Pluronic Micelles Research Articles

RETRACTED: Pluronic® F127 stabilized reduced graphene oxide hydrogel for transdermal delivery of ondansetron: Ex vivo and animal studies

Ondansetron which is used to manage vertigo, nausea and vomiting suffer from the major limitations of low oral bioavailability (60 %) and short half-life (3-4 h), which affects the routine life style of patients (noncompliance due to multiple dosing). The present work aim to developed ondansetron loaded Pluronic® F127 stabilized reduced graphene oxide hydrogel (2 % Carbopol 940 base) as a promising transdermal delivery system, capable of sustaining and tailoring the drug release profile. The fourier transform infrared spectroscopy, raman spectroscopy, and X-ray diffraction reports confirm the attachment of Pluronic® F127 on the reduced graphene oxide. The scanning electron microscopy image showed the wrinkled and flattened nano-sheet surface with the presence of Pluronic F127 micelles. The hydrogel showed sufficient mechanical properties (texture analysis) for topical application. The ex vivo permeation data suggest that the flux decreased proportionally (due to π- π stacking interaction) with increase in the level of graphene oxide in the hydrogel, which indicate that the drug release rate can be tailored by changing the level of graphene oxide in the hydrogel. The high area under the curve, mean residence time and 2.89 fold increased in the bioavailability (rat model) suggest the potential of ondansetron loaded Pluronic® F127-graphene oxide hydrogel to sustain the release of ondansetron to manage vertigo, nausea and vomiting.

Toward understanding the prolonged circulation and elimination mechanism of crosslinked polymeric micelles in zebrafish model

Understanding the behaviors of nanomedicines in vivo is one of the most important prerequisites for the design and optimization of nanomedicines. However, the in vivo tracking of nanomedicines in rodents is severely limited by the restricted imaging possibilities within these animals. To meet these needs, the FRET (fluorescence or Förster resonance energy transfer) imaging combined with visual zebrafish larvae model (7 dpf) was used to study the behaviors of polymeric micelles in vivo at high spatiotemporal resolution. Firstly, the FRET ordinary Pluronic micelles (OPMs) and disulfide bond crosslinked Pluronic micelles (CPMs) were synthesized to quantify their integrity in vitro and in vivo by FRET ratio. The behaviors and integrity of OPMs and CPMs in vivo were visually investigated in zebrafish larvae across the entire living organism and at cellular molecular level after intravenous microinjection. Results showed that OPMs were rapidly disassociated in circulation, then largely sequestrated by the endothelial cells (ECs) of caudal vein (CV) and liver in zebrafish larvae, which resulted in quick elimination from blood circulation. While the CPMs were more stable and escaped the sequestration by ECs of CV and liver, which prolonged their circulation in blood. Moreover, we pioneered to use the zebrafish model to reveal that polymeric micelles were eliminated through hepatobiliary pathway after disassociation. While the intact micelles were relatively difficult to eliminate. We further verified that the scavenger receptors of ECs but not the macrophages mainly mediated the elimination of polymeric micelles in CV and liver of zebrafish larvae. These finding on behaviors and elimination mechanisms of polymeric micelles in zebrafish model could contribute to the rational design and optimization of nanomedicines, further guide their studies in rodents.

Poloxamer/sodium cholate co-formulation for micellar encapsulation of doxorubicin with high efficiency for intracellular delivery: An in-vitro bioavailability study

HypothesisDoxorubicin hydrochloride (DX) is widely used as a chemotherapeutic agent, though its severe side-effects limit its clinical use. A way to overcome these limitations is to increase DX latency through encapsulation in suitable carriers. However, DX has a high solubility in water, hindering encapsulation. The formulation of DX with sodium cholate (NaC) will reduce aqueous solubility through charge neutralization and hydrophobic interactions thus facilitating DX encapsulation into poloxamer (F127) micelles, increasing drug latency. ExperimentsDX/NaC/PEO-PPO-PEO triblock copolymer (F127) formulations with high DX content (DX-PMs) have been prepared and characterized by scattering techniques, transmission electron microscopy and fluorescence spectroscopy. Cell proliferation has been evaluated after DX-PMs uptake in three cell lines (A549, Hela, 4T1). Cell uptake of DX has been studied by means of confocal laser scanning microscopy and flow cytometry. FindingsDX-PMs formulations result in small and stable pluronic micelles, with the drug located in the apolar core of the polymeric micelles. Cell proliferation assays show a delayed cell toxicity for the encapsulated DX compared with the free drug. Data show a good correlation between cytotoxic response and slow DX delivery to nuclei. DX-PMs offer the means to restrict DX delivery to the cell interior in a highly stable and biocompatible formulation, suitable for cancer therapy.

