Evaluation of micellar architecture based on functionalized chitosan for the in vitro release of an antibiotic

Polymeric micelles are enjoying high resurgence of interest in biomedical field as promising candidates for the delivery of water-insoluble drugs. This property was used to design and synthesize fatty acid grafted polysaccharide-based copolymer micelles for the sustained release of Cefixime trihydrate (CFX): a third-generation cephalosporin. Chitosan (CS), a polysaccharide obtained by the alkaline deacetylation of chitin emerged as a useful drug delivery matrix because of its polycationic nature, biodegradability, biocompatibility and mucoadhesiveness. The drug release was monitored in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (7.4). The in vitro release studies revealed 52% of drug release after 24 h of incubation and were enhanced to 83% after 72 h in simulated intestinal fluid condition. Antibacterial studies confirmed that the inherent properties of the drug were retained as well as enhanced by micelle formation. Thus, the synthesized copolymer micelle assures to be an excellent carrier vehicle for the sustained release of a model hydrophobic drug CFX. Smaller particle size ensures increased drug uptake and controlled release facilitates patient compliance.     

Synthesis and micellar characterization of luteinizing hormone‐releasing hormone poly(ethylene glycol)‐block‐poly(l‐histidine) copolymers

A facile and well‐controlled pathway was introduced to obtain optimal pH‐sensitive luteinizing hormone‐releasing hormone—functionalized poly(ethylene glycol)‐block‐poly(l ‐histidine) (LHRH‐PEG‐PHIS) micelles in this paper. The influence of block‐selective solvent, the weight ratio of the selective solvent to common solvent and initial polymer concentration on the self‐assembly of LHRH‐PEG‐PHIS micelles were studied. These factors exerted remarkable influence on the morphology of the resulting micelles. The micelles showed a spherical geometry and an uniform appearance under the following optimal experimental conditions: LHRH‐PEG/PHIS ratio of 1.0 by molar, DMF as the selective solvent and 3.0 mg/mL as initial concentration, 100 W of ultrasonic power. These micelles had a small diameter (about 90 nm), low CMC (10 μg/mL), and pH‐sensitive switch in surface charge and micelles' size. As the pH of the micellar solution decreased from pH 7.4 to 5.5, the zeta potential of the LHRH‐PEG‐PHIS micelles increased from ?0.02 mV to 20.7 mV and the diameter of the nanoparticles decreased from 137 nm to 76 nm. After 30 h of incubation at pH 5.0, 6.0, and 7.4 the released free Doxorubicin (DOX) was about 83.18%, 81.26%, and 30.35%, respectively. The LHRH‐PEG‐PHIS micelles could combine the characteristics of active targeting with pH‐triggered drug release promising as intracellular drug delivery carriers. POLYM. ENG. SCI., 55:277–286, 2015. © 2014 Society of Plastics Engineers     

Intracellular pH‐sensitive dextran‐based micelles as efficient drug delivery platforms

As drug delivery systems, stimuli‐responsive polymer micelles hold great potential in cancer chemotherapeutics to improve therapeutic efficiency and eliminate organism adverse effects. Here, pH‐sensitive polymeric micelles based on dextran‐g‐benzimidazole were designed and used for intracellular anticancer drug delivery. The anticancer drug doxorubicin (DOX) was effectively loaded into the micelles via hydrophobic interactions. In vitro release studies demonstrated that the release of loaded DOX was greater and faster under acid conditions such as in carcinomatous areas (pH < 6.8) than in physiological conditions (pH 7.4). MTT assays and flow cytometric analyses showed that DOX‐loaded micelles had higher cellular proliferation inhibition towards HeLa and HepG2 cells than pH‐insensitive controls. These pH‐sensitive micelles with significant efficiency for intracellular drug release will be beneficial to the future of in vivo biomedical applications. © 2014 Society of Chemical Industry     

Synthesis of pH-sensitive,water-soluble paclitaxel prodrugs based on norbornene-functional polylactide by copper-free click chemistry

