Synthesis and characterization of biodegradable amphiphilic ABC Y‐shaped miktoarm terpolymer by click chemistry for drug delivery

Biodegradable amphiphilic ABC Y‐shaped triblock copolymer (MPBC) containing PEG, PBLA, and PCL segments was synthesized via the combination of enzymatic ring‐opening polymerization (ROP) of epsilon‐caprolactone, ROP of BLA‐N‐carboxyanhydride and click chemistry, where PEG, PBLA, and PCL are poly(ethylene glycol), poly(benzyl‐l ‐aspartate), and polycaprolactone, respectively. Propynylamine was employed as ROP initiator for the preparation of alkynyl‐terminated PBLA and methyloxy‐PEG with hydroxyl and azide groups at the chain‐end was used as enzymatic ROP initiator for synthesis of monoazido‐midfunctionalized block copolymer mPEG‐b‐PCL. The subsequent click reaction led to the formation of Y‐shaped asymmetric heteroarm terpolymer MPBC. The polymer structures were characterized by different analyses. The MPBC terpolymer self‐assembled into micelles and physically encapsulated drug doxorubicin (DOX) to form DOX‐loaded micelles, which showed good stability and slow drug release. In vitro cytotoxicity study indicated that the MPBC micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3346–3355     

In situ micro-sized gel-forming injectable implant using biodegradable amphiphilic graft copolymer

A synthesized graft polymer is used as a biodegradable polymer for an in situ gel-forming injectable implant system. The amphiphilic character of the polymer in the graft structure lowered the viscosity of the polymer solution, which enabled easy injection. A micro-sized gel can be obtained with this system, which has not been found for previous in situ gel-forming systems with poly[(D,L-lactide)-co-glycolide] copolymer. In addition, a protein particle embedded gel exhibits good in vitro drug release performance as a result of the enhanced stability and shorter diffusion length.     

Thermoresponsive,Hydrolytically Degradable Polymer Micelles Intended for Radionuclide Delivery

Novel polymer micelles, prepared by self‐assembling thermoresponsive poly(N‐isopropylacrylamide)‐graft‐poly[N‐(2‐hydroxypropyl)methacrylamide] copolymers with hydrolytically degradable N‐glycosylamine groups between the polymer blocks are proposed for delivery of diagnostic and therapeutic radionuclides into solid tumors. The micelles are formed by fast heating of an aqueous solution of the copolymer to 37 °C. They have a hydrodynamic diameter of 128 nm (measured using dynamic light scattering) and slowly degrade during incubation in aqueous buffer at pH = 7.4. Labeling with both ¹³¹I and ⁹⁰Y proceeds with high yields (>85%). The unlabeled polymers are not cytotoxic for any of the tested murine and human cell lines.

     

Hydrogels for potential colon drug release by thiol-ene conjugate addition of a new inulin derivative

Inulin was chosen as a starting polymer for biocompatible, pH-sensitive and biodegradable hydrogels. Three INUDVSA-TT hydrogels were obtained by crosslinking inulin derivatives with trimethylolpropane tris(3-mercaptopropionate) under varying conditions. The resulting hydrogels were cell compatible, as demonstrated by MTS and trypan blue exclusion assays acting on Caco-2 cells, and were biodegraded by inulinase and esterase, thus suggesting their use as colonic drug delivery systems. 2-Methoxyestradiol, an anti-cancer drug, was soaked in INUDVSA-TT hydrogels and its in vitro release and apoptotic effect on Caco-2 cells were evaluated.     

Facile Synthesis of Multicompartment Micelles Based on Biocompatible Poly(3‐hydroxyalkanoate)

In this paper, a straightforward method to produce poly(3‐hydroxyalkanoate)‐based multicompartment micelles (MCMs) is presented. Thiol‐ene addition is used to graft sequentially perfluorooctyl chains and poly(ethylene glycol) oligomers onto poly(3‐hydroxyoctanoate‐co‐hydroxyundecenoate) oligomers backbone. Well‐defined copolymers are obtained as shown by ¹H NMR and size‐exclusion chromatography. After nanoprecipitation in water, novel PHA‐based MCMs are evidenced by cryo‐transmission electron microscopy. Moreover, the cytocompatibility of MCMs is demonstrated in vitro via cell viability assay.     