Targeting anticancer drugs with pluronic aggregates: Recent updates.

Pluronics are triblock (PEOa-b-PPOb-b-PEOa) copolymers, commercially available in a range of amphiphilicity. Usually, pluronics self-assemble in aqueous solution to form core-shell micelles, but their aggregation behavior is remarkably influenced by the molecular characteristics, solution temperature, and presence of additives. Accompanying transitions result into formation of rigid structures, such as liquid crystals and viscoelastic gels. Certain pluronics have been approved by United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) for usage as injectable pharmaceutical excipients. While these carriers have been explored in drug delivery since long, advancements in polymer synthesis have now shifted the focus toward pluronic-based targeted and stimulti-responsive nanomedicines. Majority of these attempts lean over chemical modification of the hydrophilic block in order to enable distinctive identification and elimination of cancerous cells. This review presents the physicochemical and design aspects of pluronic micelles relevant from the standpoint of targeted drug delivery to cancer cells. Using up-to-date literature reports, we have discussed how therapeutic outcomes can be amplified by facilitating the translocation of carriers from tumor interstitium to specific cytosolic targets.

Hierarchical mesoporous silica templated by the combination of fine emulsion and micelles

Abstract Concentrated emulsions have been widely considered as templates for the preparation of macroporous structures. Replacing concentrated emulsions by fine ones should rather lead to materials having large mesopores. However, fine emulsions were barely investigated for this purpose. On the other hand, mesostructured silica SBA-15 can be prepared from Pluronic P123 micelles according to the cooperative templating mechanism. Starting from mixture of fine emulsion and Pluronic P123 micelles, it is expected to obtain silicas with a controlled hierarchical mesoporosity. The fine emulsion has been formulated from the Kolliphor/Myristate/Water system. To get informations concerning the degree of compatibility between the two surfactants, which can affect the formation of the porous materials, the Kolliphor/P123/water system has been investigated in detail. The structural parameters of the mixed liquid crystal phases have been determined and the mixed micellar structure has been investigated by SAXS. The hierarchical porous silicas have been synthetized combining fine emulsion and Pluronic micellar solution. The materials porosity features strongly depend on the weight proportion between the fine emulsion and the P123 micelles. If this proportion is lower than 5/5, mesoporous silicas present a dual mesoporosity. By contrast, by increasing this proportion the mesopore size distribution only shows large mesopores.

Synthesis and photodynamic antimicrobial activity of amphiphilic meso-arylporphyrins with pyridyl moieties

In this work we report on the synthesis of new cationic pyridyl-containing meso-arylporphyrins and their antimicrobial photodynamic activity against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria in planktonic and biofilm modes of growth. Received compounds were characterized by EAS, fluorescence, 1H, 13C NMR spectroscopy, liquid chromatography and ESI-MS spectra. Their photophysical (absorbance and fluorescence), photochemical (singlet oxygen generation) properties dark and light-induced toxicity were studied. Aggregation behavior of PSs was investigated in the presence of nonionic solubilizers to identify the most effective nanocarrier. Pluronic F-127 polymer micelles appeared the most suitable nanocontainers for the cationic porphyrins solubilization. The structure/biological activity relationships were evaluated. The influence of aliphatic spacer length on the photochemical and biological properties of tetraphenylporphyrin derivatives was estimated. The inclusion of PSs in polymeric micelles of Pluronic F-127 noticeably increased their photodynamic activity. Our research showed that the proposed porphyrin macrocycle design offers strategies for the efficient photosensitizer modification in the field of antimicrobial photodynamic inactivation.