In this study, a novel polymeric prodrug based on norbornene-functional polylactide with functionalized paclitaxels (LEV-PTXL) covalently conjugated to water-soluble polymer carrier via a pH-sensitive hydrazone bond was developed. A series of water-soluble PTXL prodrugs with decent drug contents of 17.3 and 24.7 wt% (denoted as PTXL prodrugs 1 and 2) were prepared. The molecular structures and characteristics were confirmed by ¹H NMR, Fourier transform infrared, and gel permeation chromatography. In vitro release studies showed that PTXL release rate from polymeric prodrug were significantly accelerated under acidic medium, due to the acid-cleavable hydrazone linkage. As illustrated by cytotoxicity study, while the corresponding polymer carrier was nontoxic, the polymeric prodrug exhibited higher therapeutic efficacy toward MCF-7 and A549 (IC50 = 0.19 and 4.94 µg PTXL equiv/mL, respectively) cancer cells. The norbornene-functional polylactide-based polymeric prodrug has appeared as a novel anticancer nanomedicine for cancer therapy.     

Preparation and characterization of mPEG‐g‐α‐zein biohybrid micelles as a nano‐carrier

A new kind of block copolymer micelles methoxy polyethylene glycol (mPEG) grafted α‐zein protein (mPEG‐g‐α‐zein) was synthesized. The chemical composition of mPEG‐g‐α‐zein was identified with the help of FT‐IR and ¹H‐NMR. The biohybrid polymer can self‐assemble into spherical core–shell nanoparticles in aqueous solution. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to investigate the self‐assembled morphology of mPEG‐g‐α‐zein. Dynamic light scattering (DLS) results showed that the particle size of mPEG‐g‐α‐zein was about 90 nm. Moreover, the nanoparticles had a very low critical micelle concentration value with only 0.02 mg/mL. Then, the anticancer drug curcumin (CUR) was encapsulated into the biohybrid polymer micelles. The in vitro drug release profile showed a zero‐order release of CUR up to 12 h at 37°C. Cell viability studies revealed that the mPEG‐g‐α‐zein polymer exhibited low cytotoxicity for HepG2 cells (human hepatoma cells). Consequently, the mPEG‐g‐α‐zein micelles can be used as a potential nano‐carrier to encapsulate hydrophobic drugs and nutrients. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42555.     

Dual stimuli-responsive poly(succinyloxyethylmethacrylate-b-N-isopropylacrylamide) block copolymers as nanocarriers and respective application in doxorubicin delivery

Stimuli-responsive nanostructures were developed as anticancer drug delivery carriers. To this end, poly(2-hydroxyethylmethacrylate)-b-(N-isopropylacrylamide) (poly(HEMA-b-NIPAAm)) diblock copolymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization with two ratios remarked with (1) and (2). Based on gel permeation chromatography, the molecular weights of synthesized diblock copolymers were 17802 (1) and 13090 (2) g?mol^?1. The pH- and thermoresponsive poly(succinyloxyethylmethacrylate-b-N-isopropylacrylamide) (poly)SEMA-b-NIPAAm)) diblock copolymers were obtained by reacting poly(HEMA-b-NIPAAm) with excess succinic anhydride in pyridine under mild conditions. Developed micelles with poly(SEMA-b-NIPAAm) (1) and poly(SEMA-b-NIPAAm) (2) diblock copolymers around pH of 3–4 at 25°C demonstrated the critical micelles concentrations (CMCs) of 0.026 and 0.019?g?L^?1, respectively. The average sizes of poly)SEMA-b-NIPAAm) micelles using dynamic light scattering (DLS) measurements at pH 3.0, 6.0, and 9.0 were 240, 190, and 150?nm, respectively. The core-shell poly(SEMA-b-NIPAAm) micelles at pH 3 and 9 were 100–200?nm. The lower critical solution temperature (LCST) of poly)SEMA-b-NIPAAm) sample was determined to be 40°C by ultraviolet-visible (UV-vis) spectroscopy. The micelles of diblock copolymers were formed to enhance the drug solubility in aqueous solutions. Doxorubicin hydrochloride (DOX)-loading capacity was 99.1%. The release of DOX acted better at 42°C compared to 40°C. The results confirmed that pH- and temperature-dependent release of this drug carrier was particularly useful and important for the anticancer drug delivery at the tumor-like environment. Therefore, the biocompatibility of diblock copolymer was confirmed by assessing survival rate of breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The synthesized nanoparticles would have an excellent potential as anticancer drug delivery.     

