-NH2 terminus,and then assembled into micelles with the target moiety and fluorescence labeling.In addition,drug loaded micelles were also fabricated with anticancer drug doxorubicin (DOX) encapsulated in the hydrophobic core.The micelles were characterized in terms of size,drug loaded efficiency and critical micellization concentration (CMC) by means ofDLS,UV and fluorescence spectra.In vitro cellular uptake and cytotoxicity studies showed that FA modified PCL-b-PEO-FA micelles have a greater targeting efficiency to human bladder cancer cell (T-24 cell) compared to PCL-b-PEO-NH2 micelles due to the conjugation of FA on the surface,while no targeting effect to normal tissue originated human embryonic kidney 293 (HEK-293) cells was observed,enabling the micelles a promising drug carrier for intravesical instilled chemotherapy of bladder cancer.     

Biodegradable amphiphilic block copolymers containing functionalized PEO blocks:Controlled synthesis and biomedical potentials

A series of controllable amphiphilic block copolymers composed of poly(ethylene oxide)(PEO) as the hydrophilic block and poly(ε-caprolactone)(PCL) as the hydrophobic block with the amino terminal group at the end of the PEO chain(PCL-b-PEO-NH2) were synthesized.Based on the further reaction of reactive amino groups,diblock copolymers with functional carboxyl groups(PCL-b-PEO-COOH) and functional compounds RGD(PCL-b-PEO-RGD) as well as the triblock copolymers with thermosensitive PNIPAAm blocks(PCL-b-PEO-b-P...     

A dual ligand targeted nanoprobe with high MRI sensitivity for diagnosis of breast cancer

Antibody targeted delivery is an effective strategy to improve the diagnostic imaging outcome of nanoscale imaging agents in the focal areas.Dual targeting micelles encapsulating superparamagnetic iron oxide were prepared from the amphiphilic block copolymer poly(ethylene glycol)-poly(ε-caprolactone)(PEG-b-PCL) with different targeting ligands cRGD and scFv-ErbB single chain antibody conjugated to the distal ends of PEG block.The breast cancer animal model was established by subcutaneous injecting the BT474 cells into the BALB/c-nu female nude mice and then employed to assess the potential of the dual ligand targeted magnetic micelles as a novel MRI contrast agent on a 1.5 T clinical MRI scanner.The T2 signal intensity of the tumor in animals receiving the dual ligand targeted magnetic micelles via tail vein decreased more significantly than the single ligand targeted and nontargeted magnetic micelles.These results indicate that the dual ligand targeted magnetic micelles,cRGD/scFv-ErbB-PEG-PCL-SPION,have great potential to act as a new type of effective nanoscale MRI contrast agent for early diagnosis of breast cancer.     

Novel thermogelling poly(ε-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lactide) aqueous solutions

The aqueous solutions of poly(e-caprolactone-co-lactide)-poly(ethylene glycol)poly(e-caprolactone-co-lactide) undergoing sol-gel transition as the temperature increases from 20 to 50℃were successfully prepared. The thermogelling triblock copolymers were synthesized by subtle tuning of the chemical composition and the hydrophilicity/hydrophobicity balance. The sol-gel transition was studied focusing on structure-property relationship. The amphiphilic copolymer formed micelles in aqueous solutions. It is believed to have potential applications in drug delivery and tissue engineering.     

IMMOBILIZATION OF POTENTIALLY BIOACTIVE MOIETIES ONTO POLYETHER WITH POLY(ETHYLENE GLYCOL)-SULFONATE SPACER

A new reactive graft copolymer, poly(tetramthylene glycol) - graft-w-propyl sodiumsulfonate-poly(ethylene glycol) (PTMG-g-PEG-CH_2CH_2CH_2SO_3~-Na~+), was synthesizedby the cationic polymerization of a-w-bifunctional PEG macromonomer (O?CH_2—PEG——CH_2 CH_2 CH_2 SO_3 Na) and THF. The obtained copolymer exhibits the expected structureas indicated by the result of characterization. Two amino acids (L-arginine, L-tyrosine)were covalently attached to the copolymer after converting the sulfonate group to sulfonylchloride. So the new reactive graft copolymer (PTMG-g-PEG-CH_2CH_2CH_2SO_3~-Na~+) isexpected to be very useful in attachment of potentially bioactive moieties to polymer viaa hydrophilic PEG spacer.     