NMR relaxation and self-diffusion in aqueous micellar gels of pluronic F-127

Abstract We studied the transverse NMR relaxation of protons of different chemical groups and diffusion of molecules in an aqueous pluronic F-127 system. The system was studied at concentrations of 15, 21 and 28 wt% and in the temperature range of 293–333 K. The dynamic peculiarities in different phases were analyzed based on the NMR relaxation and diffusion data. Our study demonstrated a correlation between phase states, T2 relaxation times of “solid-like” and “liquid” protons of selected chemical groups of polypropylene oxide (PPO) and polyethylene oxide (PEO) blocks, and diffusion coefficients. Transverse NMR relaxation established that the presence of a “solid-like” component of CH3 protons of PEO blocks is observed only at temperatures and concentrations corresponding to the rigid-gel phase, due to entanglements between micellar coronas. At all temperatures and concentrations, some CH3 protons of PPO blocks and some CH2 protons of PEO blocks show “liquid-like” transverse NMR relaxation. Under the conditions corresponding to formation of the rigid-gel phase of the pluronic, relaxation of the “liquid-like” protons additionally accelerates due to entanglements of micellar coronas. Transition of the system to the rigid-gel phase is accompanied by decrease of diffusion coefficients by a factor of 10–104 relative to the diffusivity of free-moving pluronic micelles in the sol phase. Diffusion measurements show that there are pre-transition phenomena, which are characteristic for temperatures and concentrations near sol-gel phase boundaries.

Determination of critical micelle temperature of Pluronic® in Pluronic/gel phase liposome mixtures using steady-state anisotropy

Abstract Stealth strategies have improved some properties of drug nanocarriers, including circulation time in vivo and kinetic stability, which led to the novel-generation of stealth liposomes. Among these, Pluronic®/lipid mixtures provide one of the simplest and lowest-cost stealth liposomes, although the formation of Pluronic micelles above its critical micelle temperature (CMT) concurrently lead to undesirable effects in a drug-carrier approach. Recently, we proposed a fluorometric method to determine the CMT of Pluronics in Pluronic/fluid phase liposome mixtures, but the method fails in the presence of gel phase liposomes (Calori et al., 2019). The present study aimed to develop a simple and highly sensitive fluorometric method based on steady-state anisotropy (r) of 1,6-diphenyl-1,3,5-hexatriene (DPH) to determine CMT of Pluronics in Pluronic/gel phase liposome mixtures. From our results it was showed that rDPH is >0.2 in gel phase liposomes, but lower than that in Pluronic micelles. As a consequence, a drastic drop in rDPH values occurs with temperature-dependent micelle formation in Pluronic/lipid mixtures, due to the partitioning of DPH, previously loaded in liposomes, in formed micelles. The 1/rDPH values led to a clear and elegant deflection point assumed to be CMT, as confirmed by dynamic light scattering. By combining this novel method with response surface methodology, partial phase diagrams of the boundary between liposome and liposome plus Pluronic micelle can be obtained with few assays. This method may be also useful for the optimization of other stealth liposomes for application as drug delivery systems of prolonged circulation time in vivo.

Super tough, ultra-stretchable, and fast recoverable double network hydrogels physically crosslinked by triple non-covalent interactions

Incorporating sacrificial bonds into hydrogels networks has been demonstrated an efficient way to obtain ultrahigh strength, but is usually at the expense of flexibility and recoverability. This study demonstrates novel triple physically crosslinked hydrogels with very high stretchability, toughness and rapid self-recovery at ambient conditions. Physically crosslinked κ-carrageenan acts as the first network to host free radical copolymerization of polymers with Pluronic F127 diacrylate micelles. Hydrophobic association of micelles in the second network contributes to outstanding stretchability (over 1100%) and toughness (10.83 MJ/m3). Further crosslinking of the second network through tridentate Fe3+–COO− coordination significantly enhances the fracture strength up to 2.7 MPa, and elastic modulus 1171 kPa. Systematic investigations demonstrate the key roles played by non-covalent crosslinking on energy dissipation during loadings and the damaged non-covalent networks could recover 40% toughness in 1 min at ambient conditions. These hydrogels are promising for applications as biocompatible load-bearing materials.