Simple Fabrication of Glutathione-Responsive PEGylated Micellar Nanocarriers for Dual Drugs Delivery

The authors report a feasible simple method to fabricate two kinds of micellar nanocarriers (MPEG-SS-CPT/DOX) with polyethylene glycol (PEG) based on the self-assembly of glutathione (GSH)-responsive amphiphilic PEGylated polymers (MPEG-SS-CPT) in free doxorubicin (DOX) solution, which could carry two anticancer drugs of camptothecin (CPT) and DOX toward cancer cells together. In in vitro release studies, the micelles of MPEG-SS-CPT/DOX could undergo the triggered disassembly to release CPT and DOX under GSH stimulus much faster than without GSH. Furthermore, the MPEG-SS-CPT nanocarriers could release CPT with no change of its original structure after degradation. From the experiments of loading and release of drugs, the cell viability assay, cellular uptake, and flow cytometry studies, it was found that the fibrous micelles modified by PEG with a molecular weight of 350 had greater potential in the field of drug delivery than the other with a molecular weight of 1900.     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Self‐assembly and drug delivery behaviors of thermo‐sensitive poly(t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) micelles

Self‐assembly of thermo‐sensitive poly (t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) (PtBA‐ b‐PNIPAM) micelles in aqueous medium and its applications in controlled release of hydrophobic drugs were described. PtBA‐b‐PNIPAM was synthesized by atom transfer radical polymerization and aggregated into thermo‐sensitive core‐shell micelles with regular spheres in water, which was confirmed by ¹H‐NMR, fluorescence spectroscopy, transmission electron microscopic (TEM), and UV–vis spectroscopic techniques. The critical micelle concentration of micelles decreased with the increase of the hydrophobic components. The anti‐inflammation drug naproxen (NAP) was loaded as the model drug into polymeric micelles, which showed a dramatic thermo‐sensitive fast/slow switching behavior around the lower critical solution temperature (LCST). When the temperature was enhanced above LCST, release of NAP from core‐shell micelles was accelerated ascribed to the temperature‐induced deformation of micelles. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Zero‐order release three‐layered tablet with an acemetacin solid dispersion core and a hydroxypropyl methylcellulose capped matrix

The purpose of this study was to prepare a three‐layered tablet with hydroxypropyl methylcellulose (HPMC) polymers as a capped matrix to achieve a zero‐order release for acemetacin. As the middle active core, a solid dispersion in poly(vinyl pyrrolidone)–K30 polymers was manufactured via a solvent method to improve the solubility of acemetacin. A Box–Behnken design was used to optimize the formula, when the amounts of HPMC in the middle layer, HPMC in the external layer, and mannitol in the middle layer were chosen as the influencing factors. The dissolution profiles of the optimized formula exhibited superior fitting to the zero‐order release in 24 h. A bioavailability experiment was carried out by the administration of those three‐layered tablets to rabbits and their comparison with market Gaoshunsong controlled release capsules. The delayed time to reach the maximum plasma concentration, decreased the maximum plasma concentration, area under the plasma concentration‐time curve (0–48 h) AUC_0–48, and area under the plasma concentration‐time curve (0–∞) AUC_0–∞ were 9.33 ± 2.51 h, 8.59 ± 0.94 µg/mL, 200.81 ± 11.36 µg h/mL, and 212.902 ± 31.66 µg h/mL, respectively. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42059.     

Novel polymersomes based on amphiphilic graft polyphosphazenes and their encapsulation of water-soluble anti-cancer drug

A series of amphiphilic graft polyphosphazenes with hydrophilic weight fraction ranging from 0.40 to 0.55 were synthesized. These copolymers could self-assemble into distinct aggregates in aqueous solutions. Spherical micelles were observed for the copolymer sample with higher hydrophilic weight fraction. However, when the hydrophilic weight fractions decreased to less than 0.50, vesicle-like polymersomes were formed. Doxorubicin hydrochloride (DOX·HCl), a water-soluble anti-cancer drug, was successfully loaded into the aqueous core of polymersome, which was clearly observed by transmission electron microscopy. The in vitro release of DOX·HCl from polymersome carries further confirmed its encapsulation. In addition, the cytotoxicity of DOX against HepG2 cells was significantly enhanced via polymersome delivery. These results suggest that amphiphilic graft polyphosphazenes could be used for the delivery of water-soluble drugs as polymersome vehicles.     

