Polymeric micelle composed of PLA and chitosan as a drug carrier

Water soluble chitosan (CS) oligomer was hydrophobically modified with PLA unit. The chemical structure and physical properties of CS derivatives were confirmed by FTIR, ¹HNMR, TGA and X-RD. Formation and characteristics of polymeric micelles of graft copolymers were studied by fluorescence spectroscopy and dynamic light scattering (DLS) method. To estimate the feasibility as novel drug carriers, the copolymer micelles were prepared by the phase separation-dialysis method. Rifampin was incorporated into polymeric micelles as a lipophilic model drug to investigate the drug release behavior. As PLA weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

Self-assembled polymeric micelles based on THP and THF linkage for pH-responsive drug delivery

Developing smart nanocarriers for drug delivery system is advantageous for many kinds of successful biomedicinal therapy. In this study, we designed an amphiphilic block copolymers containing pH-responsive tetrahydropyran (THP) and tetrahydrofuran (THF) linkage. Their structures were confirmed by ¹H NMR and gel permeation chromatography (GPC). The release rate of encapsulated drugs depends upon the pH value and pH sensitive linkage in the backbone of copolymers. For PLA–THP–PEG micelles the cumulative release amount of doxorubicin (DOX) was 62% at pH 5.0, which is about four times higher than that at pH 7.4. Under the same conditions the release rate for PLA–THF–PEG micelles is a little faster than that of the PLA–THP–PEG micelles. Cellular uptake study demonstrates that DOX-loaded micelles can easily enter the cells and produce the desired pharmacological action and minimizing the side effect of free DOX. These findings indicate that THP and THF linked diblock copolymer micelles is a promising candidate for drug carrier.     

Synthesis and characterization of an amphiphilic graft polymer and its potential as a pH-sensitive drug carrier

The synthesis and properties of a new pH-sensitive polymer Poly(?-caprolactone) Grafted Poly(ethylene glycol) Based Poly(ß-amino ester) (PEGAE-g-PCL) are described here. The successful synthesis of the graft copolymer was confirmed by ¹H NMR. The self-assemble behavior of the amphiphilic polymer was investigated using pyrene as a probe. Dynamic light scattering (DLS) showed that the polymeric micelles had a size of 60 nm at physiological pH and were responsive to pH. A spherical morphology was observed for the micelles using transmission electron microscopy (TEM). Zeta-potential measurement at different pH showed that the micelles were neutral at pH 7.4 and positively charged at lower pH. Doxorubicin (DOX) was used as a model drug and loaded in the micelles. The drug loaded micelles showed a slow and pH-dependant drug release behavior. The remaining hydroxyl groups on the main chain made it possible the further conjugation of imaging agents or targeting groups.     

Physicochemical characteristics of poly(2-ethyl-2-oxazoline)/poly(ε-caprolactone) block copolymer micelles in water

Summary Polymeric micelles have found numerous applications in the area of biomedical engineering, including the delivery of bioactive molecules. Block copolymers, typical polymeric amphiphiles, form micelles in aqueous phases containing a hydrophobic inner core and hydrophilic outer shell. The unique characteristics of polymeric micelles are mainly controlled by the chemical structure and length of the hydrophilic and hydrophobic blocks. In this study we hypothesized that the solubility parameter values of the organic solvents typically used to dissolve the polymeric amphiphiles and eventually removed from an aqueous phase could significantly influence the characteristics of the resultant micelles in an aqueous phase. Poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) (PEtOz-b-PCL) was synthesized and dissolved in various organic solvents to prepare micelles in water. Their various physicochemical characteristics were investigated by the dynamic light scattering method and fluorescence spectroscopy.     

Polymeric micelles based on hyaluronic acid and phospholipids: Design,characterization, and cytotoxicity

Novel amphiphilic copolymers were synthesized and characterized by ¹H NMR using Hyaluronic acid (HA) as a hydrophilic part and phosphatidylethanolamine (PE) including 1,2‐dimiristoyl‐sn‐glycerol‐3‐phosphatidylethanolamine (DMPE) and 1,2‐distearoyl‐sn‐glycerol‐3‐phosphatidylethanolamine (DSPE) as a hydrophobic segment. The newly developed HA‐PE copolymers form a micelle in an aqueous media. The micellar properties, including critical micelle concentration (CMC) with pyrene as a fluorescence probe and micelle morphology, using transmission electron microscopy were assessed. It was found that the CMC values for HA‐DMPE and HA‐DSPE were 15.5 and 13.4 μg/mL, respectively. Also micelles were spherical in shape and within the size range of 162–214 nm. The solubility of cholesterol, a highly hydrophobic compound, was enhanced to 0.25 mg/mL which is much higher than it is in water (0.0001 mg/mL). In vitro cytotoxicity assay of HA‐PE copolymers showed no toxicity on human breast cancer cell line (MCF‐7). These results suggest that HA‐PE micelles could be considered as a promising carrier for delivery of hydrophobic compounds. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40944.     