Block Copolymer Networks Composed of Poly(ε-caprolactone) and Polyethylene with Triple Shape Memory Properties

In this contribution, we reported a novel synthesis of block copolymer networks composed of poly(ε-caprolactone)(PCL) and polyethylene(PE) via the co-hydrolysis and condensation of α,ω-ditriethoxylsilane-terminated PCL and PE telechelics. First, α,ω-dihydroxylterminated PCL and PE telechelics were synthesized via the ring-opening polymerization of ε-caprolactone and the ring-opening metathesis polymerization of cyclooctene followed by hydrogenation of polycyclooctene. Both α,ω-ditriethoxylsilane-terminated PCL and PE telechelics were obtained via in situ reaction of α,ω-dihydroxyl-terminated PCL and PE telechelics with 3-isocyanatopropyltriethoxysilane. The formation of networks was evidenced by the solubility and rheological tests. It was found that the block copolymer networks were microphase-separated. The PCL and PE blocks still preserved the crystallinity. Owing to the formation of crosslinked networks, the materials displayed shape memory properties. More importantly, the combination of PCL with PE resulted that the block copolymer networks had the triple shape memory properties, which can be triggered with the melting and crystallization of PCL and PE blocks. The results reported in this work demonstrated that triple shape memory polymers could be prepared via the formation of block copolymer networks.     

TRANSESTERIFICATION OF POLY(ETHYLENE TEREPHTHALATE) WITH POLY(ε-CAPROLACTONE)*

Transesterification of poly(ethylene terephthalate) (PET) with poly(ε-caprolactone) (PCL) was investigated bymeans of NMR spectroscopy, extraction experiments, differential scanning calorimetry (DSC) and phase contrast microscopy(PCM). The ~1H-NMR results show that transesterification takes place in the melt blends and leads to the formation of thePET-PCL copolyester with a chemical structure similar to ethylene terephthalate-ε-caprolactonc copolycster (TCL)synthesized directly from monomers. However, even in the blend that has been transesterified for 8 h, the random PET-PCLcopolyester, PET-PCL copolyester with long PET or long PCL segments and the unreacted PET and PCL homopolymersmay coexist. Due to the low mobility of PET and PCL chains and the high viscosity of the two macromolecules, thetransesterification proceeds with difficulty. Furthermore, PET is incompatible with PCL, the transesterification can onlyoccur at the interface or in the interfacial region between two phases, and finally the reaction can only reach a localequilibrium. These results indicate that in fact the transesterification in the melt blend between two incompatiblehomopolymers could not lead to the formation of completely random or typical block copolyesters.     

SYNTHESIS OF NOVEL BLOCK COPOLYMERS OF POLY(3-HYDROXYBUTYRIC ACID)WITH POLY(ETHYLENE GLYCOL)THROUGH ANIONIC POLYMERISATION

A novel kind of copolymer with ABA-type block structure was synthesized by anionic ring-openingpolymerization of β-butyrolactone (β-BL) in the presence of a PEG-based dicarboxylates as macroinitiators which wereprepared by the esterification of aliphatic cyclic anhydride and poly(ethylene glycol) (PEG) oligomers (M_n=2000, 4000 and6000) and conversion of potassium dicarboxylates. The resultant copolymers as well as the intermediates were characterizedby IR,~1H-NMR and GPC.     