Synthesis of pH-Responsive Multilayer Micelles for Sustained Release of Folic Acid

Two novel triblock copolymers poly(hydroxypropyl acrylate)-b-poly (methyl methacrylate)-b-poly(N,N-dimethylaminoethyl methacrylate) and poly(hydroxypropyl acrylate)-b-poly(methyl methacrylate)-b-poly(acrylic acid) were successfully synthesized. In acetone media, using the electrostatic interactions between N,N-dimethylaminoethyl methacrylate and acrylic acid units, they could form spherically shaped multilayer micelles with pH-responsive, and have a mean diameter around 110 nm. The critical micelle concentration of it was determined to be 2.42 mg/L. In vitro release experiments, the folic acid-loaded micelles exhibited sustained release behavior and the drug release rate was affected by the pH value of release media. These results indicate that the multilayer micelles may serve as a novel intelligent drug delivery system.     

Spray-dried Cefixime Encapsulated Poly(lactide-co-glycolide) Microparticles: Characterization and Evaluation of In Vitro Release Kinetics with Antibacterial Activity

Our study reports on the development of novel biodegradable microparticles prepared by a spray-drying technique using the poly(lactide-co-glycolide) (PLGA), a biodegradable polymer for the controlled delivery of cefixime. Cefixime is a water-soluble drug having short biological half-life of 3 h. The behavior of PLGA in controlling drug release responses of cefixime microparticles was investigated. The resultant microparticles were characterized by scanning electron microscopy, encapsulation efficiency, particle-size distribution, X-ray diffraction, and in vitro dissolution studies (pH 7.2). To investigate the type of release mechanism that occurs, dissolution data were plotted according to different kinetic models. The in vitro release profiles from microparticles followed first order and Higuchi model release. Antibacterial studies were carried out using a standard agar diffusion method to determine the effectiveness of formulations in inhibiting the growth of microorganisms. It showed that the released drug from the formulations was effectively inhibiting the growth of microorganisms with the minimum inhibitory concentration of < 1 µg/mL. Data revealed the potential of formulations for treatment of infections caused by various microorganisms. Thus, this study demonstrates the high potential of the spray-drying technique to obtain stable cefixime microparticles with good encapsulation efficiency to achieve a delivery profile that would yield the controlled released level of the drug over a long period of time (74 h).     

Preparation of new dendrimer‐like star‐shaped amphiphilic poly(ethylene glycol)–poly(ϵ‐caprolactone) copolymers for biocompatible and high‐efficiency curcumin delivery

Novel amphiphilic star‐shaped terpolymers comprised of hydrophobic poly(?‐caprolactone), pH‐sensitive polyaminoester block and hydrophilic poly(ethylene glycol) (M_n = 1100, 2000 g mol^?1) were synthesized using symmetric pentaerythritol as the core initiator for ring‐opening polymerization (ROP) reaction of ?‐caprolactone functionalized with amino ester dendrimer structure at all chain ends. Subsequently, a second ROP reaction was performed by means of four‐arm star‐shaped poly(?‐caprolactone) macromer with eight ‐OH end groups as the macro‐initiator followed by the attachment of a poly(ethylene glycol) block at the end of each chain via a macromolecular coupling reaction. The molecular structures were verified using Fourier transform infrared and ¹H NMR spectroscopies and gel permeation chromatography. The terpolymers easily formed core–shell structural nanoparticles as micelles in aqueous solution which enhanced drug solubility. The hydrodynamic diameter of these agglomerates was found to be 91–104 nm, as measured using dynamic light scattering. The hydrophobic anticancer drug curcumin was loaded effectively into the polymeric micelles. The drug‐loaded nanoparticles were characterized for drug loading content, encapsulation efficiency, drug–polymer interaction and in vitro drug release profiles. Drug release studies showed an initial burst followed by a sustained release of the entrapped drug over a period of 7days at pH = 7.4 and 5.5. The release behaviours from the obtained drug‐loaded nanoparticles indicated that the rate of drug release could be effectively controlled by pH value. Altogether, these results demonstrate that the designed nanoparticles have great potential as hydrophobic drug delivery carriers for cancer therapy. © 2015 Society of Chemical Industry     

Thermosensitive biotinylated hydroxypropyl cellulose-based polymer micelles as a nano-carrier for cancer-targeted drug delivery