基于表面活性剂的反胶团萃取技术

基于表面活性剂的反胶团萃取技术是一种新型的有发展前途的生物分离技术。介绍了反胶团萃取技术的驱动力、表面活性剂选择和影响因素,提出了反胶团萃取技术目前存在的问题,探讨了反胶团萃取技术在其酶促反应和纳米材料制备方面的应用及其发展方向。     

Complex aggregates formed with a hyperbranched polyglycerol derivative for drug delivery

An amphiphilic hyperbranched polyglycerol derivative (HPG‐C18) was synthesized by the anionic ring‐opening copolymerization with glycidol and 1,2‐epoxyloctadecane as the monomers. This hyperbranched polymer formed large complex aggregates as confirmed by dynamic light scattering and transmission electron microscopy tests. Because of its amphiphilic properties, HPG‐C18 was explored to load hydrophobic docetaxel, a clinical antitumor drug, and deliver it into breast cancer cell line (MCF‐7) cells. To investigate the application of the aggregates in drug delivery, blood compatibility was studied by hemolysis analysis, red blood cell observation, and thromboelastography assay. These results indicate that HPG‐C18 inhibited MCF‐7 proliferation effectively with good blood compatibility, and this suggested a potential application in tumor therapy. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42895.     

Crosslinkable micelles from diblock amphiphilic copolymers based on vinylbenzyl thymine and vinylbenzyl triethylammonium chloride

Polymeric micelles (PMs) composed of self‐assembled amphiphilic block copolymers were synthesized from vinylbenzyl thymine (VBT) and vinylbenzyl triethylammonium chloride (VBA) exhibiting improved physical stability. Three diblock copolymers of different chemical compositions and similar molecular weights (polydispersities below 1.5) were obtained via nitroxide mediated radical polymerization. Critical micelle concentration (CMC) was determined by dye micellization method, the shift of the absorption peak of the anionic (EY) due to the interactions with non‐assembled chains and auto‐assembled copolymers was followed. Polymeric systems exhibited good stability revealing that a higher proportion of cationic monomers in the diblock reduce the CMC. Furthermore, after the core of PMs was photocrosslinked by UV irradiation, the CMC decreases notably. Kinetic release studies using EY dye as probe demonstrated that both, higher VBA ratios in the polymer and higher UV‐irradiation, slow down the dye release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41947.     

Biodegradable polylactide/poly(ethylene glycol)/polylactide triblock copolymer micelles as anticancer drug carriers

Adriamycin (ADR) was selected as a model drug to evaluate the potential applications of polylactide/poly(ethylene glycol)/polylactide (PLA/PEG/PLA) micelles as drug carriers in parenteral delivery systems. The PLA/PEG/PLA triblock copolymer micelles were characterized by dynamic light scattering and transmission electron microscopy. It was found that the micelle size increased with the increasing of the PLA chain length. The average size of ADR‐loaded micelles was 143.2 nm. The histogram analysis showed that the ADR‐loaded micelles possessed a narrow unimodal size distribution. The ADR loading contents of the micelles and ADR entrapment efficiency were dependent on the PLA chain length and PEG chain length in the copolymer. They increased with the increase of the PLA chain length, but the PEG chain length was identical and decreased with the increase of the PEG chain length; the length of the PLA block was similar. The initial amount of ADR also influenced the drug contents and entrapment efficiency (i.e., the more the initial amount added, the more the drug contents and the higher encapsulation efficiency). The drug release experiments indicated that the ADR‐loaded micelles possessed sustained release characteristics. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 80: 1976–1982, 2001     

Dual-sensitive and folate-conjugated mixed polymeric micelles for controlled and targeted drug delivery

For this study, we prepared a new type of drug carrier with the characteristics of stimuli-responsive transition and tumor-specific recognition through the co-assembly of two series of amphiphilic block copolymers, poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-methacryloyl caproic acid] and poly(ε-caprolactone)-b-poly[triethylene glycol methacrylate-co-N-(2-(methacrylamido)ethyl) folatic amide]. The pH-dependent thermal transition and the content of the targeting ligands of the mixed polymeric micelles are well correlated with the chemical structures and compositions of these two copolymers. Doxorubicin-loaded mixed polymeric micelles are stable at body temperature in the neutral condition for prolonged circulation in blood vessels, and demonstrated rapid drug release at acidic pH levels. The cumulative drug release profiles showed a relatively slow release at pH 7.4, and a quick release of 85% in 3 h at pH 5.3. The cytotoxicity tests against FA-positive (HeLa) and FA-negative (HT-29) tumor cell lines suggest that this mixed polymeric micelle system has potential merits as a controlled and targeted drug delivery system.     