SYNTHESIS OF POLY(ETHYLENE TEREPHTHALATE)-POLYCAPROLACTONE BLOCK COPOLYMER BY DIRECT COPOLYMERIZATION*

Poly(ethylene terephthalate) -polycaprolactone block copolymer (PCL- b-PET) is a polyester withimproved biodegradability. In the present paper, a new direct copolymerization method of ε-caprolactone (ε-CL) and bishydroxyethylene terephthalate (BHET) in the presence of Ti(OBu)_4 was proposed for thesynthesis of PCL-b-PET. The PCL-b-PET copolymer was characterized by IR, GPC and ~1H-NMRtechniques, and the effects of synthesis conditions, such as temperature, reaction time and concentration ofcatalyst on the copolymerization were discussed.     

Effect of surface charge of polymeric micelles on in vitro cellular uptake

This work focuses on the interaction between polymeric micelles with different charged surfaces and cancer cells in order to study the influence of surface charge on the in vitro cellular uptake efficiency. The amphiphilic diblock copolymers poly(ε-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) with different functional groups at the end of hydrophilic block were synthesized. The functional groups endue the micelles with different charges on the surfaces. The cellular uptake of micelles to T-24 cells (human bladder tumor cells), HepG2 cells (human liver hepatocellular carcinoma cell line) and Hela cells (human epithelial cervical cancer cells) was studied by means of flow cytometer and confocal laser scanning microscopy. The results indicate that the surface charges showed great influence on zeta potential of micelles at different pH values. The in vitro cellular uptake efficiency of micelles with different charged surfaces demonstrated different cellular uptake patterns to three kinds of cancer cells.     

Synthesis and characterization of a novel amphiphilic biodegradable β-cyclodextrin/poly(γ-benzyl L-glutamate) copolymer

β-Cyclodextrin/poly(γ-benzyl L-glutamate) (β-CD-PBLG) copolymers were synthesized by ring-opening polymerization of N-carboxy-γ-benzyl L-glutamate anhydride (BLG-NCA) in N,N-dimethylformamide (DMF) initiated by mono-amino-β-cyclodex-trin(H2N-β-CD). The structures of the copolymers were confirmed by IR, 1H NMR and GPC. The fluorescence technique was used to determine the critical micelle concentrations (CMC) of copolymer miceU solution, the diameter and the distribution of micelles were characterized by DLS. The results showed that BLG-NCA could be initiated by H2N-β-CD to produce copolymer. The nano-micells were formed by these copolymers in water.     

Pegylated single-walled carbon nanotubes with gelable block copolymers

Functional amphiphilic block copolymer poly（ethylene glycol）-block-poly[（3-（triethoxysilyl）propyl methacrylate）-co -（1-pyrene-methyl） methacrylate],PEG₁₁₃-b-P(TEPM₂₆-co-PyMMA₄),was synthesized via atom transfer radical polymerization（ATRP） initiated by monomethoxy capped poly（ethylene glycol） bromoisobutyratc.This polymer exhibited strong ability to disperse and exfoliate single-walled carbon nanotubes（SWNTs） in different solvents due to the adhesion of pyrene units to surface of SWNTs.In aqueous solution,the PTEPM segments that were located on the nanotube surfaces with the pyrene units could be gelated and,as a result,the silica oxide networks with PEG coronas were formed on the surface of nanotubes,which ensured the composites with a good dispersibility and stability.Furthermore,functional silane coupling agents,3-mercaptopropyltrimethoxysilane and 3-aminopropyltriethoxysilanc,were introduced during dispersion of SWNTs using the block copolymers.They were co-gelated with PTEPM segments,and the-SH and-NH₂ functionalities were introduced into the silica oxide coats respectively.     

SYNTHESIS OF AN AMPHIPHILIC PPESK-g-P(PEGMA) GRAFT COPOLYMER VIA ATRP AND ITS USE IN BLEND MODIFICATION OF PPESK MEMBRANES

Preparation of an amphiphilic graft copolymer having poly(phthalazinone ether sulfone ketone)(PPESK) as main chains was carried out by atom transfer radical polymerization(ATRP).The precursor,chloromethylated PPESK (CMPPESK),was prepared by using chioromethylether as chloromethylation agent.Then,poly(ethylene glycol) methyl ether methacrylate(PEGMA) was used as monomer to synthesize PPESK-g-P(PEGMA) by ATRP method under the catalysis of a cuprous chloride/2,2'-bipyridyl system.PPESK/PPESK-g-P(PEGMA) blen...     

