Morphology Of Micelles Research Articles

Anti-tumor and repairing nerve injuries: A drug-loaded monosialoganliosides micelles delivered to brain for glioblastoma

Event Abstract Back to Event Anti-tumor and repairing nerve injuries: A drug-loaded monosialoganliosides micelles delivered to brain for glioblastoma Dan Zou1, Yazhou Wang1, Zong Li1, Wei Wang1, Tieying Yin1, Bochu Wang1 and Guixue Wang1 1 College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, China Introduction: Compared with clinical remission and extending life, quality of life in patients with glioblastoma have not been given enough attention in clinical treatment. Nerve injuries directly or indirectly effect on life of patients with glioblastoma. And the treatment of brain cancers remains great challenges because most of the therapeutic drugs can’t be delivered to the tumors in the brain directly for the existence of blood-brain barrier (BBB)[1]. Therefore, we applied monosialoganglioside GM1 as drug-loaded nanosized carrier, which is amphiphilic molecules that spontaneously self-assemble into micelles. Moreover, GM1 is a kind of drug that can cross the BBB and treat neurological disease, exogenously administered GM1 have been proved to provoke regeneration and neurite outgrowth in the injured nervous system[2]-[4]. The anti-tumor drugs can be encapsulated in self-assembled micelles of GM1 and are delivered to brain. Therefore, this drug delivery system has the capabilities of overcoming BBB, repairing nerve injuries, and eliminating tumor cells. Materials and Methods: Stock solution of DOX were prepared by dissolving the drug in dimethylsulfoxide (DMSO). Stock solution of purified monosialogangliosides GM1 were prepared by dissolving the gangliosides in tri-distilled water, and the solution were maintained at 4℃, they should be centrifuged and filtered prior to use. Stock solutions of DOX were slowly added to the solution of GM1micelles. Then the mixed micelles were incubated at 4℃ for 24h and dialyzed for 24h. The structure and morphology were characterized by TEM, and the mean diameter and its distribution were measured by means of Zetasizer. The method of DIR-loaded micelles is consistent with the preparation of mixed micelles of GM1 and DOX. Fluorescent micelles were injected intravenously in the caudal vein. Discussion and Conclusion: The morphology of micelles was detected using a JEM 1200EX transmission electron microscope. Fig A showed micelles GM1/DOX mixed micelles with about 20nm of mean diameter tends to evenly distributed. A normal mouse was injected with GM1/DIR micelles, distribution and intensity of DIR were monitored by In-Vivo FX PRO for small animal imaging. It revealed that GM1 can cross blood-brain barrier and target to brain because DIR were concentrated mainly in the brain tissue. (Fig.B). Figure A. Electron microscopy of GM1 and DOX mixed micelles. Scale bar: 200nm.B. Experimental group (A) was injected with GM1/Dir micelles after 5 hours. National Natural Science Foundation of China (31200713); National Key Basic Research Project (“973” Project) （2014CB541600）; Fundamental Research Funds for the Central Universities(106112015CDJZR235514)

Compatibility studies between an amphiphilic pH-sensitive polymer and hydrophobic drug using multiscale simulations

Dissipative particle dynamics simulations are integrated to investigate the morphologies of drug-loaded micelles and the drug distributions inside the micelles at different pH conditions.

Microstructural morphologies of CTAB micelles modulated by aromatic acids

pH and temperature-dependent aggregation behaviour of CTAB with solubilized aromatic acids.

Synergistic effect of pH-responsive wormlike micelles based on a simple amphiphile.

Imagine a novel solution that can be switched reversibly from low viscosity to high viscosity with only one additive, upon different commands. To this end, we have developed a simple and effective route to form smart, multi-response wormlike micelles based on a synthesized surfactant, N-cetyl-N,N-diisopropanolammonium bromide (CDIAB). Moreover, we provide new insight into the effects of synergy on this smart wormlike micelle. Rheological measurements were used to study the morphology of the wormlike micelles; (1)H NMR spectroscopy and density functional theory (DFT) calculations were employed to investigate the molecular arrangements and mechanism of the synergy involved in the reversible reactions of pH-response and CO2-response of the micelles in solution. Based on the abovementioned results, it is encouraging to discover that binding energy and electrostatic interaction are the basic driving forces in the formation of wormlike micelles. Moreover, stable viscoelastic behavior was observed in the CDIAB system, with strong binding energy and electrostatic interactions. It is highly anticipated that the synergy observed in this surfactant will be of particular interest due to its novel mechanism and unique properties.

