Comparison of PEG chain length and density on amphiphilic macromolecular nanocarriers: Self-assembled and unimolecular micelles (original) (raw)
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New amphiphilic PEG-b-P(ester–ether) micelles as potential drug nanocarriers
A range of diblock and triblock copolymers of dioxanone and methyl dioxanone (MeDX) were synthesized by ring-opening polymerization of dioxanone and MeDX initiated by hydroxyl-terminated PEG (MPEG) or di-amino-terminated PEG (Jeffamine) as macroinitiator in the presence of Sn(Oct)2. The copolymers exhibit amphiphilic behavior in water forming core–shell micelles in the size range 120–300 nm as measured by DLS. DSC measurements exhibit only one melting transition for all copolymers and confirm that increasing MeDX content of the copolymers lead to decreasing crystalline character and hydrophobic–hydrophilic chain entanglement. Anti-inflammatory drug ketoprofen was successfully loaded into the hydrophobic core of the micelles. Various key parameters such as micelle size, drug entrapment efficiency and drug release, which are dependent on crystalline structure and biodegradability characteristics of the hydrophobic core, could effectively be controlled by varying the dioxanone/MeDX ratio of the (ester–ether) copolymer.
Polymeric micelle as a nanocarrier for delivery of therapeutic agents: A comprehensive review
Journal of Drug Delivery and Therapeutics
For selective and effective drug delivery of therapeutic agent nanocarriers are the most effective agents. Micelles are an aggregate of surfactant molecules that dispersed in a liquid colloid. Micelles have a variety of shapes such as spheres, rods, vesicles, tubules, and lamellae. The shape and size of a micelle are a function of the molecular geometry of its surfactant molecules and solution conditions such as surfactant concentration, temperature, pH, and ionic strength. Poly Ethylene Glycol (PEG) is the most commonly used hydrophilic segment of micelles for drug delivery. Besides PEG, other polymers including poly (N-vinyl pyrrolidone) (PVP) and poly (N-isopropyl acrylamide) (pNIPAM) have also been used as hydrophilic portion of micelles. In this review we all discus about the polymeric micelles (PMs) as a nanocarriers for delivery of therapeutic agents. Keywords: Polymeric Micelles, Colloids, Nanocarriers, Drug Delivery, Poly Ethylene Glycol(PEG)
Colloidal Drug Delivery Systems – Recent Advances With Polymeric Micelles
CHIMIA, 2008
With the emergence of nanotechnology in drug delivery, colloidal systems and particularly polymeric micelles have attracted great attention. Polymeric micelles formed by the self-assembly of amphiphilic copolymers adopt a core-shell structure, which can be loaded with drugs and used as drug delivery systems for various medical applications. The most interesting aspects involve extended blood circulation times and stability upon dilution, which enable polymeric micelles to accumulate in tumor or inflammation sites due to the enhanced permeation and retention effect (EPR). In the first part of this paper polymeric micelles with different morphologies and different circulating-, active- and passive targeting, and stimuli responsive properties will be reviewed. Furthermore amphiphilic block copolymers of different compositions for pharmaceutical micelle formulations will be discussed. The hydrophilic block is often composed of the biocompatible polyethylene glycol (PEG), whereas diverse...
Journal of Visualized Experiments, 2015
Amphiphilic block copolymers like polyethyleneglycol-block-polylactic acid (PEG-b-PLA) can self-assemble into micelles above their critical micellar concentration forming hydrophobic cores surrounded by hydrophilic shells in aqueous environments. The core of these micelles can be utilized to load hydrophobic, poorly water soluble drugs like docetaxel (DTX) and everolimus (EVR). Systematic characterization of the micelle structure and drug loading capabilities are important before in vitro and in vivo studies can be conducted. The goal of the protocol described herein is to provide the necessary characterization steps to achieve standardized micellar products. DTX and EVR have intrinsic solubilities of 1.9 and 9.6 µg/ml respectively Preparation of these micelles can be achieved through solvent casting which increases the aqueous solubility of DTX and EVR to 1.86 and 1.85 mg/ml, respectively. Drug stability in micelles evaluated at room temperature over 48 hr indicates that 97% or more of the drugs are retained in solution. Micelle size was assessed using dynamic light scattering and indicated that the size of these micelles was below 50 nm and depended on the molecular weight of the polymer. Drug release from the micelles was assessed using dialysis under sink conditions at pH 7.4 at 37 o C over 48 hr. Curve fitting results indicate that drug release is driven by a first order process indicating that it is diffusion driven.