Synthesis of self‐assembled sphingolipid conjugates and their morphology effect on anticancer therapeutic potency

The shape of self‐assembling polymer–drug conjugates, influencing the cellular uptake, is one of the important factors to be considered for effective drug delivery. In this study, we described synthesis of polymeric drug conjugates of different morphologies with phytosphingosine (PHS) as a hydrophobic model drug and poly(amino acid) as a hydrophilic host polymer. By varying the amount of PHS grafted to poly(amino acid), PHS–poly(amino acid) conjugates exhibited morphological transition from spherical to worm‐like micellar aggregates in the aqueous media. We investigated the physicochemical properties of self‐assembled structures in terms of hydrodynamic size, surface charge, and critical aggregation concentration. The anticancer therapeutic potency of these self‐assembled structures was also discussed in terms of cellular uptake and cytotoxicity of prodrug micelles as a function of dose and time by in vitro cell study. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synergistic anticancer effects achieved by co-delivery of TRAIL and paclitaxel using cationic polymeric micelles

Cationic micellar nanoparticles self‐assembled from a biodegradable amphiphilic copolymer have been used to deliver human TRAIL and paclitaxel simultaneously. Polyplexes formed between paclitaxel‐loaded nanoparticles and TRAIL are stable with a size of ≈180 nm and a zeta potential at ≈75 mV. Anticancer effects and apoptotic pathway mechanisms of this drug‐and‐protein co‐delivery system are investigated in various human breast cancer cell lines with different TRAIL sensitivity. The co‐delivery nanoparticulate system induces synergistic anti‐cancer activities with limited toxicity in non‐cancerous cells. An advantage of this co‐delivery is a significantly higher anti‐cancer effect as compared to free drug and protein formulations.

     

Block copolymer micelles conjugated with anti‐EGFR antibody for targeted delivery of anticancer drug

Antiepidermal growth factor receptor antibody (anti‐EGFR antibody) was conjugated with the block copolymer micelle based on poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) for active targeting to EGFR overexpressing cancer cells. Doxorubicin (DOX) was encapsulated in the core of the block copolymer (MePEG‐b‐PCL) micelle (DOX‐micelle). The mean diameters of the DOX‐micelle and the anti‐EGFR‐PEG‐b‐PCL copolymer micelles loaded with DOX (DOX‐anti‐EGFR‐micelle) were about 25 and 31 nm, respectively. The RKO human colorectal cancer cells expressing moderate degree of EGFR were incubated with free DOX, DOX‐micelle, or DOX‐anti‐EGFR‐micelle to study the distribution of DOX in the cells. When cells were incubated with free DOX, moderate degree of DOX fluorescence was observed in the nuclei. In the cells treated with DOX‐micelle, the DOX fluorescence intensity in the cytoplasm was much greater than that in the nuclei. On the other hand, the nuclei of the cells treated with DOX‐anti‐EGFR‐micelle exhibited DOX fluorescence intensity similar to that in the cytoplasm. The cytotoxicity of DOX‐anti‐EGFR‐micelle to induce apoptosis in RKO cells was significantly greater than that of free DOX or DOX‐micelle. These results demonstrated that the presence of anti‐EGFR antibody on the DOX‐micelle surface (DOX‐anti‐EGFR‐micelle) increased the internalization of the DOX‐micelle and nuclear accumulation of DOX, and enhanced the DOX‐induced cell death. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7321–7331, 2008     

Self‐Assembled Micelles Based on PEG‐Polypeptide Hybrid Copolymers for Drug Delivery

A series of amphiphilic poly(L ‐leucine)‐block‐poly(ethylene glycol)‐block‐poly(L ‐leucine) (PLL‐PEG‐PLL) hybrid triblock copolymers have been synthesized. All the blocks in this system have good biocompatibility and low toxicity. The PLL‐PEG‐PLL copolymers could self‐assemble into micelles with PLL blocks as the hydrophobic core and PEG blocks as the hydrophilic shell, which were characterized by FT‐IR, ¹H NMR, and transmission electron microscopy analysis. The critical micellar concentration of the copolymer was 95.0 mg · L⁻¹. The circular dichroism spectrum shows that the PLL segments adopt a unique α‐helical conformation, which is found to play an important role in controlling the drug release rate. The drug release could be effectively sustained by encapsulation in the micelles. The copolymers may have potential applications in drug delivery.