Pluronic micelles with suppressing doxorubicin efflux and detoxification for efficiently reversing breast cancer resistance

The antitumor activity of doxorubicin (DOX) is often limited owing to the occurrence of multidrug resistance (MDR) during treatment. Herein, we developed hybrid polymeric micelles, which consisted of pluronic F127 as long-circulating helper in blood, and phenylboronic ester-grafted pluronic P123 (PHE) as efflux and detoxification regulator to efficiently deliver DOX and reverse MDR in vivo. Hybrid F127/PHE micelles exhibited higher stability and drug encapsulation (~80%) than simple F127/P123 micelles due to its lower CMC, and displayed in vitro drug release in a hydrogen peroxide (H2O2)-sensitive manner. Besides, DOX-loaded hybrid micelles (F127/PHE-DOX) possessed higher cell-killing ability and induce more apoptotic in MDR-cells than other groups, which was probably because it not only could greatly increase intracellular drug concentration by inhibiting P-gp mediated drug efflux, but also promote reactive oxygen species (ROS) generation by decreasing glutathione (GSH) levels. Besides, in vivo evaluation indicated that F127/PHE-DOX could well accumulate at tumor regions and exhibit the strongest tumor growth inhibition (TGI 87.87%) accompanied with low side effects. As a result, F127/PHE micelles had great potentials as a platform for anticancer drugs delivery and tumor MDR reversal in clinical application.

New intranasal cross-linked mosapride xyloglucan pluronics micelles (MOS-XPMs) for reflux esophagitis disease: In-vitro optimization and improved therapeutic efficacy

Mosapride belongs to class IV in BiopharmaceuticsClassificationSystem and is used in the treatment of reflux esophagitis. It exhibits poor bioavailability due to limited permeability, solubility and extensive first-pass metabolism. In this study, intranasal mosapride-loaded cross-linked xyloglucan Pluronic micelles (MOS-XPMs) was formulated and optimized to improve the low solubility & bioavailability of MOS. The solid dispersion technique using 23 full factorial design was applied. (MOS-XPMs) (F4) had the highest desirability value (0.952) and, therefore, it was selected as an optimal system. Xyloglucan cross-linked in the shell of Pluronic micelles offered improved stability and mucoadhesiveness to MOS-XPMs. 1H NMR spectra ensured the cross-linking of xyloglucan with Pluronic micelle shell and micelle stabilization. A Pharmacodynamic study revealed that MOS-XPMs showed 1.5-fold increase in duodenal and cecal motility compared to MOS suspension and 1.7-fold increase compared to the oral marketed product. The new MOS-XPMs were shown to be successful at improving the therapeutic efficacy of mosapride.

Experimental study on interactions occurring between Pluronics and leflunomide in solution

The influence of Pluronics L64, F68, F88 and F127 on the solubility and membrane permeability of leflunomide (LEF) in acidic and alkaline buffer solutions with physiological pHs was revealed. A noticeable increase of LEF solubility in the presence of Pluronics was revealed. It was demonstrated that the structure of Pluronics has influence on the manifestation of a solubilizing effect. Namely, more efficient solubilizers for LEF were found to be L64 and F127, having the lowest content of ethylene oxide groups in the structure and lower HLB indices in comparison with F68 and F88. The binding of LEF with the core of Pluronic micelles was proposed on the basis of the obtained 1Н NMR data. Permeability of LEF through an artificial Permeapad barrier composed of phospholipids was measured using the Franz diffusion cell. Decrease of the LEF permeability in the presence of all investigated Pluronics was detected. The location of hydrophobic fragment of LEF molecule inside the micelle leads to a decrease in the non-polar surface area and the ability of the drug to pass through the lipophilic layer of the membrane.

Molecular interactions between Pluronic F127 and saponin in aqueous solution

Nanotechnology is important for the development of new materials capable to improve the development of novel drug delivery systems. Such systems may result in more efficient therapeutic effects with reduced toxicity and extended time in the organism and increase in bioavailability, biocompatibility, and solubility of drugs. Here it was investigated the interaction between the triblock copolymer Pluronic F127 (F127) and a natural bioactive amphiphilic saponin (SAP), extracted from Glycyrrhiza glabra roots, aiming to form micelle-like F127-SAP complexes in a pH 7.4 HEPES buffered aqueous solution, with potential nanobiotechnological applications. Differential scanning calorimetry (DSC), dynamic light scattering (DLS), and dynamic electrophoretic light scattering (DESL) were the techniques used in this investigation, at varied SAP concentrations below and above CMC at fixed 500 μM F127. The SAP-F127 molecular interactions were verified by changes in the critical micellar temperature (CMT) of F127 obtained from the DSC thermograms, while DLS and DELS data showed, respectively, the formation larger structures of the complexes relative to the single Pluronic micelles and zeta potential (ζ) values ranging from ca − 6.5 to − 9 mV, on varying the SAP concentration. Combined, these results indicate the formation of micelle-like complexes, with structure dependent on the SAP concentration, as highly promising agents in nanobiotechnology applications.