CO2-switchable fluorescence of a dendritic polymer and its applications.

The synthesis and properties of CO2 responsive and fluorescent dendritic polymers, poly(amido amine)/Pluronic F127 (PAMAM/F127), are reported in this paper. The morphologies and sizes of PAMAM/F127 dendritic polymers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). PAMAM/F127 dendritic polymers showed unimolecular micelle morphologies at low concentrations, and changed to multimolecular micelles at higher concentrations. Additionally, fluorescence spectra and confocal laser scanning microscopy images showed that PAMAM/F127 dendritic polymers exhibited a fluorescent enhancement response to the presence of CO2. Apart from that, the release behavior of PAMAM/F127 gels under simulated body fluids was investigated by choosing curcumin as the hydrophobic drug. The results indicated that PAMAM/F127 dendritic polymers can be used to improve the solubility of curcumin, and the drug released faster in the presence of CO2. Such CO2 responsive fluorescent dendritic polymers are potentially applicable in cellular imaging or drug controlled release.

Fine-tuning of gold nanorod dimensions and plasmonic properties using the Hofmeister effects

CTAB micelle morphology changes induced by the addition of Hofmeister salts have been studied by cryo-electron microscopy for the first time. The effect of those changes is correlated to the growth of the rods, providing a new method for the fine-tuning of their dimensions.

Mesoscopic simulation studies on the formation mechanism of drug loaded polymeric micelles

In this work, the formation of polymeric micelles as drug delivery vehicles in an aqueous environment is investigated by dissipative particle dynamics (DPD) simulations. Doxorubicin (DOX) is selected as the model drug, whereas docosahexaenoic acid (DHA) conjugated His10Lys10 (DHA-His10Lys10) as the drug carrier. It is shown from DPD simulation that drug molecules and DHA-His10Lys10 molecules could aggregate and form micelles under a defined composition recipe; drug molecules are homogeneously distributed inside the carrier matrix, on whose surface the stabilizer lysine segments are absorbed. Under different compositions of drug and water, aggregate morphologies of polymeric micelles are observed as spherical, columnar, and lamellar structures. We finally proposed the formation mechanism of drug loaded polymeric micelles and apply it in practice by analyzing the simulated phenomena. All the results can effectively guide the experimental preparation of drug delivery system with desired properties or explore a novel polymeric micelle with high performance.

Morphology and Luminescent Properties of Solid Micelles based on Europium(III) Complexes with Diblock Copolymers of Methyl Methylacrylate and Acrylic Acid

In this article, diblock copolymer (DBC), poly (methyl methacrylate)-block-poly (acrylic acid) was synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT). The DBC-Eu3+ solid micelles were prepared through the complex interaction between DBC and Eu3+ ions. As cross-linker, Eu3+ ions accept the electron donation of the ligand groups (carboxyl) sited on the polar PAA segments of DBC and form the DBC-Eu3+ solid micelles. The observations by transmission electron microscopy showed the embedment of Eu3+ ions in DBC and the nonpolar segments [poly (methyl methacrylate)] of DBC play a role of compatible agent for DBC-Eu3+ solid micelles to disperse in hydrophobic solvent [for example, dimethyl formamide] or polymer matrix. Very importantly, we found the dependence of the morphological structure (i.e. the size of solid micelles) on the molecular weight of DBC. On the other hand, the dependence of photoluminescent property of DBC-Eu3+ solid micelles on the molecular weight of DBC and the ratio of polar and nonpolar segments was confirmed through our experiments. The results showed the existence of enhanced photoluminescent property of DBC-Eu3+ solid micelles.