     

Novel hepatoma‐targeting micelles based on chemoenzymatic synthesis and self‐assembly of galactose‐functionalized ribavirin‐containing amphiphilic random copolymer

Hepatoma‐targeting micelles were successfully prepared by self‐assembly of galactose‐functionalized ribavirin‐containing amphiphilic random copolymer as novel drug delivery vehicles. The ribavirin‐containing random copolymer with galactose as the targeting ligand was facilely synthesized by combining enzymatic transesterification with radical polymerization and fully characterized by FTIR, NMR, and GPC. The formation of micelle‐type aggregates from the random copolymer was verified by UV–vis and fluorescence spectroscopy using pyrene as the guest molecule. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) experiments revealed that the micelles were well dispersed as spherical nanoparticles in water, whose hydrodynamic diameter was 217 ± 19 nm. Their biological recognition to fluorescein‐labeled peanut agglutinin investigated by confocal laser scanning microscopy (CLSM) proved the existence of hydrophilic galactose targeting moieties on the surface of micelles. Cell cytotoxicity tests and the inhibition experiment of galactose performed by MTT assay showed that the micelles had evident targeting function to hepG2 cells and the galactose moieties on the surface of micelles mediated cellar uptake of micelles. In vitro release studies indicated that ribavirin could be slowly released from the copolymer with pseudo zero‐order kinetics. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2734–2744, 2008     

Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer

Colorectal cancer (CRC) is a usual digestive tract malignancy and the third main cause of cancer death around the world, with a high occurrence rate and mortality rate. Conventional therapies for CRC have certain side effects and restrictions. However, the exciting thing is that with the rapid development of nanotechnology, nanoparticles have gradually become more valuable drug delivery systems than traditional therapies because of their capacity to control drug release and target CRC. This also promotes the application of nano-drug targeted delivery systems in the therapy of CRC. Moreover, to make nanoparticles have a better colon targeting effect, many approaches have been used, including nanoparticles targeting CRC and in response to environmental signals. In this review, we focus on various targeting mechanisms of CRC-targeted nanoparticles and their latest research progress in the last three years, hoping to give researchers some inspiration on the design of CRC-targeted nanoparticles.     

Synthesis,characterization and cleavage of linear polymers attached to silica nanoparticles formed using thiol‐acrylate conjugate addition reactions

This study investigates the formation of linear polymer grafts using thiol‐acrylate conjugate addition reactions on nanoparticle surfaces. Silica nanoparticles were first modified with an amine functionality, followed by the attachment of a photocleavable acrylate. Dithiol‐diacrylate films were attached to the particles through the surface acrylate groups at various stoichiometric ratios of thiol to acrylate by conducting amine‐catalyzed conjugate addition polymerizations. The particles were then exposed to UV light to release the grafted polymer by photocleavage. The cleaved, grafted polymers were analyzed using infrared spectroscopy and gel permeation chromatography and compared to polymers formed in the bulk, which remained unattached to the particles. The measured number and weight average molecular weights were similar for both polymer types within experimental error and increased from 2000 to 5000 g/mol and 4000 to 10,000 g/mol, respectively, as the ratio of limiting to excess functionality increased from 0.8 to 1. Both number and weight average molecular weights followed the trend of step growth polymers with the highest molecular weight achieved for stoichiometric monomeric mixtures. Surface coverage of the nanoparticles was estimated using the molecular weight and thermogravimetric data and was found to be uniform (～0.15 chains/nm²) irrespective of the stoichiometry of the reacting monomers. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6896–6906, 2008     

Synthesis of water‐soluble allyl‐functionalized oligochitosan and its modification by thiol–ene addition in water

A novel, straightforward and versatile chemical pathway has been studied to functionalize water‐soluble chitosan oligomers. This metal‐free methodology is based on the epoxy‐amine reaction of the allyl glycidyl ether with chitosan, followed by thiol‐ene radical coupling reaction of ω‐functional mercaptans, using 4,4′‐Azobis(4‐cyanovaleric acid) as a free radical initiator. Both reactions were entirely carried out in water. In a preliminary step, chitosan depolymerization was carried out using H₂O₂ in an acetic medium under 100 W microwave irradiation, optimizing the yield of water‐soluble oligomers. Functionalization by six different thiols bearing alcohol, carboxylic acid, ester, and amino groups was then performed, leading to a range of functional oligochitosans with different grafting efficiencies. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 39–48     

光控释药型药物递送系统的研究进展

释药可控的药物递送系统能够在特定刺激条件下,在时间和空间上精确实现在病灶处释放包载的药物分子,具有药物利用率高、毒副作用低等诸多优点,为各种重大疾病,如肿瘤的精准治疗提供了新思路.在众多的可控释药递送系统中,利用特定光照控制药物释放的光控释药型药物递送系统展现出广阔的应用潜力,受到研究者的广泛关注.近年来,基于不同光响应机理的光控释药型药物递送系统被设计开发用于药物的精确可控释放,本文介绍了四种光敏感基团的不同光响应机理,对基于不同光响应机理的光控释药型药物递送系统的研究进展进行了综述,指出现有光控释药型药物递送系统存在的问题及对未来的研究方向进行了展望.     