Controlled Self-assembly of Thermo-responsive Amphiphilic H-shaped Polymer for Adjustable Drug Release

Despite the fact that some progress has been made in the self-assembly of H-shaped polymers,the corresponding self-assemblies that respond to external stimulus and are further utilized to adjust the release of drugs are still deficient.The stimuli-responsive segments with amphiphilic H-shaped structure are generally expected to enhance the controllability of self-assembly process.The synthesis and self-assembly behavior of thermo-responsive amphiphilic H-shaped polymers with poly(ethylene glycol) (PEG),polytetrahydrofuran (PTHF) and poly(N-isopropyl acrylamide) (PNIPAM) as building blocks are reported in this paper.The inner architecture structure and size of complex micelles formed by H-shaped self-assemblies were effectively adjusted when the solution temperature was increased above the lower critical solution temperature of PNIPAM segments.Furthermore,it was found that the architecture of self-assemblies underwent a transition from the complex micelles based on primary micelles with hybrid PEG/PNIPAM shells to large complex micelles based on primary micelles with hybrid PTHF/PNIPAM cores and PEG shells during the thermal-induced self-assembly process.The adjustable release rate of doxorubicin (DOX) from the DOX-loaded complex micelles and basic cell experiments further proved the feasibility of these self-assemblies as the thermal-responsive drug delivery system.     

Synthesis and Characterization of ABBA Block Copolymer of Glycolide and ε-Caprolactone

A biodegradable ABBA block copolymer was synthesized via the ring-opening co-polymerization of ε-Scaprolactone (CL, B) and glycolide (A) by means of step polymerization in the presence of ethylene glycol as an initiator and stannous octanoate as a catalyst at 110 ℃ for 48 h. The molecular length of the PCL prepolymer(BB) could be adjusted by controlling the molar ratio of the ethylene glycol initiator to ε-caprolactone monomer. The structure and the composition of the block copolymer were determined by the weight ratio of the monomer glycolide (A) to PCL pre-polymer(BB). The block copolymers were characterized by ^1H NMR, GPC, DSC and X-ray. The results confirm the successful synthesis of an ABBA block copolymer.     

Thermosensitive polyion complex micelles prepared by self-assembly of two oppositely charged diblock copolymers

Polyion complex (PIC) micelles were spontaneously formed in aqueous solutions through electrostatic interaction between two oppositely charged block copolymers, poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) and poly(N-isopropylacrylamide)-b-poly(L-lysine). Their controlled synthesis was achieved via the ring opening polymerization of N-carboxyanhydrides (NCA), ε-benzyloxycarbonyl-L-lysine (Lys(Z)-NCA) or γ-benzyl-L-glutamate (BLG-NCA) with amino-terminated poly(N-isopropylacrylamide) macroinitiator and the subsequent deprotection reaction. The formation of PIC micelles was confirmed by dynamic light scattering and transmission electron microscopy. Turbidimetric characterization suggested that the formed PIC micelles had a concentration-dependent thermosensitivity and their phase transition behaviors could be easily adjusted either by the block length of coplymers or the concentration of micelles.     

Temperature and pH Dually-responsive Poly(β-amino ester) Nanoparticles for Drug Delivery

Stimuli-responsive polymers have undoubtedly been of great interest in the past decades due to a variety of their potential applications in biomedical territory. However, their non-degradability limits their in vivo applications. Herein, we report a novel pH and temperature dual-stimuli responsive-poly(β-amino ester). The pH/temperature sensitivities are interrelated and can be easily tuned by changing PEG-diacrylate chain length and the percentage of biamines in the feed ratio. These dual-responsive polymers are very useful in drug delivery. Reaction of methyl ether poly(ethylene glycol)(MPEG) and poly(β-amino ester) resulted in an amphiphilic MPEG-PBAE block copolymer which could form nanoparticles by selfassembly. A hydrophobic drug(DOX) was loaded in the self-assembled nanoparticles at low temperature without using organic solvents. The loaded drug was released very slowly and steadily at 37 ℃ under physiological conditions(p H 7.4), but rapidly released from the micelles in weakly acidic environments(pH 6.4 and 5.0) for intracellular drug release. Thus, these poly(β-amino ester) polymers constitute ideal drug carriers since their thermal sensitivity allows the drug loadings without using organic solvent and their pH sensitivity permits fast intracellular drug release.     

