Effect of the Molecular Weights of Poly‐L‐Arginine on Membrane Strength and Permeability of Poly‐L‐Arginine Group Microcapsules

A novel poly‐L ‐arginine group microcapsule was produced to investigate its nutritional function and pharmacological efficacy. The molecular weight of poly‐L ‐arginine is an important parameter for its membrane strength, but does not obviously affect its release property. Thus, poly‐L ‐arginine can be used as a kind of new membrane material in microcapsules, and it is expected to be used as an therapeutic and biodegradable drug carrier.

Influence of the molecular weight of poly‐L ‐arginine on membrane thickness.     

Efficient Synthesis of 1,2,3,4,6‐Penta‐O‐acetyl‐L‐idopyranose

An efficient synthesis of 1,2,3,4,6‐penta‐O‐acetyl‐L ‐idopyranose 2 from 3,5‐O‐benzylidene‐1,2‐O‐isopropylidene‐α‐D ‐glucofuranose in five steps in 45% overall yield via hydroboration of enol ether, hydrolysis of L ‐idofuranosyl sugar and acetolysis of 1,6‐anhydro‐β‐L ‐idopyranose as key steps is described here.     

Synthesis of star‐shaped poly(D,L‐lactic acid‐alt‐glycolic acid)‐b‐poly(L‐lactic acid) with the poly(D,L‐lactic acid‐alt‐glycolic acid) macroinitiator and stannous octoate catalyst

Two types of three‐arm and four‐arm, star‐shaped poly(D,L ‐lactic acid‐alt‐glycolic acid)‐b‐poly(L ‐lactic acid) (D,L ‐PLGA50‐b‐PLLA) were successfully synthesized via the sequential ring‐opening polymerization of D,L ‐3‐methylglycolide (MG) and L ‐lactide (L ‐LA) with a multifunctional initiator, such as trimethylolpropane and pentaerythritol, and stannous octoate (SnOct₂) as a catalyst. Star‐shaped, hydroxy‐terminated poly(D,L ‐lactic acid‐alt‐glycolic acid) (D,L ‐PLGA50) obtained from the polymerization of MG was used as a macroinitiator to initiate the block polymerization of L ‐LA with the SnOct₂ catalyst in bulk at 130 °C. For the polymerization of L ‐LA with the three‐arm, star‐shaped D,L ‐PLGA50 macroinitiator (number‐average molecular weight = 6800) and the SnOct₂ catalyst, the molecular weight of the resulting D,L ‐PLGA50‐b‐PLLA polymer linearly increased from 12,600 to 27,400 with the increasing molar ratio (1:1 to 3:1) of L ‐LA to MG, and the molecular weight distribution was rather narrow (weight‐average molecular weight/number‐average molecular weight = 1.09–1.15). The ¹H NMR spectrum of the D,L ‐PLGA50‐b‐PLLA block copolymer showed that the molecular weight and unit composition of the block copolymer were controlled by the molar ratio of L ‐LA to the macroinitiator. The ¹³C NMR spectrum of the block copolymer clearly showed its diblock structures, that is, D,L ‐PLGA50 as the first block and poly(L ‐lactic acid) as the second block. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 40: 409–415, 2002     

New hydrophobic L‐amino acid salts: maleates of L‐leucine,L‐isoleucine and L‐norvaline

Crystals of maleates of three amino acids with hydrophobic side chains [L‐leucenium hydrogen maleate, C₆H₁₄NO₂⁺·C₄H₃O₄⁻, (I), L‐isoleucenium hydrogen maleate hemihydrate, C₆H₁₄NO₂⁺·C₄H₃O₄⁻·0.5H₂O, (II), and L‐norvalinium hydrogen maleate–L‐norvaline (1/1), C₅H₁₁NO₂⁺·C₄H₃O₄⁻·C₅H₁₂NO₂, (III)], were obtained. The new structures contain C₂²(12) chains, or variants thereof, that are a common feature in the crystal structures of amino acid maleates. The L‐leucenium salt is remarkable due to a large number of symmetrically non‐equivalent units (Z′ = 3). The L‐isoleucenium salt is a hydrate despite the fact that L‐isoleucine is a nonpolar hydrophobic amino acid (previously known amino acid maleates formed hydrates only with lysine and histidine, which are polar and hydrophilic). The L‐norvalinium salt provides the first example where the dimeric cation L‐Nva...L‐NvaH⁺ was observed. All three compounds have layered noncentrosymmetric structures. Preliminary tests have shown the presence of the second harmonic generation (SGH) effect for all three compounds.     