Thiol‐responsive micelles based on nonionic gemini surfactants with a cystine disulfide spacer

Thiol‐responsive micelles consisting of novel nonionic gemini surfactants with a cystine disulfide spacer are reported. The gemini surfactants, (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂, were synthesized from polyethylene glycol, cysteine, and stearic acid, and their structures were confirmed by ¹H NMR and gel permeation chromatography. (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ formed micelles with average diameters of 13 and 22 nm above the critical micelle concentration of 6.5 and 4.7 µg mL^?1, respectively. The micelles of ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ containing more stearoyl groups showed encapsulated more hydrophobic indomethacin (IMC) with higher entrapment efficiencies than those of (C₁₈‐Cys‐mPEG)₂. The gemini surfactant micelles exhibited an accelerated release of encapsulated IMC with the concentration of the reducing agent, glutathione (GSH), whereas they were unaffected by the presence of reduced GSH (GSSG). The 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)?2‐(4‐sulfophenyl)?2H‐tetrazolium studies revealed the noncytotoxic nature of the gemini surfactant micelles. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 582–589     

From well‐defined diblock copolymers prepared by a versatile atom transfer radical polymerization method to supramolecular assemblies

The synthesis of well‐defined diblock copolymers by atom transfer radical polymerization (ATRP) was explored in detail for the development of new colloidal carriers. The ATRP technique allowed the preparation of diblock copolymers of poly(ethylene glycol) (PEG) (number‐average molecular weight: 2000) and ionic or nonionizable hydrophobic segments. Using monofunctionalized PEG macroinitiator, ionizable and hydrophobic monomers were polymerized to obtain the diblock copolymers. This polymerization method provided good control over molecular weights and molecular weight distributions, with monomer conversions as high as 98%. Moreover, the copolymerization of hydrophobic and ionizable monomers using the PEG macroinitiator made it possible to modulate the physicochemical properties of the resulting polymers in solution. Depending on the length and nature of the hydrophobic segment, the nonionic copolymers could self‐assemble in water into nanoparticles or polymeric micelles. For example, the copolymers having a short hydrophobic block (5 < degree of polymerization < 9) formed polymeric micelles in aqueous solution, with an apparent critical association concentration between 2 and 20 mg/L. The interchain association of PEG‐based polymethacrylic acid derivatives was found to be pH‐dependent and occurred at low pH. The amphiphilic and nonionic copolymers could be suitable for the solubilization and delivery of water‐insoluble drugs, whereas the ionic diblock copolymers offer promising characteristics for the delivery of electrostatically charged compounds (e.g., DNA) through the formation of polyion complex micelles. Thus, ATRP represents a promising technique for the design of new multiblock copolymers in drug delivery. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3861–3874, 2001     

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm‐co‐AN)‐g‐PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC₅₀ decreased from 4.6 to 1.6 μg mL^?1, tumor inhibition rate increased from 55.6 % to 92.8 %) was observed. These results suggest that UCST‐based drug delivery can be an alternative to thermally sensitive LCST‐based drug delivery systems for an enhanced antitumor efficiency.     

Amphiphilic comb-like polymers based on poly(oxyethylene)s as drug-delivery carriers

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.     

Aminosalicylate-based biodegradable polymers: Syntheses and in vitro characterization of poly(anhydride-ester)s and poly(anhydride-amide)s

Poly(anhydride-ester)s and poly(anhydride-amide)s derived from both 4- and 5-aminosalicylate acids (4- and 5-ASA) were synthesized and characterized by physicochemical methods. Thermal and solubility characteristics directly correlated to the polymer backbone composition; polymers based on 5-ASA had greater solubilities in organic solvents than polymers based on 4-ASA, and the poly(anhydride-ester)s thermally decomposed at temperatures nearly 100 °C higher than the corresponding poly(anhydride-amide)s. The polymers were self-contained, controlled-release systems that combine the drug and controlled-release mechanism into the polymer backbone. The erosion and degradation characteristics of the polymers were measured in physiologically relevant media. All polymer matrices fully degraded in media buffered to pH 7.4, whereas in acidic media (pH 1.2), all polymer matrices maintained greater than 50% mass over a 90-day time period. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3667–3679, 2003