PH-sensitive pluronic micelles combined with oxidative stress amplification for enhancing multidrug resistance breast cancer therapy

Multidrug resistance (MDR) is one of the major obstacles to clinical cancer chemotherapy. Herein, we designed new pH-sensitive pluronic micelles with the synergistic effects of oxidative therapy and MDR reversal. Pluronic (P123) was modified with α-tocopheryl succinate (α-TOS) via an acid-labile ortho ester (OE) linkage to give a pH-sensitive copolymer (POT). Self-assembled POT micelles exhibited desirable size (~80 nm), excellent anti-dilution ability, high drug loading (~85%), acid-triggered degradation and drug release behaviours. In vitro cell experiments verified that POT micelles could significantly reverse MDR through suppressing the function of drug effluxs mediated by P123 and induce more reactive oxygen species (ROS) generation mediated by α-TOS, resulting in enhanced cytotoxicity and apoptosis in MDR cells. In vivo studies further revealed that DOX-loaded POT micelles (POT-DOX) possessed the highest drug accumulation (3.03% ID/g at 24 h) and the strongest tumour growth inhibition (TGI 83.48%). Pathological analysis also indicated that POT-DOX could induce more apoptosis or necrosis at the site of tumour without distinct damage to normal tissues. Overall, these smart POT micelles have great potential as promising nano-carriers for MDR reversal and cancer treatment.

Small molecule-mediated self-assembly behaviors of Pluronic block copolymers in aqueous solution: impact of hydrogen bonding on the morphological transition of Pluronic micelles.

The influence of hydrogen bonding on the self-assembly behaviors of Pluronic P123 micelles is experimentally and theoretically investigated by introducing three small molecules, i.e. propyl benzoate (PB), propyl paraben (PP) and propyl gallate (PG) into the aqueous solution. It is discovered that the number of phenolic hydroxyl groups and concentration of the tested small molecules exhibit a profound impact on the micellar morphology. Although all the small molecules increase the size and polydispersity of Pluronic micelles in a concentration-dependent manner, the micellar morphologies induced by them vary considerably as demonstrated by DLS and cryo-TEM measurement. PB, without phenolic hydroxyl, cannot bring about the morphological change of P123 micelles, while PP induces a series of morphological transitions from spheres to long worm-like micelles and then to unilamellar vesicles by increasing the PP content. Upon increasing the number of phenolic hydroxyls in small molecules, i.e. PG, the fusion of the intermicellar core takes place, resulting in the formation of large micelles and micellar clusters. A qualitative study by NMR reveals that the different locations of small molecules within the micelles are attributed to the balance of hydrogen bonding and hydrophobic interaction between small molecules and copolymers. In addition, molecular dynamics simulations (MDS) are performed to further confirm the experimental results and provide quantitative information on intermolecular interaction strength. It is supposed that the mechanism of micellar morphological transition mediated by small molecules is ascribed to the hydrogen bonding interactions with varying strengths between the PEO blocks and their phenolic hydroxyls, which governs their locations in micelles, affecting the free energies from different regions of micelles, and consequently leads to the varying micellar morphologies. This study deepens our understanding of the role of hydrgen bonding in the self-assembly behaviors of Pluronic micelles and provides an alternative strategy for manipulating the nanostructure of Pluronic micelles.

Anticancer potency of novel organometallic Ir(iii) complexes with phosphine derivatives of fluoroquinolones encapsulated in polymeric micelles

A 3D model of cell culturing (spheroids) was explored and the anticancer potential of the selected novel organometallic Ir(iii) complex encapsulated in Pluronic p-123 micelles was clearly proved.

Active-targeting and acid-sensitive pluronic prodrug micelles for efficiently overcoming MDR in breast cancer.