pH‐responsive ionic poly(N,N‐diethylaminoethyl methacrylate‐co‐N‐vinyl‐2‐pyrrolidone) hydrogels: Synthesis and swelling properties

A series of an ionic hydrogels composed of N,N‐diethylaminoethyl methacrylamide (DEAEMA), N‐vinyl‐2‐pyrrolidone (VP), and itaconic acid were synthesized by free‐radical cross‐linking copolymerization in water–ethanol mixture by using N,N‐methylenebis(acrylamide) as the cross‐linker, ammonium persulfate as the initiator, and N,N,N′,N′‐tetramethylenediamine as the activator. The swelling behaviors of these hydrogels were analyzed in buffer solutions at various pH. It was observed that the swelling behavior of cross‐linked ionic poly(N,N‐diethylaminoethyl methacrylamide‐co‐N‐vinyl‐2‐pyrrolidone) [P(DEAEMA/VP)] hydrogels at different pH agreed with the modified Flory–Rehner equation based on the affine network model and the ideal Donnan theory. The swelling process in buffer solutions at various pH was found to be Fickian‐type diffusion. The pH‐reversibility and on–off switching properties of the P(DEAEMA/VP) hydrogels may be considered as good candidate to design novel drug‐delivery system. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2819–2828, 2005     

Rapid Ring‐Opening Polymerization of D,L‐Lactide by Microwaves

Summary: Poly(D ,L ‐lactide) with a molar mass of 10⁵ g · mol⁻¹ and a yield over 90% was produced in 10 min by the ring‐opening polymerization of D ,L ‐lactide under microwave irradiation with forward power of 255 W. A degradation of the poly(D ,L ‐lactide) was also induced by microwaves with a power level over 340 W. The molar mass of poly(D ,L ‐lactide) was dependent upon the competition between the polymerization of D ,L ‐lactide and the degradation of the resulting polymer.

Profiles of molar mass versus microwave irradiation time (1.8 g DLLA, 0.1% Sn(Oct)₂).     

三(2,4,6-三甲基苯氧基)稀土配合物引发DL-丙交酯开环聚合特征与机理的研究

Tris(2,4,6-trimethylphenolate) lanthartide [Ln(OTMP)3] has been prepared and employed for ring-opening polymerization of D,L-lactide (LA) as single-component catalysts. The characteristics, kinetics and mechanism were examined. The polymerization is first-order with respect to monomer and initiator concentration, and the overall activation energy amounts to 62.9 kJ/mol. DSC curve disclosed the random structure of PLA. ^1H NMR spectrum analysis demonstrates that the polymerization of LA proceeded through acyl-oxygen bond cleavage.     

Paclitaxel‐Loaded Stabilizer‐Free Poly(D,L‐lactide‐co‐glycolide) Nanoparticles Conjugated with Quantum Dots for Reversion of Anti‐Cancer Drug Resistance and Cancer Cellular Imaging

We prepared the PLGA‐loaded anti‐cancer drug and coated it with quantum dots to make it a dual‐function nanoparticles, and analyzed its potential use in cellular imaging and curing cancers. Two cancer cell lines, paclitaxel‐sensitive KB and paclitaxel‐resistant KB paclitaxel‐50 cervical carcinoma cells, were the relativistic models for analysis of the cytotoxicity of free paclitaxel and paclitaxel‐loaded PLGA conjugated with quantum‐dot nanoparticles. The paclitaxel‐loaded PLGA conjugated with quantum dots nanoparticles were significantly more cytotoxic than the free paclitaxel drug in paclitaxel‐resistant KB paclitaxel‐50 cells. This might have been because the cancer cells developed multi‐drug resistance (MDR), which hampered the action of free paclitaxel by pumping its molecules to extracellular areas. Addition of verapamil, a P‐glycoprotein inhibitor, reversed the MDR mechanism and significantly reduced KB paclitaxel‐50 cell viability. As a result, KB paclitaxel‐50 was highly associated with MDR on the cell membrane. The cytotoxicity results indicated that PLGA nanoparticles served as drug carriers and protected the drugs from MDR‐accelerated efflux. Combined quantum dots with PLGA nanoparticles allowed additional functionality for cellular imaging.     

