Structural and therapeutic properties of salicylic acid-solubilized Pluronic solutions and hydrogels.

Salicylic acid (SA) finds extensive applications in the treatment of rheumatic and skin diseases because of its analgesic, anti-inflammatory and exfoliating properties. As it is lipophilic in nature, there is a need for appropriate delivery systems to harness these properties for different applications. Herein, we examined the suitability of Pluronic P123/F127 micellar systems as delivery media by investigating the structural, flow and antimicrobial properties of P123/F127-SA solutions and hydrogels using DLS, SANS, rheological and zone inhibition measurement techniques. SA modulates the aggregation characteristics of these surfactant systems and brings about spherical-to-worm-like micelle-to-vesicular structural transitions in the hydrophobic Pluronic P123 system, a spherical-to-worm-like micellar transition in the mixed P123/F127 system and an onset of inter-micellar attraction in the hydrophilic Pluronic F127 system. SA-solubilized systems of both hydrophobic and hydrophilic Pluronics inhibit the growth of Gram-positive and Gram-negative bacteria with comparable MIC values. This suggests that the interaction of SA molecules with the bacterial cell membrane remains unobstructed upon encapsulation in Pluronic micelles. F127 hydrogel-based SA formulations with rheological properties suitable for topical applications and up to 15% SA loading were prepared. These will be useful SA ointments as F127 is an FDA-approved excipient for topical drug delivery applications. The results indicate that Pluronics remain effective as delivery agents for SA and exhibit interesting structural polymorphism upon its solubilization.

Development and Characterization of Curcumin-Loaded TPGS/F127/P123 Polymeric Micelles as a Potential Therapy for Colorectal Cancer.

Colorectal cancer (CRC) is the third most prominent cancer worldwide, and the second leading cause of cancer death. Poor outcomes and limitations of current treatments fuel the search for new therapeutic options. Curcumin (CUR) is often presented as a safer alternative for cancer treatment with a staggering number of molecular targets involved in tumor initiation, promotion, and progression. Despite being promising, its therapeutic potential is hindered due to its hydrophobic nature. Hence, the ongoing development of optimal delivery strategies based on nanotechnology, such as polymeric micelles (PMs), to overcome issues in CUR solubilization and delivery to tumor cells. In this sense, this study aimed to optimize the development and stability of CUR-loaded P123:F127:TPGS PMs (PFT:CUR) based on the thin-film approach and evaluate their therapeutic potential in CRC. Overall, the results revealed that the solubility of CUR was improved when room temperature was used to hydrate the film. The PFT-CUR hydrated at room temperature presents an average hydrodynamic diameter of 15.9 ± 0.3 nm with a polydispersity index (PDI) of 0.251 ± 0.103 and a zeta potential of -1.5 ± 1.9 mV, and a 35.083 ± 1.144 encapsulation efficiency (EE%) and 3.217 ± 0.091 drug loading (DL%) were observed. To ensure the stability of the optimized PFT-CUR nanosystems, different lyophilization protocols were tested, the use of 1% of glycine (GLY) being the most promising protocol. Regarding the critical micellar concentration (CMC), it was shown that the cryoprotectant and the lyophilization process could impact it, with an increase from 0.064 mg/mL to 0.119 mg/mL. In vitro results showed greater cytotoxic effects when CUR was encapsulated compared to its free form, yet further analysis revealed the heightened cytotoxicity could be attributed to the system itself. Despite challenges, the developed CUR-loaded PM shows potential as an effective therapeutic agent for CRC. Nonetheless, the system must undergo refinements to enhance drug entrapment as well as improve overall stability.

The characterization of Pluronic P123 micelles in the presence of sunscreen agents.

