PEGylated Polyurea Bearing Hindered Urea Bond for Drug Delivery
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In recent years, polyureas with dynamic hindered urea bonds (HUBs), as a class of promising biomedical polymers, have attracted attention as a benefit of their controlled hydrolytic property. The effect of the chemical structures on the properties of polyureas and their assemblies was rarely reported. In this study, four kinds of polyureas with different chemical groups have been synthesized, and the polyurea from cyclohexyl diisocyanate and tert-butyl diamine showed the fastest hydrolytic rate. The amphiphilic polyurea composed of hydrophobic cyclohexyl-tert-butyl polyurea and hydrophilic poly(ethylene glycol) was synthesized for controlled delivery of antitumor drug paclitaxel (PTX). The PTX-loaded PEGylated polyurea micelle more effectively entered into the murine breast cancer 4T1 cells and inhibited the corresponding tumor growth in vitro and in vivo. Therefore, the PEGylated polyurea with adjustable degradation might be a promising polymer matrix for drug delivery.Keywords:
Polyurea
Amphiphilic poly(L-aspartate)-b-poly(ethylene glycol) block copolymers were synthesized and immobilized on polyhedral oligomeric silsesquioxanes (POSS) to obtain star shaped copolymers. 1-(3-Aminopropyl) imidazole was conjugated to the pendant groups of poly(L-aspartate) segments to fabricate pH-sensitive micelles. The anticancer drug doxorubicin (DOX) was trapped in the micelles to investigate the effects of side groups on the drug release behaviors. The mean diameters of DOX loaded micelles were around 50–60 nm, which were much smaller than those of blank micelles (100–200 nm). Both the drug loading content and encapsulation efficiency of the micelles decreased with the sequence of the side group substitution of carboxyl, benzyl and imidazole. The release of DOX loaded micelles with imidazole groups was pH-dependent, and more than 90% of the loaded DOX could be released within 48 hours in a weak acidic medium (pH 5.0). The flow cytometry and confocal laser scanning microscopy results revealed that the pH-sensitive micelles exhibited better anticancer activity.
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Abstract The synthesis of a new cyclic carbonate monomer containing an allyl group was reported and its biodegradable amphiphilic block copolymer, poly(ethylene glycol)‐ block ‐poly( L ‐lactide‐ co ‐5‐methyl‐5‐allyloxycarbonyl‐propylene carbonate) [PEG‐ b ‐P(LA‐ co ‐MAC)] was synthesized by ring‐opening polymerization (ROP) of L ‐lactide (LA) and 5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxan‐2‐one (MAC) in the presence of poly (ethylene glycol) as a macroinitiator, with diethyl zinc as a catalyst. 13 C NMR and 1 H NMR were used for microstructure identification of the copolymers. The copolymer could form micelles in aqueous solution. The core of the micelles is built of the hydrophobic P(LA‐ co ‐MAC) chains, whereas the shell is set up by the hydrophilic PEG blocks. The micelles exhibited a homogeneous spherical morphology and unimodal size distribution. By using the cyclic carbonate monomer containing allyl side‐groups, crosslinking of the PEG‐ b ‐P(LA‐ co ‐MAC) inner core was possible. The adhesion and spreading of ECV‐304 cells on the copolymer were better than that on PLA films. Therefore, this biodegradable amphiphilic block copolymer is expected to be used as a biomaterial for drug delivery and tissue engineering. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5518–5528, 2007
Trimethylene carbonate
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Raft
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Abstract Amphiphilic block copolyphosphates (PEP ‐b‐ PIPPs) are synthesized by two‐step ROP of cyclic phosphate monomers with different pedant groups. They can spontaneously self‐assemble into approximately spherical micelles ranging in size between 89 and 198 nm in water. A typical hydrophobic anti‐cancer drug DOX is encapsulated into the micelles. The release rate of DOX slows down with increasing hydrophobic block length of PIPP. DOX‐loaded micelles are investigated for the proliferation inhibition of Hela cells and the DOX dose required for 50% cellular growth inhibition is found to be 0.8 µg mL −1 . It is demonstrated that PEP ‐b‐ PIPP micelles can be used as a safe and promising drug delivery system. magnified image
HeLa
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Formation of amphiphilic poly(ethylene glycol)-b-polylactide (PEG/PLA) block copolymers was accomplished by using potassium alkoxides to initiate the anionic polymerization of ethylene oxide, with the living chain end initiating the polymerization of lactide. By using potassium 3,3-diethoxypropoxide as an initiator, block copolymers with an acetal moiety at the PEG chain end, which was later converted into an aldehyde group, were obtained. The amphiphilic block copolymers formed micelles in aqueous milieu. The conversion of acetal end groups to aldehyde groups was carried out by an acid treatment using 0.01 mol L-1 hydrochloric acid. The extent of the conversion attained was >90%, without any side reaction such as aldol condensation. The micellar structure may play an important role in preventing a possible aldol condensation between the neighboring two aldehyde groups at the PEG chain end. From dynamic light scattering measurements, no angular dependence of the scaled characteristic line width was observed in the case of the acetal-PEG/PLA(52/56) micelle, suggesting the spherical structure. The diameter and polydispersity factor of the polymeric micelle were influenced by the molecular weights and the composition of two components of the block copolymer. The block copolymer with the molecular weight of 5200 for PEG and 5600 for PLA was a most suitable balance for micelle formation with narrow distribution. Actually, the diameter and polydispersity factor (μ/Γ2) of acetal-PEG/PLA(52/56), determined by a cumulative method, were 33 nm and 0.03, respectively. No change in the micelle size and shape was observed before and after the conversion of the acetal end groups to aldehyde groups on the micelle. The critical micelle concentrations (cmc) of the polymeric micelle was 2−4 mg L-1, as determined by fluorescence spectroscopy using pyrene. This functionalized micelle, in particular the one carrying terminal aldehyde groups, is expected to have a wide utility not only in biomedical applications (e.g., drug delivery, diagnosis, and surface modification through the coupling of bioactive substances), but also for the construction of the supramolecular architecture.