Supersaturation induced by Itraconazole/Soluplus® micelles provided high GI absorption in vivo

To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole (ITZ)/Soluplus® solid dispersion. Solid dispersions prepared by hot melt extrusion (HME) were compressed into tablets directly with other excipients. Dissolution behavior of ITZ tablets was studied by dissolution testing and the morphology of micelles in dissolution media was studied using transmission electron microscopy (TEM). Drug transferring from stomach into intestine was simulated to obtain a supersaturated drug solution. Bioavailability studies were performed on the ITZ tablets and Sporanox® in beagle dogs. The morphology of micelles in the dissolution media was observed to be spherical in shape, with an average size smaller than 100 nm. The supersaturated solutions formed by Soluplus® micelles were stable and no precipitation took place over a period of 180 min. Compared with Sporanox®, ITZ tablets exhibited a 2.50-fold increase in the AUC(0–96) of ITZ and a 1.95-fold increase in its active metabolite hydroxyitraconazole (OH-ITZ) in the plasma of beagle dogs. The results obtained provided clear evidence that not only the increase in the dissolution rate in the stomach, but also the supersaturation produced by micelles in the small intestine may be of great assistance in the successful development of poorly water-soluble drugs. The micelles formed by Soluplus® enwrapped the molecular ITZ inside the core which promoted the amount of free drug in the intestinal cavity and carried ITZ through the aqueous boundary layer (ABL), resulting in high absorption by passive transportation across biological membranes. The uptake of intact micelles through pinocytosis together with the inhibition of P-glycoprotein-mediated drug efflux in intestinal epithelia contributed to the absorption of ITZ in the gastrointestinal tract. These results indicate that HME with Soluplus®, which can induce supersaturation by micelle formation, may be of great assistance to the successful development of poorly water-soluble drugs.

Micelle formation from hydrophobically end-capped poly(ethylene oxide) and its application for delivery of poorly water-soluble drug

The formation of micelle self-assembled from hydrophobically end-capped poly(ethylene oxide) (PEO) and its application for drug delivery have been investigated. As an important ABA-type associative triblock copolymer, a series of hydrophobically end-capped poly(ethylene oxide) [H(CH2)nO(CH2CH2O)m(CH2)nH], consisting of PEO (B) as hydrophilic segment and alkyl groups as hydrophobic block, are synthesized successfully according to 1H NMR, Fourier transform infrared (FTIR), and differential scanning calorimetry (DSC) measurements. The triblock polymer is easy to form aggregates (micelles) under the appropriate conditions. The morphologies of micelles are found to be spherical confirmed by atomic force microscopy (AFM) measurement. Then, the polymeric micelles self-assembled from the triblock copolymer are used as a nanocarrier to solubilize poorly water-soluble drug spironolactone (a typical hydrophobicity drug). In vitro release behavior of spironolactone from triblock copolymer micelle is investigated carefully. It indicates interestingly that the drug can be released from triblock copolymer micelle stably and the release rate can be modulated by the variation of copolymer composition.

Preparation and in vivo/in vitro evaluation of formononetin phospholipid/vitamin E TPGS micelles

To enhance the formononetin (FN) antitumor effect, we developed a passive targeting FN-contained formulation. FN-contained Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS)/phospholipid micelles were prepared by the solvent injection method. Particle size, polydispersity, zeta potential, encapsulation efficiency, drug release profile, and micelles morphology were evaluated and characterized by various methods including high-performance liquid chromatography, dynamic light scattering, and transmission electron microscopy. Cellular uptake of micelles was evaluated with fluorescence imaging coupled with HPLC method. Cytotoxicity of FN micelles and free FN was compared using MTT method. In vivo imaging was employed to assess the accumulation of DiR micelles and free DiR at tumor site. The antitumor effect of FN micelles was examined in tumor-bearing mice. The results showed that prepared FN micelles had an average particle diameter of 111.91 ± 5.82 nm with good stability. FN micelles enhanced the cellular uptake and improved cell cytotoxicity than free FN. Furthermore, DiR micelles quickly accumulated at the tumor site than free DiR. FN micelles significantly improved tumor inhibition rate compared to that observed with free FN in tumor-bearing mice with great biosafety. Thus, FN micelles demonstrated a clear treatment advantage and provided an ideal drug administration system to improve the antitumor effect of FN.