Synthesis and characterization of dual-stimuli-responsive micelles based on poly(N-isopropylacrylamide) and polycarbonate with photocleavable moieties

Dual-sensitive block copolymers, PNiPAAm-b-PNBTMC, were synthesized via the ring-opening polymerization of 3-methyl-3-nitrobenzyl-trimethylene carbonate (NBTMC) bearing numerous 2-nitro-benzoxycarbonyl photolabile groups with a PNiPAAm macroinitiator in the presence of an organocatalyst, 1,5,7-triazobicyclo-[4.4.0]dec-5-ene (TBD). When the polymer solutions were exposed to ultraviolet (UV) irradiation, we observed significant changes in the structure and morphology of the particles. Fluorescence spectroscopy studies revealed that the copolymers underwent micellization or dissociation transitions in water in response to temperature changes and UV irradiation. No significant toxicity of these nanoparticles was found at concentrations up to 300 μg mL^− 1.     

Polymeric ionic liquids based on ether functionalized ammoniums and perfluorinated sulfonimides

A new family of polymeric ionic liquids (PILs) based on alkyl and alkyl ether substituted ammoniums and perfluorinated sulfonimides (i.e., bis(fluorosulfonyl)imide (FSI⁻), and bis(trifluoromethanesulfonyl)imide (TFSI⁻)) have been synthesized by polymerization of the corresponding ionic liquid monomers (ILMs). Their structures and compositions have been characterized by ¹H and ¹⁹F NMR, FTIR and viscosity-average molecular weight (M_v). The physicochemical properties of both the ILMs and the PILs have been studied in terms of thermal stability, phase transition, and ionic conductivity. All the prepared ILMs and PILs reveal excellent thermal stabilities to greater than 250 °C. The PILs containing alkyl ether side unit show significant decrease in glass transition temperature (T_g), the values of T_g of the alkyl ether based-PILs are all significantly lower by 10–77 °C in magnitude than those of the corresponding alkyl based ones. The ionic conductivity of alkyl ether based-PILs in the best case increases up to 4.0 × 10⁻⁶ S cm⁻¹ at 30 °C, and reaches 7.6 × 10⁻⁵ S cm⁻¹ at 60 °C, and outperform their ammonium counterparts with alkyl side chain that were synthesized as references.     

A pH-Sensitive Polymeric Micellar System Based on Chitosan Derivative for Efficient Delivery of Paclitaxel

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.     

Reduction‐sensitive carrier containing disulfide bond based on Pluronic F68 with cholesterol for drug delivery

The reduction‐sensitive amphiphilic polymer chol‐SS‐F68‐SS‐Chol (F68‐CDEC. chol, SS and F68 represent cholesterol, disulfide bond and Pluronic F68, respectively) was easily synthesized by two steps of esterification reactions. The self‐assembly behavior of the polymer was studied by fluorescence spectrophotometry, dynamic light scattering and TEM. Impressively, the critical micelle concentration of F68‐CDEC was 58‐fold smaller than that of F68. Besides, the drug loading content (LC = 20.25%) was higher than that of F68 (LC = 13.42%). In vitro release experiments showed that the reductant dithiothreitol triggered rapid disintegration of micelles with an accumulated drug amount of 55%, compared with an accumulated drug amount of 20% in phosphate‐buffered saline solution. These good abilities were further proved by cell uptake experiments. More importantly, almost no cytotoxicity was observed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) colorimetric assay and immunofluorescence staining experiments. There are reasons to believe that the polymer F68‐CDEC can be used as a reduction‐sensitive drug delivery material. © 2020 Society of Industrial Chemistry     

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis,characterization, and application as anticancer drug carrier

Amphiphilic A₂(BC)₂ miktoarm star polymers [poly(ϵ-caprolactone)]₂-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]₂ [(PCL)₂(PDEA-b-PPEGMA)₂] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC₅₀ of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)₂(PDEA-b-PPEGMA)₂ micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.     

pH-responsive drug delivery system based on hollow silicon dioxide micropillars coated with polyelectrolyte multilayers

We report on the fabrication of polyelectrolyte multilayer-coated hollow silicon dioxide micropillars as pH-responsive drug delivery systems. Silicon dioxide micropillars are based on macroporous silicon formed by electrochemical etching. Due to their hollow core capable of being loaded with chemically active agents, silicon dioxide micropillars provide additional function such as drug delivery system. The polyelectrolyte multilayer was assembled by the layer-by-layer technique based on the alternative deposition of cationic and anionic polyelectrolytes. The polyelectrolyte pair poly(allylamine hydrochloride) and sodium poly(styrene sulfonate) exhibited pH-responsive properties for the loading and release of a positively charged drug doxorubicin. The drug release rate was observed to be higher at pH 5.2 compared to that at pH 7.4. Furthermore, we assessed the effect of the number of polyelectrolyte bilayers on the drug release loading and release rate. Thus, this hybrid composite could be potentially applicable as a pH-controlled system for localized drug release.     