Synthesis and characterization of poly(vinyl alcohol)‐graft‐[poly(D,L‐lactide)/poly(D,L‐lactide‐co‐glycolide)] hydrogels

Poly(D ,L ‐lactide) and poly(D ,L ‐lactide‐co‐glycolide) with various composition and with one methacrylate and one carboxylate end group were synthesized and grafted onto poly(vinyl alcohol) (PVA) via the carboxylate group. The graft copolymers were crosslinked via the methacrylate groups using a free radical initiator. The polymer networks were characterized by means of NMR and studied qualitatively by means of IR spectroscopy. The influence of the glycolide content in the polyester grafts and of the number of ester units in the grafts on thermal properties and swellability were studied as well. The high swellability in water is characteristic of all hydrogels. Differential scanning calorimetry (DSC) showed a single glass transition temperature that occurs in the range between 51 and 69 °C. Thermogravimetric analysis (TGA) of the networks showed the main loss in weight in the temperature range between 290 and 370 °C. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4536–4544, 2007     

Isocyanide‐Based Three‐Component Synthesis of Highly Substituted 1,6‐Dihydro‐6,6‐dimethylpyrazine‐2,3‐dicarbonitrile, 3,4‐Dihydrobenzo[g]quinoxalin‐2‐amine,and 3,4‐Dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine Derivatives

A novel and efficient isocyanide‐based multicomponent reaction between alkyl or aryl isocyanides 1 , 2,3‐diaminomaleonitrile ( 2 ), naphthalene‐2,3‐diamines ( 6 ) or benzene‐1,2‐diamine ( 9 ), and 3‐oxopentanedioic acid ( 3 ) or Meldrum's acid ( 4 ) or ketones 7 was developed for the ecologic synthesis, at room temperature under mild conditions, of 1,6‐dihydropyrazine‐2,3‐dicarbonitriles 5a – 5f in H₂O without using any catalyst, and of 3,4‐dihydrobenzo[g]quinoxalin‐2‐amine and 3,4‐dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine derivatives 8a – 8g and 10a – 10e , respectively, in the presence of a catalytic amount of p‐toluenesulfonic acid (TsOH) in EtOH, in good to excellent yields (Scheme 1).     

Cancer‐associated pH‐responsive tetracopolymeric micelles composed of poly(ethylene glycol)‐b‐poly(L‐histidine)‐b‐poly(L‐lactic acid)‐b‐poly(ethylene glycol)

To create a novel vector for specifically delivering anticancer therapy to solid tumors, we used diafiltration to synthesize pH‐sensitive polymeric micelles. The micelles, formed from a tetrablock copolymer [poly(ethylene glycol)‐b‐poly(L ‐histidine)‐b‐poly(L ‐lactic acid)‐b‐poly(ethylene glycol)] consisted of a hydrophobic poly(L ‐histidine) (polyHis) and poly(L ‐lactic acid) (PLA) core and a hydrophilic poly(ethylene glycol) (PEG) shell, in which we encapsulated the model anticancer drug doxorubicin (DOX). The robust micelles exhibited a critical micellar concentration (CMC) of 2.1–3.5 µg/ml and an average size of 65–80 nm pH 7.4. Importantly, they showed a pH‐dependent micellar destabilization, due to the concurrent ionization of the polyHis and the rigidity of the PLA in the micellar core. In particular, the molecular weight of PLA block affected the ionization of the micellar core. Depending on the molecular weight of the PLA block, the micelles triggering released DOX at pH 6.8 (i.e. cancer acidic pH) or pH 6.4 (i.e. endosomal pH), making this system a useful tool for specifically treating solid cancers or delivering cytoplasmic cargo in vivo. Copyright © 2008 John Wiley & Sons, Ltd.     