Reverse micelles prepared from amphiphilic polylactide-b-poly(ethylene glycol) block copolymers for controlled release of hydrophilic drugs

This work aims to evaluate the potential of reverse micelles prepared from amphiphilic polylactide-b-poly(ethylene glycol) (PLA-b-PEG) block copolymers for controlled release of hydrophilic drugs. Different PLA-b-PEG diblock and triblock copolymers were synthesized by ring-opening polymerization of D- or l-lactide in the presence of a PEG macroinitiator. Reverse micelles were prepared by self-assembly of copolymers in a solvent/co-solvent/water system. Toluene was used as solvent, and ethanol as co-solvent to solubilize appropriate amount of water. The resulting nano-sized reverse micelles were able to encapsulate heparin in the hydrophilic core. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to determine the size and morphology of reverse micelles. The results show that reverse micelles are spherical in shape with sizes below 100nm. Drug loaded reverse micelles were embedded in biocompatible membranes by mixing with 10% PLA solution in toluene with 1:3 volume ratio. In vitro release studies were realized in phosphate buffer saline (PBS) at 37°C. Heparin was almost totally released within 24h. Triblock copolymer reverse micelles exhibited faster drug release than diblock ones probably due to the more compact micelle structure of the latter. Therefore, PLA-b-PEG reverse micelles could be promising for applications as carrier of hydrophilic drugs when embedded in biocompatible membranes.

Organic solvent-free low temperature method of preparation for self assembled amphiphilic poly(ϵ-caprolactone)–poly(ethylene glycol) block copolymer based nanocarriers for protein delivery

Degradation and denaturation of labile biomolecules during preparation of micelles by organic solvent at high temperature are some of the limitations for fabrication of advanced polymer based protein delivery systems. In this paper, effectiveness of heat–chill method for preparation of micelles containing large labile biomolecules was investigated using insulin as a model protein molecule. Micelles (average size, <120nm) were prepared using amphiphilic diblock and triblock copolymers of poly(ethylene glycol) (PEG) and poly(ϵ-caprolactone) (PCL). Micelles were prepared by heating PEG–PCL block copolymers with distilled water at 60°C followed by sudden chilling in an ice-water bath. Effects of molecular architecture on morphology, stability and protein loading capacity of micelles were investigated. Micelles prepared using high molecular weight block copolymers exhibited good colloidal stability, encapsulation efficiency and insulin release characteristics. Insulin retained its secondary structure after micelles preparation as confirmed by CD spectroscopic study. Furthermore, in vitro cytotoxicity test suggested that the prepared micellar nanoparticles possessed biocompatibility. In a nut shell, heat–chill method of micellar nanoparticles preparation is well suited for encapsulating labile proteins and other allied biomolecules which degrade in presence of toxic organic solvents and at elevated temperatures.

Preparation of multicompartment micelles from amphiphilic linear triblock terpolymers by pH-responsive self-assembly