Drug and plasmid DNA co-delivery nanocarriers based on abctype polypeptide hybrid miktoarm star copolymers

We report on the fabrication of self-assembled micelles from ABC-type miktoarm star polypeptide hybrid copolymers consisting of poly(ethylene oxide), poly(L-lysine), and poly(ε-caprolactone) arms, PEO(-b-PLL)-b-PCL, and their functional applications as co-delivery nanocarriers of chemotherapeutic drugs and plasmid DNA. Miktoarm star copolymer precursors, PEO(-b-PZLL)-b-PCL, were synthesized at first via the combination of consecutive "click" reactions and ring-opening polymerizations (ROP), where PZLL is poly(ε-benzyloxycarbonyl-L-lysine). Subsequently, the deprotection of PZLL arm afforded amphiphilic miktoarm star copolymers, PEO(-b-PLL)-b-PCL. In aqueous media at pH 7.4, PEO(-b-PLL)-b-PCL self-assembles into micelles consisting of PCL cores and hydrophilic PEO/PLL hybrid coronas. The hydrophobic micellar cores can effectively encapsulate model hydrophobic anticancer drug, paclitaxel; whereas positively charged PLL arms within mixed micellar corona are capable of forming electrostatic polyplexes with negatively charged plasmid DNA (pDNA) at N/P ratios higher than ca. 2. Thus, PEO(-b-PLL)-b-PCL micelles can act as co-delivery nanovehicles for both chemotherapeutic drugs and genes. Furthermore, polyplexes of pDNA with paclitaxel-loaded PEO(-b-PLL)-b-PCL micelles exhibited improved transfection efficiency compared to that of pDNA/blank micelles. We expect that the reported strategy of varying chain topologies for the fabrication of co-delivery polymeric nanocarriers can be further applied to integrate with other advantageous functions such as targeting, imaging, and diagnostics.     

Synthesis and characterization of biodegradable amphiphilic PEG-grafted poly(DTC-co-CL)

<正>A novel biodegradable copolymer,poly(5,5-dibromomethyltrimethylene carbonate-co-ε-caprolactone)(poly(DBTC-co-CL)) with pendant bromine groups,was synthesized via ring-opening polymerization(ROP) ofε-caprolactone(CL) and 5,5- dibromomethyltrimethylene carbonate(DBTC) using stannous octoate(Sn(Oct)_2) as catalyst.Then the pendant bromine groups were completely converted into azide form,which permitted"click"reaction with alkyne-terminated polyethylene(A-PEG) by Huisgen 1,3-dipolar cycloadditions preparing biodegradable amphiphilic poly(DTC-co-CL)-g-PEG graft copolymer.The graft copolymer was characterized by nuclear magnetic resonance(NMR) and size-exclusion chromatography(SEC).     

Studies on Isosorbide-enhanced Biodegradable Poly(ethylene succinate)

To improve the mechanical properties of bio-based poly(ethylene succinate),the sugar monomer isosorbide,whicli is relatively easy to obtain,was used as a copolymerized third monomer to synthesize poly(ethyleneco-isosorbide succinate),a 100%biomass copolyester.The effects of isosorbide on the crystallinity and thermal properties of copolyester were studied by nuclear magnetic resonancefH NMR),differential scanning calorimeter(DSC),and thermogravimetric(TG).Owing to its distinct rigid bicyclic structure,isosorbide can improve the glass transition temperature of the copolyester and decrease the crystallization rate,as well as accelerate the hydrolysis of the copolyester.Simultaneously,the introduction of isosorbide can effectively improve the antistatic properties of copolyester.