Biomacromolecules, 2014
3-Helix micelles have demonstrated excellent in vitro and in vivo stability. Previous studies showed that the unique design of the peptide− polymer conjugate based on protein tertiary structure as the headgroup is the main design factor to achieve high kinetic stability. In this contribution, using amphiphiles with different alkyl tails, namely, C16 and C18, we quantified the effect of alkyl length on the stability of 3-helix micelles to delineate the contribution of the micellar core and shell on the micelle stability. Both amphiphiles form well-defined micelles, <20 nm in size, and show good stability, which can be attributed to the headgroup design. C18micelles exhibit slightly higher kinetic stability in the presence of serum proteins at 37°C, where the rate constant of subunit exchange is 0.20 h −1 for C18-micelles vs 0.22 h −1 for C16-micelles. The diffusion constant for drug release from C18-micelles is approximately half of that for C16-micelles. The differences between the two micelles are significantly more pronounced in terms of in vivo stability and extent of tumor accumulation. C18-micelles exhibit significantly longer blood circulation time of 29.5 h, whereas C16-micelles have a circulation time of 16.1 h. The extent of tumor accumulation at 48 h after injection is ∼43% higher for C18-micelles. The present studies underscore the importance of core composition on the biological behavior of 3-helix micelles. The quantification of the effect of this key design parameter on the stability of 3-helix micelles provides important guidelines for carrier selection and use in complex environment.
Drug Development and Industrial Pharmacy, 2017
Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. A conjugate of the antitumor drug, doxorubicin, with diblock methoxy poly (ethylene glycol)-poly caprolactone (mPEG-PCL) copolymer was synthesized by the reaction of mPEG-PCL copolymer with doxorubicin in the presence of pnitrophenylchloroformate. The conjugated copolymer was characterized in vitro by 1 H NMR, FTIR, DSC and GPC techniques. Then, the doxorubicin conjugated mPEG-PCL(DOX-mPEG-PCL) was self-assembled into micelles in the presence of curcumin in aqueous solution.The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).The encapsulation efficiency of doxorubicin and curcumin were 82.31±3.32% and 78.15±3.14%, respectively. The results revealed that the micelles formed by the DOX-mPEG-PCL with and without curcumin have spherical structure withthe average size of 116 and 134 nm respectively.The release behavior of curcumin and doxorubicin loaded to micelles were investigated in different media. The release rate of micelles consisted of the conjugated copolymer was dependent on pH asit was higher at lower pH than in neutral condition. Another feature of the conjugated micelles was a sustained release profile. The cytotoxicity of micelles were evaluated by MTT (3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide, atetrazole) assay on lung cancer A549 cell lines. In vitro cytotoxicity assay showed that the mPEG-PCL copolymer did not affect the growth of A549 cells. The cytotoxic activity of the micelles against A549 cells was greater than free doxorubicin and free curcumin.