Multicompartment micelles, as an intriguing class of self-assembled aggregates with subdivided solvophobic cores, show high potentials for various applications. Their unique morphologies and sequestration properties depend highly on structure and chemical composition of the building blocks as well as self-assembly environments. To further understand their relationships, a series of well-defined amphiphilic triblock terpolymers poly(methyl methacrylate)-block-poly(2-(cinnamoyloxy)ethyl methacrylate)-block-poly(2-dimethylaminoethyl methacrylate) (PMMA-b-PCEMA-b-PDMAEMA) was synthesized via sequential atom transfer radical polymerization (ATRP) followed by selective modification of the middle block, and the self-assembly of PMMA-b-PCEMA-b-PDMAEMA via direct dispersing in water and step-wise procedures through solvent exchange was studied, respectively. Dynamic laser scattering (DLS) studies showed the existence of large-sized aggregates formed through direct self-assembly of PMMA-b-PCEMA-b-PDMAEMA triblock terpolymers in water, and the aqueous solutions were found to exhibit the surface tension reduction. This is probably caused by the frozen micelles adsorbed on the air/water interface which play the role of Pickering emulsifiers. However, PMMA-b-PCEMA-b-PDMAEMA multicompartment micelles could be successfully prepared by the step-wise self-assembly method, inhibiting the formation of frozen micelles and large aggregates. Prepared from different PMMA-b-PCEMA-b-PDMAEMA triblock terpolymers, the homogeneously nano-sized multicompartment micelles of oval morphologies with distinct subdivided core domains were confirmed by transmission electron microscope (TEM). Besides, various morphologies of the multicompartment micelles were obtained simply by altering the pH value of water. This multicompartment micelle system with adjustable pH response holds potential for therapeutic delivery of multiple incompatible drug payloads and is believed to contribute to enriching the research field of tunable polymer self-assemblies.

H-Shaped copolymer ((His)PHEMA)2-b-PEG-b-(PHEMA(His))2 with histidine modified: Synthesis, characterization and its drug release study

Through H-shaped macroinitiator glycol-chlorine((Cl)2-PEG-(Cl)2) to initiate the ATRP reaction of 2-Hydroxyethyl Methacrylate (HEMA) we synthesized H-shaped copolymer (PHEMA)2-b-PEG-b-(PHEMA)2. After we modified the copolymer with histidine (His), the self-assembling and drug release behavior was studied. The morphology of the copolymer micelles and drug loaded micelles were examined by transmission electron microscope (TEM). Spherical micelles and core-shell structure with a diameter of 165 nm were obtained (at pH = 7.0). Due to the presence of imidazole-ring in histidine the copolymer show commendable pH-sensitivity, which made the copolymer potential application as drug carrier exhibiting good control-released property.

In Vitro and In Vivo Efficacy of Self-Assembling RGD Peptide Amphiphiles for Targeted Delivery of Paclitaxel

The objective of this work was to compare the efficacy of self-assembling cyclic and linear RGD peptide amphiphiles as carriers for delivering paclitaxel to αvβ3 integrin overexpressing tumors. Linear (C18-ADA5-RGD) and cyclic (C18-ADA5-cRGDfK) peptide amphiphiles were synthesized and characterized for CMC, aggregation number and micelle stability using fluorescence spectroscopy methods. Size and morphology of micelles was studied using TEM. Fluorescence polarization and confocal microscopy assays were established to compare binding and internalization of micelles. The targeting efficacy was studied in A2058 cells using cytotoxicity assay as well as in vivo in melanoma xenograft mouse model. The linear and cyclic RGD amphiphiles exhibited CMC of 25 and 8 μM, respectively, formed nano-sized spherical micelles and showed competitive binding to αvβ3 integrin protein. FITC-loaded RGD micelles rapidly internalized into A2058 melanoma cells. Paclitaxel-loaded RGD micelles exhibited higher cytotoxicity compared with free drug in A2058 cells in vitro as well as in vivo. Cyclic RGD micelles exhibited better targeting efficacy but were less effective compared to linear RGD micelles as drug delivery vehicle due to lower drug solubilization capacity and lesser kinetic stability. Results from the study proved the effectiveness of self-assembling low molecular weight RGD amphiphiles as carriers for targeted delivery of paclitaxel.

Chemoenzymatic Synthesis of Amphiphilic Core-Shell TMP-(PCL-b-PGMA2)3 Star-Block Copolymer.

A novel well-defined amphiphilic Core-Shell star-block copolymer was synthesized from trimethylolpropane, ε-caprolactone, and glycidyl methacrylate by a combination of enzymatic ring-opening polymerization and atom transfer radical polymerization. The structure and molecular weight of the macroinitiator and the star-block copolymer were confirmed by means of nuclear magnetic resonance and gel permeation chromatography. The effects of the glycidyl methacrylate sequence length on the hydrodynamic diameter and morphology of the polymer micelles were investigated by dynamic light scattering and transmission electron microscopy, respectively.