In this article, we report the synthesis of a novel amphiphilic hydroxypropyl cellulose-based polymer (HPC-PEG-Chol) that contained poly (ethylene glycol) and cholesterol-containing moieties with specific degrees of substitution. The resulting polymer was subsequently converted to a biotin conjugate (HPC-PEG-Chol-biotin), to develop a new potential cancer-targeted drug delivery system. The biotin conjugate was used to prepare micelles via the dialysis method. The polymeric micelles in aqueous solution presented a lower critical solution temperature (LCST) of 39.8 ^oC. The critical micelle concentration (CMC) values of the polymeric micelles at 25 and 45 °C were evaluated to be about 0.32 and 0. 25 g/L, respectively. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses of the micelles revealed the spherical shapes of the micelles, with 84 nm mean diameters that increased with the increase of the temperature above LCST. The hydrophobic anticancer drug paclitaxel (PTX) was loaded in the micelles and the in vitro release behaviors of PTX were investigated at different temperatures. The release profile of PTX from the polymeric micelles revealed a thermosensitivity, since its release rate was higher at 41 °C than at 37 °C. Fluorescent microscopy analyses confirm that the PTX-loaded HPC-PEG-Chol-biotin is superior in cellular uptake, with very strong adsorption to both HeLa and MDA-MB-231 cancer cell lines. MTT assay in normal cells indicated that HPC-PEG-Chol-biotin micelles have great potential to be safely used in tumor-targeting chemotherapy.     

Synthesis and in vitro biological evaluation as antitumour drug carriers of folate‐targeted N‐isopropylacrylamide‐based nanohydrogels

Copolymeric nanohydrogels based on N‐isopropylacrylamide, N‐(pyridin‐4‐ylmethyl)acrylamide and tert‐butyl‐2‐acrylamidoethyl carbamate, synthesized by microemulsion polymerization, were characterized using Fourier transform infrared spectroscopy and their size (38–52 nm) determined using quasielastic light scattering. Folic acid was covalently attached to the nanohydrogels (1.40 ± 0.07 mmol g^?1). Tamoxifen (6.7 ± 0.2–7.3 ± 1.2 µg TMX mg^?1 nanohydrogel), a hydrophobic anticancer drug, and 5‐fluorouracil (7.7 ± 0.7–10.14 ± 1.75 µg 5‐FU mg^?1 nanohydrogel), a hydrophilic anticancer drug, were loaded into the nanohydrogels. Maximum in vitro TMX release (77–84% of loaded drug) depended on interactions of the drug with hydrophobic clusters of the nanogels; however, no nanogel/5‐FU interactions allowed total release of the loaded drug. The cytotoxicity of unloaded nanohydrogels in MCF7, T47D and HeLa cells was low. Cell uptake of nanogels without bound folic acid took place in the three cell types by unspecific internalization in a time‐dependent process. Cell uptake increased for folic acid‐targeted nanohydrogels in T47D and HeLa cells, which have folate receptors. The administration of 10 and 30 µmol L^?1 TMX by TMX‐loaded nanogels and 10 µmol L^?1 5‐FU by 5‐FU‐loaded nanogels was effective on the three cell types, and the best results were obtained for folic acid‐targeted nanohydrogels. Copyright © 2012 Society of Chemical Industry     

Synthesis of pH-responsive cellulose-g-P4VP by atom transfer radical polymerization in ionic liquid,loading, and controlled release of aspirin

A pH-responsive cellulose-g-P4VP copolymer was synthesized by atom transfer radical polymerization (ATRP) in ionic liquid 1-allyl-3-methylimidazolium chloride [AMIM]Cl. The polymer structure was characterized by Fourier transform infrared (FT-IR), ¹H nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). The P4VP brushes that were covalently bonded to the cellulose backbone had a narrow molecular weight distribution, which was helpful for use in drug loading. The loading and controlled release of drug using aspirin as model drug in the micelles obtained the cellulose-g-P4VP copolymer was investigated. The structure and size of the copolymeric micelles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and ultraviolet–visible (UV-Vis) spectroscopy, respectively. Blank micelles presented a stably spherical morphology with dimeter about 90 nm in aqueous solution. The resultant micelles had clear pH-sensitivity with a pH-dependent phase transition point at a pH of about 5.7. Drug-loaded micelles had a spherical, core–shell structure with dimeter about 150 nm. The polymeric micelles revealed an excellent controlled drug release at different pH values and the cumulative release of aspirin in phosphate buffer reached to 86.4% at pH 5.8, 60.9% at pH 7.4 and 42.2% at pH 8.0.at 50 h. The pH-sensitive cellulose-g-P4VP copolymer had an enormous potential as carriers for released drug delivery.     