OBJECTIVES: The triblock copolymer Pluronic® is widely used in the personal care industry, including sun protection, for its film-forming and solubilization capabilities. In this study, the effect of three commonly used organic UV filters (ethylhexyl methoxycinnamate [EMC], ethylhexyl triazone [EHT], and avobenzone [AVB]) on the structure of Pluronic P123 micelles was investigated. METHODS: The Pluronic P123 micelle structure has been investigated using dynamic surface tension, nuclear magnetic resonance (NMR) and small-angle neutron scattering (SANS). RESULTS: Dynamic surface tension results show strong interactions between the UV filters and Pluronic® evident by sharp changes in the surface activity of the latter. The NMR results have revealed the creation of a hydrophobic microenvironment special to the Pluronic PPO core group in the presence of UV filters. Some interaction with the hydrophilic EO was also recorded, albeit weaker. This is further confirmed by SANS, where the Pluronic P123 micelles interacted with varying strengths with the UV filters, resulting in sharp changes in their size and shape. CONCLUSIONS: We have demonstrated the sensitivity of the Pluronic P123 micelles to the presence of various UVA/B filters. The micelles shape varied from spherical to cylindrical as the concentration and type of the UV filters were varied. These variations in the shape are expected to have a significant effect on the sun protection factor (SPF), as it affects the solubilization of the UV filters within a formulation in addition to the formulations' rheological profile and film-forming behaviour.

OBJECTIFS: le copolymère tribloc Pluronic® est largement utilisé dans le domaine des soins personnels, notamment la protection solaire, pour ses capacités de formation de film et de solubilisation. Cette étude a permis d'étudier l'effet de trois filtres UV organiques couramment utilisés (éthylhexyl méthoxycinnamate [EMC], éthylhexyl triazone [EHT] et avobenzone [AVB]) sur la structure des micelles P123 Pluronic. MÉTHODES: la structure de la micelle P123 Pluronic a été étudiée à l'aide d'une tension superficielle dynamique, d'une résonance magnétique nucléaire (RMN) et d'une diffusion de neutrons aux petits angles (DNPA). RÉSULTATS: les résultats de la tension superficielle dynamique montrent de fortes interactions entre les filtres UV et Pluronic®, ce qui se traduit par de fortes variations de l'activité superficielle de ce dernier. Les résultats de la RMN ont montré la création d'un micro-environnement hydrophobe spécifique au groupe principal de l'OPP pluronique en présence de filtres UV. Une certaine interaction avec l'OE hydrophile a également été enregistrée, quoique plus faible. Ceci est confirmé par la DNPA, où les micelles P123 Pluronic ont interagi avec des forces variables avec les filtres UV, entraînant des changements importants dans leur taille et leur forme. CONCLUSIONS: nous avons démontré la sensibilité des micelles P123 Pluronic à la présence de différents filtres UVA/B. La forme des micelles variait de sphérique à cylindrique en fonction de la concentration et du type de filtres UV. Ces variations de forme devraient avoir un effet significatif sur le facteur de protection solaire (SPF), car elles affectent la solubilisation des filtres UV dans une formulation, en plus du profil rhéologique et du comportement de formation de film des formulations.

A Fluorescence Study of the Interaction of Anticancer Drug Molecule Doxorubicin Hydrochloride in Pluronic P123 and F127 Micelles.

Drug delivery systems for the sustained and target delivery of doxorubicin to tumor cells are a topic of interest due to the efficacy of the doxorubicin in cancer treatment. The use of polymers such as Pluronic is being studied widely for the formulation of doxorubicin hydrochloride. However, the basic understanding of the physicochemical properties of pluronic micelles in presence of doxorubicin hydrochloride is a very essential topic of study. Doxorubicin hydrochloride is fluorescent; this helped us to study its sensitivity towards the Pluronic microenvironment using the fluorescence technique. In this work, the interaction and place of location of doxorubicin hydrochloride in Pluronic F127 and P123 micelles has been studied extensively using steady-state fluorescence intensity, dynamic fluorescence lifetime, quenching studies, dynamic light scattering, and zeta potential measurements, at different Pluronic concentrations. Using a fluorescence quenching experiment, doxorubicin hydrochloride was found to reside near the hydrophilic PEO corona region of the Pluronic micelles. For both the Pluronic, in the concentration range of study, the micellar size was found to be below 30 nm; this may have a greater advantage for various applications.

pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer.