Morphology and thermoresponsive behavior of hybrid micelles of polystyrene-b-poly((N-isopropyl acrylamide)-co-(4-vinylbenzyl chloride)) with Prussian blue

The hybrid micelles of polystyrene-b-poly((N-isopropyl acrylamide)-co-(4-vinylbenzyl chloride)) block copolymer (PS-b-P(NIPAM-co-VBC)) with Prussian blue (PB) in the corona were prepared by reaction of pentacyano(4-(dimethylamino)-pyridine)ferrate (Fe-DMAP)-attached PS-b-P(NIPAM-co-VBC) with FeCl3. The formation of the PB framework inside the micelles was verified by UV-Vis, FTIR and TGA. The morphology of the hybrid micelles was studied by TEM and compared with that of the neat and Fe-DMAP-attached PS-b-P(NIPAM-co-VBC). It is found that attachment of Fe-DMAP may change the short rod-like micelles of the neat PS-b-P(NIPAM-co-VBC) into spherical ones and lead to a smaller micelle size. The morphology of the hybrid micelles may be altered or remain unchanged after formation of the PB framework, depending on the chain structure of PS-b-P(NIPAM-co-VBC) and starting concentration. The thermoresponsive behavior of different micelles was studied using DLS. It is observed that attachment of Fe-DMAP can improve the hydrophilicity of the P(NIPAM-co-VBC) block, leading to weaker hysteresis of the micelle size during the heating and cooling cycle. However, the crosslinked PB framework in the micellar corona may result in a more evident hysteresis phenomenon and blur the two-stepwise change of the micellar size with temperature.

Probing competitive interactions in quaternary formulations

HypothesisThe interaction of amphiphilic block copolymers of the poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) group with small molecule surfactants may be “tuned” by the presence of selected alcohols, with strong interactions leading to substantial changes in (mixed) micelle morphology, whilst weaker interactions lead to coexisting micelle types. ExperimentsThe nature and the strength of the interactions between Pluronic P123 (EO20PO70EO20) and small molecule surfactants (anionic sodium dodecylsulfate, SDS, C12SO4Na), (cationic dodecyltrimethylammonium bromide, C12TAB) and (non-ionic polyoxyethylene(23)lauryl ether, Brij 35, C12EO23OH) is expected to depend on the partitioning of the short, medium and long chain alcohols (ethanol, hexanol and decanol respectively) and was probed using tensiometry, pulsed-gradient spin-echo nuclear magnetic resonance (PGSE-NMR) and small-angle neutron scattering (SANS). FindingsThe SANS data for aqueous P123 solutions with added alcohols were well described by a charged spherical core/shell model for the micelle morphology. The addition of the surfactants led to significantly smaller, oblate elliptical mixed micelles in the absence of alcohols. Addition of ethanol to these systems led to a decrease in the micelle size, whereas larger micelles were observed upon addition of the longer chain alcohols. NMR studies provided complementary estimates of the micelle composition, and the partitioning of the various components into the micelle.

Amine-Functionalized CO2 Responsive Triblock Copolymer Micelles—A Small-Angle X-ray Scattering Study

CO2 responsive colloids are of interest for the delivery of active molecules in both pharmaceutical applications and for gas treatment technologies, among others. Primary and secondary organic amines react with CO2 gas in aqueous solution to form ionic carbamates in an exothermic “CO2 sequestration” reaction. Several amines important in this context are 2-aminoethanol, 2,2′-iminodiethanol, and piperazine. We have used small-angle X-ray scattering at a high intensity synchrotron source to demonstrate that triblock copolymer micelles containing carbamate-forming amines change shape upon exposure to CO2. Modeling of the scattering data is used to elucidate the effects of exposure on micelle size and morphology. Electron density distribution within the micelles, derived from the SAXS data, established that the amines interact with the polymer micelles. The products of CO2 exposure, namely, carbamate, bicarbonate anions, and protons, modify the packing of the polymer chains, and occupy the volume within the polymer aggregates. Our findings contribute to the detailed understanding and optimization of liquid based CO2-responsive systems.