透明质酸自组装聚合物胶束的制备及表征

为了增强抗肿瘤药物的靶向性与抗肿瘤活性,本文制备了透明质酸-十八烷聚合物,用其对阿霉素进行包载,考察其理化性质及体外细胞毒性。合成两亲性透明质酸-十八烷聚合物,利用核磁对其结构进行确证。选择超声法制备载阿霉素的聚合物胶束,考察胶束的粒径、电位、包封率、载药量以及体外释放行为。选择乳腺癌细胞MCF-7为肿瘤细胞模型,考察载药胶束的体外抗肿瘤活性。成功合成了透明质酸-十八烷聚合物。制备的空白胶束和载药的胶束的粒径分别为（180.7±1.25）nm和（178.3±2.24）nm,Zeta电位分别为（-21.3±0.25）mV和（-18.1±0.31）mV。载阿霉素聚合物胶束的包封率为（96.1%±0.72%）,载药量为16.1%±1.18%,体外释放行为表明在72h的累计药物释放率仅为40%左右,具有明显的缓释行为。体外细胞毒性结果表明,空白聚合物胶束对肿瘤细胞几乎没有毒性,而载阿霉素的聚合物胶束具有较好的抗肿瘤活性。结论：透明质酸-十八烷聚合物胶束可以有效地包载抗肿瘤药物阿霉素,具有良好的缓释特性和抗肿瘤活性。     

Synthesis, characterization, and drug delivery research of an amphiphilic biodegradable star-shaped block copolymer

An amphiphilic biodegradable three-arm star-shaped diblock copolymer containing poly(ε-caprolactone) (PCL) and poly(N-vinylpyrrolidone) (PVP) (TEA(PCL-b-PVP)₃) has been successfully synthesized by the ring-opening polymerization of ε-caprolactone (ε-CL), RAFT polymerization of N-vinylpyrrolidone and a coupling reaction of PCL with carboxyl-terminated PVP (PVP-COOH). In aqueous media, the star-shaped copolymer self-assembled into spherical micelles with diameters of near 106 nm. The critical micelle concentration of TEA(PCL-b-PVP)₃ copolymer was determined to be 5.96 × 10^?3 mg/mL. Folic acid was then used as a model drug to incorporate into TEA(PCL-b-PVP)₃ micelles, the drug loading content and encapsulation efficiency is 16.36 and 49.08 %, respectively. In vitro release experiments of the drug-loaded micelles exhibited sustained release behavior and it was affected by the pH of release media. These results indicate that the copolymer may serve as a promising “intelligent” drug delivery alternative.     

Core/shell pH‐sensitive micelles self‐assembled from cholesterol conjugated oligopeptides for anticancer drug delivery

A doxorubicin (DOX) delivery system of pH‐sensitive micelles self‐assembled from cholesterol conjugated His₅Arg₁₀ (HR15‐Chol) and His₁₀Arg₁₀ (HR20‐Chol) has been described in this article. The amphiphilic molecules have low critical micelle concentrations of 17.8 and 28.2 μg/mL for HR15‐Chol and HR20‐Chol, respectively, even at a low pH of 5.0. The pH‐sensitive histidine segment of the polypeptide block is insoluble at pH 7.4 but becomes positively charged and soluble via protonation at pH lower than 6.0. The size and zeta potential of DOX‐loaded micelles increases with the decrease in pH. Coarse‐grained simulations were performed to verify the structure of DOX‐loaded micelles and pH sensitivity of HR15/20‐Chol. The in vitro DOX release from the micelles is significantly accelerated by decreasing pH from 7.4 to 5.0. Furthermore, DOX release from the micelles is controlled by a Fickian diffusion mechanism. These micelles have great potential applications in delivering hydrophobic anticancer drugs for improved cancer therapy. © 2009 American Institute of Chemical Engineers AIChE J, 2010