Micelles formed by self‐assembling of low molecular weight phosphorylcholine‐containing poly(L‐lactide)

Phosphorylcholine‐containing poly(L‐lactide) (PLLA‐PC) was synthesized by ring‐opening polymerization of L‐lactide in the presence of glycerophosphorylcholine originated from egg lecithin. Self‐assembling micelles were then obtained by film hydration, ultrasonication and stirring. Transmission electron microscopy and confocal laser scanning microscopy confirmed the micellar structure with hydrophobic core and hydrophilic shell. The critical micellar concentration (CMC) value of PLLA‐PC was only 1/50 that of naturally occurring PC, in agreement with a better surfactant property of the former. Dynamic light scattering showed that the size and size distribution of micelles varied with dilution, but the CMC was independent of the concentration of NaCl solution within 0.9 wt%, indicating that the micelles could be stable upon intravenous injection. In addition, the micelle solution could be stored at 4 °C over 30 days without any noticeable changes, whereas at 37 °C, the size, size distribution and the number of micelles decreased over time due to degradation. The solubility of clofazimine, a highly hydrophobic drug, was found to be 11.9 µg/ml in the PLLA‐PC micellar solution, which was 40 times that in pure water. This preliminary study suggests that PLLA‐PC micelles present a great potential as delivery system for hydrophobic drugs. Copyright © 2011 John Wiley & Sons, Ltd.     

A Convenient Synthesis of 2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridin‐4‐ones by the Reaction of the Corresponding 1‐(Chloropyridinyl)alk‐2‐en‐1‐ones with NaSH

2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]pyridin‐4‐ones 4 were prepared by a three‐step sequence from commercially available 2‐chloropyridine ( 1 ). Thus, successive treatment of 1 with ⁱPr₂NLi (LDA) and α,β‐unsaturated aldehydes gave 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ols 2 , which were oxidized with MnO₂ to 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ones 3 . The reactions of 3 with NaSH?n H₂O proceeded smoothly at 0° in DMF to provide the desired thiopyranopyridinones. Similarly, 2,3‐dihydro‐4H‐thiopyrano[2,3‐c]pyridin‐4‐ones 8 and 2,3‐dihydro‐4H‐thiopyrano[3,2‐c]pyridin‐4‐ones 12 were obtained starting from 3‐chloropyridine ( 5 ) and 4‐chloropyridine ( 9 ), respectively.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

One‐Pot Synthesis of 3‐Alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones by the Reactions of 2‐(Azidomethyl)benzoates with NaH

A new and facile method for the general preparation of 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones has been developed. Thus, the reaction of 2‐(azidomethyl)benzoates with NaH affords, after workup with H₂O, 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones 2 . 2‐Substituted 3‐alkoxy‐2,3‐dihydro‐1H‐isoindol‐1‐ones 4 can be obtained by adding alkyl halides prior to workup with H₂O.     

Synthesis of 4‐Aryl‐8‐fluoro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolines and Their Ozonides

4‐Aryl‐8‐fluoro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolines are synthesized by acid‐catalyzed (CF₃CO₂H) three‐component cyclocondensation of 4‐fluoroaniline with aromatic aldehydes and cyclopentadiene. Stable ozonides with (1R*,4S*,5aR*,6S*,11bS*)‐configurations are obtained by ozonolysis of corresponding trifluoroacetyl derivatives.     

Resilient Amorphous Networks Prepared by Photo‐Crosslinking High‐Molecular‐Weight D,L‐Lactide and Trimethylene Carbonate Macromers: Mechanical Properties and Shape‐Memory Behavior

Tough networks are prepared by photo‐crosslinking high‐molecular‐weight DLLA and TMC macromers. These amorphous networks exhibit tunable thermal and mechanical properties and have excellent shape‐memory features. Variation of the monomer ratio allows adjustment of T_g between approximately ?13 and +51 °C. The elastic moduli at room temperature can be varied between 4.5 and 2730 MPa. The crosslinks allow the networks to return to their original shape after deformation. 60:40 DLLA:TMC networks have T_g values between room temperature and body temperature, with mechanical properties at body temperature close to soft tissues. Several medical devices are prepared from these networks.

     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.