Star‐shaped amphiphilic block polyurethane with pentaerythritol core for a hydrophobic drug delivery carrier

To obtain polyurethane micelles with excellent stability as a drug delivery carrier, star‐shaped amphiphilic block polyurethane (SAPU) was successfully synthesized by the ‘arm‐first’ method, using methoxypoly(ethylene glycol) and poly(ε‐caprolactone) diol as soft segments, hexamethylene diisocyanate as hard segments and pentaerythritol as the core. The structure of the SAPU was characterized by Fourier transform infrared spectroscopy, ¹H NMR spectroscopy and gel permeation chromatography. The micellization behaviour and micelle properties of SAPU were measured by the pyrene fluorescence probe technique, ¹H NMR, SEM and dynamic light scattering. The results indicated that SAPU could self‐assemble to form nanomicelles in aqueous solution and that the micelles showed excellent stability upon dilution and storage. Indometacin as a model drug could be incorporated into SAPU micelles and be released sustainedly. Meanwhile, the hydrophilic segment content and the molecular weight of SAPU had effects on the micelle properties. In addition, SAPU exhibited good cytocompatibility estimated by methylthiazole‐tetrazolium assay. © 2016 Society of Chemical Industry     

Interpenetrating networks hydrogels based on hyaluronic acid for drug delivery and tissue engineering

There are several techniques for preparing hydrogel biomaterials. Among these techniques, preparation of interpenetrating polymer networks hydrogel (IPNs) has been more interested during last years. IPNs are fabricated by the incorporation of monomers or polymeric chains in hydrogel network. Natural polymers such as hyaluronic acids have some advantages such as biocompatibility, biodegradability and non-toxicity. In this review, we would have a brief view to the interpenetrating polymer networks hydrogel based on hyaluronic acids and its applications as a drug delivery system and tissue engineering applications.     

Biodegradable vesicular nanocarriers based on poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) for drug delivery

Biodegradable polymer vesicle for drug delivery is reported. Poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) with well-defined structure (PCL₁₅₀-b-PEEP₃₀) has been prepared by ring-opening polymerization. It forms vesicles in aqueous solution using the thin-film hydration method and further exclusion of the as-formed vesicles results in vesicles at nano-size, demonstrated by confocal laser scanning microscope (CLSM) and transmission electron microscopy observations. Doxorubicin (DOX) has been loaded into the vesicles with a loading content of 4.38% using an acid gradient method. The release of DOX from the vesicles is accelerated in the presence of an enzyme phosphodiesterase I that is known to catalyze the degradation of polyphosphoester, achieving 83.8% release of total loaded DOX in 140 h. The DOX-loaded vesicles can be successfully internalized by A549 cells, and it results in enhanced inhibition to A549 cell proliferation, likely owning to the sustained intracellular release of DOX as observed by CLSM. With these properties, the vesicles based on the block copolymer of PCL and PEEP are attractive as drug carriers for pharmaceutical application.     

Synthesis and self-assembly of amphiphilic poly(acrylic acid-b-dl-lactide) to form micelles for pH-responsive drug delivery

An amphiphilic diblock copolymer of poly(acrylic acid-b-dl-lactide) (PAAc-b-PDLLA) was synthesized by ring-opening polymerization of dl-lactide initiated by hydroxyl-terminated polyacrylic acid (PAAc-OH). The critical micelle concentration (CMC) of PAAc-b-PDLLA in aqueous solution, determined by fluorescence spectroscopy using pyrene as a probe, was found about 80 mg L⁻¹. A solution of PAAc-b-PDLLA in tetrahydrofuran (THF) was dialyzed against pure water to form pH-responsive micelles. Transmission electron microscopy (TEM) measurement showed that the micelles exhibited regular spherical morphology and the diameters of particles were in the range from 40 to 90 nm. The micelles were stable at a pH above 3 or at an ionic strength below 1.0, however, they aggregated and precipitated in the solutions when further decreasing pH or increasing ionic strength. Prednisone acetate, as a model hydrophobic drug, was loaded into the polymeric micelles. In vitro release of prednisone acetate from polymeric micelles showed that the release kinetics was strongly pH-dependent. Hydrophobic drug displayed “burst” release at pH 7.4, while only a small part of loaded drug released at pH 1.4. This provides a new choice to design delivery system for the gastrointestinal tract (GI tract), where the pH environment is strongly acidic in stomach and basic in intestine. The cytotoxicity measurement by MTT assay indicated that PAAc-b-PDLLA was low toxic in HeLa cells with an IC50 value of 2.8 mg mL⁻¹, which suggests that PAAc-b-PDLLA could be used as a safe candidate for pH-responsive drug delivery.