Multidrug resistance (MDR) seriously hinders therapeutic efficacy in clinical cancer treatment. Herein, we reported new polymeric prodrug micelles with tumor-targeting and acid-sensitivity properties based on two different pluronic copolymers (F127 and P123) for enhancing tumor MDR reversal and chemotherapy efficiency in breast cancer. Hybrid micelles were composed of phenylboric acid (PBA)-modified F127 (active-targeting group) and doxorubicin (DOX)-grafted P123 (prodrug groups), which were named as FBP-CAD. FBP-CAD exhibited good stability in a neutral environment and accelerated drug release under mildly acidic conditions by the cleavage of β-carboxylic amides bonds. In vitro studies demonstrated that FBP-CAD significantly increased cellular uptake and drug concentration in MCF-7/ADR cells through the homing ability of PBA and the anti-MDR effect of P123. In vivo testing further indicated that hybrid micelles facilitated drug accumulation at tumor sites as well as reduced side effects to normal organs. The synergistic effect of active-targeting and MDR-reversal leads to the highest tumor growth inhibition (TGI 78.2%). Thus, these multifunctional micelles provide a feasible approach in nanomedicine for resistant-cancer treatment.

Dual-targeting nanocarrier based on glucose and folic acid functionalized pluronic P105 polymeric micelles for enhanced brain distribution

Chemotherapeutics cannot effectively reach brain glioma due to the blood-brain barrier (BBB) and blood-brain tumour barrier (BBTB). To overcome these obstacles, dual-targeting DOX micelles (GF-DOX) were developed to deliver the drug across the BBB and reach the tumour site. In this study, we investigated the BBB targeting ability and the brain delivery of GF-DOX in mice. Results showed that the cellular uptake by brain microvascular endothelial cells (BMVECs) of GF-DOX was significantly higher than that by P105-DOX through caveolae- and clathrin-mediated endocytosis. An in vivo pharmacokinetic study in rats indicated that GF-DOX significantly increased the bioavailability of DOX (4.6-fold), as opposed to the control solution. The distribution of preparations in mice showed that GF-DOX could significantly increase the amount of DOX in the brain (P < 0.05). The survival time of tumour-bearing mice of the GF-DOX group (32 days) was significantly longer than that of the free DOX group (19 days, P = 0.024), or other controls due to the dual-targeting effect of GF-DOX. In conclusion, the dual-targeting GF-DOX could improve the efficacy of anti-tumour drugs in the treatment of brain glioma in vitro and in vivo.

Near-Infrared Optogenetic Genome Engineering Based on Photon-Upconversion Hydrogels.

Photon upconversion (UC) from near-infrared (NIR) light to visible light has enabled optogenetic manipulations in deep tissues. However, materials for NIR optogenetics have been limited to inorganic UC nanoparticles. Herein, NIR-light-triggered optogenetics using biocompatible, organic TTA-UC hydrogels is reported. To achieve triplet sensitization even in highly viscous hydrogel matrices, a NIR-absorbing complex is covalently linked with energy-pooling acceptor chromophores, which significantly elongates the donor triplet lifetime. The donor and acceptor are solubilized in hydrogels formed from biocompatible Pluronic F127 micelles, and heat treatment endows the excited triplets in the hydrogel with remarkable oxygen tolerance. Combined with photoactivatable Cre recombinase technology, NIR-light stimulation successfully performs genome engineering resulting in the formation of dendritic-spine-like structures of hippocampal neurons.

Near‐Infrared Optogenetic Genome Engineering Based on Photon‐Upconversion Hydrogels

AbstractPhoton upconversion (UC) from near‐infrared (NIR) light to visible light has enabled optogenetic manipulations in deep tissues. However, materials for NIR optogenetics have been limited to inorganic UC nanoparticles. Herein, NIR‐light‐triggered optogenetics using biocompatible, organic TTA‐UC hydrogels is reported. To achieve triplet sensitization even in highly viscous hydrogel matrices, a NIR‐absorbing complex is covalently linked with energy‐pooling acceptor chromophores, which significantly elongates the donor triplet lifetime. The donor and acceptor are solubilized in hydrogels formed from biocompatible Pluronic F127 micelles, and heat treatment endows the excited triplets in the hydrogel with remarkable oxygen tolerance. Combined with photoactivatable Cre recombinase technology, NIR‐light stimulation successfully performs genome engineering resulting in the formation of dendritic‐spine‐like structures of hippocampal neurons.