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Here we report, for the first time to our knowledge, a method to synthesize AB2 monomers, the corresponding hyperbranched and the corresponding amphiphilic hyperbranched polymers in a one-pot procedure, starting from two commercial available compounds. Since the B groups were blocked isocyanates (BIs), the end groups of the hyperbranched polyurea were BIs as well. Coupling of a range of monomethoxy-poly(ethylene glycol)s onto the BIs yielded a platform of amphiphilic hyperbranched polymers, with controllable hydrophobic cores and hydrophilic shells. After the three consecutive reaction steps, without intermediate purification, the final polymers were purified by precipitation in a nonsolvent, in which the polymer precipitated and the excess PEG remained dissolved. Pyrene inclusion experiments showed the formation of micelles above a critical concentration. Both cryo-EM and DLS revealed the presence of two distinct particle populations, being the primary micelles and aggregates thereof. All micelles showed a LCST behavior, with transitions close to body temperature. The low cytotoxicity of the micelles make them promising for drug delivery.
Polyurea
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The hydrolysis of p-nitrophenyl acetate at pH 8 and 25°C is demonstrated to be a good test reaction to study the influence of the structure of several long-chain derivatives of urocanic acid on the imidazole ring reactivity in organized media. Cetyltrimethylammonium bromide micelles including (E)-dodecyl urocanate gave an approximately 7-fold rate enhancement over (Z)-dodecyl urocanate, 30-fold over (E)-urocanic acid and 4790-fold over CTABr. The behavior of (E)-dodecyl urocanate in the presence of excess substrate was also been investigated. The value of kobs decreased by 37% as the substrate:catalyst ratio was increased from 1:10 to 10:1. Under the same conditions, the total activity was restored when one equivalent of chloral was added to one equivalent of (E)-dodecyl urocanate. Chloral significantly enhanced the deacylation rate of N-acetyl dodecyl urocanate, giving a good reaction turnover.
Imidazole
Urocanic acid
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Three biodegradable amphiphilic triblock copolymers: polylactide-poly (ethylene glycol)-polylactide (PLA-PEG-PLA), poly ( ε -caprolactone)-poly (ethylene glycol)-poly ( ε -caprolactone) (PCL-PEG-PCL) and poly (lactide-glycolide)-poly (ethylene glycol)-poly (lactide-glycolide) (PLGA-PEG-PLGA) were synthesized. Their chemical structures were characterized. In aqueous solution, their self-assembly and degradation were studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Spherical micelles were formed in aqueous solution via self-assembly of the amphiphilic triblock copolymers. After degradation, the PLA-PEG-PLA and PCL-PEG-PCL micelles became smaller and the PLGA-PEG-PLGA micelles change to vesicles, which should mainly attribute to their different degradation speed.
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Comb-like polymers with biocompatible oxyethylene backbones and amphiphilic side groups were synthesized via polymer-analogous reactions. Using these polymers, indomethacin-loaded polymeric micelles were fabricated with various drug-to-polymer weight ratios using the oil-in-water emulsion technique. In addition, the size, size distribution, CMC, drug-loading content, and entrapment efficiency of the polymeric micelles were analyzed. The volume-weighted diameters of polymeric micelles ranged from 10 to 140 nm and were narrowly distributed for passive targeting drug delivery. The CMCs were lower (approximately 10(-8) M) than for conventional surfactants and block copolymers.
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