Biomacromolecules, 2014
One constrain in the use of micellar carriers as drug delivery systems (DDSs) is their low stability in aqueous solution. In this study "tree-shaped" copolymers of general formula mPEG-(PLA) n (n = 1, 2 or 4; mPEG = poly(ethylene glycol) monomethylether 2K or 5K Da; PLA = atactic or isotactic poly(lactide)) were synthesized to evaluate the architecture and chemical composition effect on the micelles formation and stability. Copolymers with mPEG/PLA ratio of about 1:1 wt/wt were obtained using a "core-first" synthetic route. Dynamic Light Scattering (DLS), Field Emission Scanning Electron Microscopy (FESEM), and Zeta Potential measurements showed that mPEG 2K -(PD,LLA) 2 copolymer, characterized by mPEG chain of 2000 Da and two blocks of atactic PLA, was able to form monodisperse and stable micelles. To analyze the interaction among micelles and tumor cells, FITC conjugated mPEG-(PLA) n were synthesized. The derived micelles were tested on two, histological different, tumor cell lines: HEK293t and HeLa cells. Fluorescence Activated Cells Sorter (FACS) analysis showed that the FITC conjugated mPEG 2K -(PD,LLA) 2 copolymer stain tumor cells with high efficiency. Our data demonstrate that both PEG size and PLA structure control the biological interaction between the micelles and biological systems. Moreover, using confocal microscopy analysis, the staining of tumor cells obtained after incubation with mPEG 2K -(PD,LLA) 2 was shown to be localized inside the tumor cells. Indeed, the mPEG 2K -(PD,LLA) 2 paclitaxel-loaded micelles mediate a potent antitumor cytotoxicity effect.
A novel monomethyl itaconate-based copolymer (PEG-PMMI-CholC 6 ) bearing cholesteryl (CholC 6 ) and poly(ethylene glycol) (PEG) side chains with specific degrees of side-chain substitution (DS Chol =4.85 and DS PEG =16.41) was synthesized by performing a reaction involving cholesterol-containing poly(monomethyl itaconate) (PMMI-CholC 6 ) and polyethylene glycol monomethyl ether (PEG, M W ∼2000). In aqueous solution, reversible pH-responsive micelle-like aggregates of PMMI-CholC 6 and PEG-PMMI-CholC 6 amphiphilic copolymers formed, with their phase transitions occurring around pH 3.8 and 5.12, respectively. The presence of the PEG groups improved the hydrophilicity of the copolymer and suppressed excessive micelle aggregation. The critical micelle concentration (CMC) of the PEG-PMMI-CholC 6 copolymeric micelles at pH5.12 was about 1 mg/L. DLS and TEM studies revealed that the spherical micelles had mean diameters of <50 nm, which increased in basic solution. On the other hand, upon increasing the pH, the zeta potential decreased from −0.645 to −47.1 due to increased negative charge on the surfaces of the micelles. These pH-responsive micelles were then loaded with piroxicam (PX), a hydrophobic anticancer drug. High drug entrapment efficiencies (>40 %) of the PEG-PMMI-CholC 6 micelles were observed due to the enhanced surface hydrophilicity of these micelles. In vitro release studies performed in buffer solutions at pH 1.2, 4.5, and 7.4 indicated that the PEG-PMMI-CholC 6 delivery system can act as a stable nanocarrier allowing controlled drug release at target sites in the pH range 4.5-7.4. Interestingly, MTT assays indicated that the PEG-PMMI-CholC 6 micelles did not inhibit HeLa cells regrowth, even at high micellar concentrations. These results suggest that PEG-PMMI-CholC 6 micelles have great potential to be safely used in tumor-targeting chemotherapy.
Polymeric micelles as drug delivery vehicles
Though much progress has been made in drug delivery systems, the design of a suitable carrier for the delivery of hydrophobic drugs is still a major challenge for researchers. The use of micellar solutions of low molecular weight surfactants has been one of the popular methods for the solubilization of hydrophobic drugs; however, such surfactants suffer from high critical micelle concentration and concomitant low stabilities. In contrast to surfactants of low molecular masses, polymeric micelles are associated with general advantages like higher stability, tailorability, greater cargo capacity, non-toxicity and controlled drug release. Therefore, the current review article is focused on the engineering of the core of polymeric micelles for maximum therapeutic effect. For enhanced drug encapsulation capacity and getting useful insights into the controlled release mechanism we have reviewed the effects of temperature and pH on responsive polymeric micelles. The article also presents important research outcomes about mixed polymeric micelles as better drug carriers in comparison to single polymeric micelles.