BACKGROUND: Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. RESULTS: Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. CONCLUSIONS: These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. GRAPHIC ABSTARCT.

Targeted and Synergic Glioblastoma Treatment: Multifunctional Nanoparticles Delivering Verteporfin as Adjuvant Therapy for Temozolomide Chemotherapy.

Despite advances in cancer therapies, glioblastoma multiforme treatment remains inefficient due to the brain-blood barrier (BBB) inhibitory activity and to the low temozolomide (TMZ) chemotherapeutic selectivity. To improve therapeutic outcomes, in this work we propose two strategies, (i) photodynamic therapy (PDT) as adjuvant treatment and (ii) engineering of multifunctional theranostic/targeted nanoparticles ( m-NPs) that integrate biotin as a targeting moiety with rhodamine-B as a theranostic agent in pluronic P85/F127 copolymers. These smart m-NPs can surmount the BBB and coencapsulate multiple cargoes under optimized conditions. Overall, the present study conducts a rational m-NP design, characterization, and optimizes the formulation conditions. Confocal microscopy studies on T98-G, U87-MG, and U343 glioblastoma cells and on NIH-3T3 normal fibroblast cells show that the m-NPs and the encapsulated drugs are selectively taken up by tumor cells presenting a broad intracellular distribution. The formulations display no toxicity in the absence of light and are not toxic to healthy cells, but they exert a robust synergic action in cancer cells in the case of concomitant PDT/TMZ treatment, especially at low TMZ concentrations and higher light doses, as demonstrated by nonlinear dose-effect curves based on the Chou-Talalay method. The results evidenced different mechanisms of action related to the disjoint cell cycle phases at the optimal PDT/TMZ ratio. This effect favors synergism between the PDT and the chemotherapy with TMZ, enhances the antiproliferative effect, and overcomes cross-resistance mechanisms. These results point out that m-NP-based PDT adjuvant therapy is a promising strategy to improve TMZ-based glioblastoma multiforme treatments.

Dexamethasone loaded multi-layer poly-l-lactic acid/pluronic P123 composite electrospun nanofiber scaffolds for bone tissue engineering and drug delivery.

In tissue engineering, it is common to mix drugs that can control proliferation and differentiation of cells into polymeric solutions as part of composite to get bioactive scaffolds. However, direct incorporation of drugs might potentially result in undesired burst release. To overcome this problem, here we developed electrospun multilayer drug loaded poly-l-lactic acid/pluronic P123 (PLLA-P123) composite scaffolds. The drug was loaded into the middle layer. The surface, the mechanical and physiochemical properties of the scaffolds were evaluated. The drug release profiles were monitored. Finally, the osteogenic proliferation and differentiation potential were determined. The scaffolds fabricated here have appropriate surface properties, but with different mechanical strength and osteogenic proliferation and differentiation. Multi-layer scaffolds where the drug was in the middle layer and PLLA-plasma and PLLA-P123 with cover layer showed the best osteogenic proliferation and differentiation than the other groups of scaffolds. The drug release profiles of the scaffolds were completely different: single layer scaffolds showed burst release within the first day, while multilayer scaffolds showed controlled release. Therefore, the multilayer drug loaded scaffolds prepared have dual benefits can provide both better osteogenesis and controlled release of drugs and bioactive molecules at the implant site.

Preparation and in vitro and in vivo evaluation of quercetin-loaded mixed micelles for oral delivery.

Quercetin (QT) is a plant polyphenol with various pharmacological properties. However, the low water solubility limits its therapeutic efficacy. In the present study, QT-loaded sodium taurocholate-Pluronic P123 (QT-loaded ST/P123) mixed micelles were developed and characterized, and the effect of the formulation on improving the water solubility of QT was investigated. QT-loaded ST/P123 mixed micelles were prepared by thin film hydration-direct dissolution and optimized by uniform design. The optimal formulation possessed high drug loading (12.6%) and entrapment efficiency (95.9%) in small (16.20 nm) spherically-shaped micelles. A low critical micelle concentration indicated that the micelles were stable, and they showed a sustained release pattern, as determined in vitro in simulated gastric fluid and intestinal fluid. Pharmacokinetic evaluation showed the Cmax and AUC0-24 were 1.8-fold and 1.6-fold higher than the QT suspension. The present results indicate that QT-loaded ST/P123 micelles are potential candidates to improve the solubility and oral bioavailability of QT.

Pluronic P85/F68 Micelles of Baicalein Could Interfere with Mitochondria to Overcome MRP2-Mediated Efflux and Offer Improved Anti-Parkinsonian Activity.

Overexpression of the drug efflux transporter multidrug resistance-associated protein 2 (MRP2) in the gastrointestinal tract and blood-brain barrier compromises the oral delivery of drugs to the circulation system and brain in the treatment of Parkinson's disease (PD). In this study, we aim to develop small-sized Pluronic P85/F68 micelles loaded with baicalein (B-MCs) to overcome MRP2-mediated efflux and to investigate related mechanism, as well as the anti-Parkinsonian efficacy. Spherical and sustained-release B-MCs have a mean particle size of 40.61 nm, a low critical micelle concentration (CMC) of 5.01 × 10-3 mg/mL with an encapsulation efficiency of 95.47% and a drug loading of 7.07%. In comparison with the free baicalein, the cellular uptake and apparent permeability coefficient (Papp) of B-MCs were significantly enhanced (p < 0.01). Fluorescence resonance energy transfer (FRET) analysis indicated that micelles carrying the hydrophobic fluorophores were internalized intact, followed by a rapid release of fluorophores inside the cells, and then the released free fluorophores were transported across the cell monolayers to the basolateral side. Further study on the MRP2 inhibitory effect showed that B-MCs could reverse the MRP2-mediated efflux of baicalein via interfering with the structure and function of mitochondria, i.e., reducing mitochondrial membrane potential and intracellular ATP level and influencing the respiration chain of mitochondria. In addition, B-MCs exerted strong neuroprotective effects on zebrafish model of PD. In summary, Pluronic P85/F68 micelles could be considered as a promising drug delivery system to reverse MRP2-mediated efflux and improve the bioactivity of this MRP2 substrate, baicalein, for the treatment of PD.

Poloxamer P85 increases anticancer activity of Schiff base against prostate cancer in vitro and in vivo.

Prostate cancer is the second most common cancer among men and the leading cause of death after lung cancer. Development of hormone-refractory disease is a crucial step for prostate cancer progression for which an effective treatment option is currently unavailable. Therefore, there is a need for new agents that can efficiently target cancer cells, decrease tumor growth, and thereby extend the survival of patients in late-stage castration-resistant prostate cancer. In the current study, a novel heterodinuclear copper(II)Mn(II) Schiff base complex combined with P85 was used to evaluate anticancer activity against prostate cancer in vitro and in vivo. Cell proliferation and cytotoxicity were evaluated by cell viability, gene, and protein expression assays in vitro. Results showed that the heterodinuclear copper(II)Mn(II) complex-P85 combination decreased cell proliferation by upregulating the apoptotic gene expressions and blocking the cell proliferation-related pathways. Tramp-C1-injected C57/B16 mice were used to mimic a prostate cancer model. Treatment combination of Schiff base complex and P85 significantly enhanced the cellular uptake of chemicals (by blocking the drug transporters and increased life time), suppressed tumor growth, and decreased tumor volume steadily over the course of the experiments. Overall, heterodinuclear copper(II)Mn(II) complex-P85 showed remarkable anticancer activity against prostate cancer in in vitro and in vivo.

Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells.

Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB-loaded CP micelles (ATB-CP1, ATB-CP2) were prepared using an emulsion/solvent evaporation technique. They were spherical in shape with a particle size of 40-50 nm, showed a neutral zeta potential, and had acceptable encapsulation efficiency (>90%). Compared to the free ATB (IC50=2.94 µmol/L), ATB-loaded CP micelles exerted much stronger cytotoxicity against human lung cancer A549 cells with lower IC50 values (0.76 and 1.44 µmol/L for ATB-CP1 and ATB-CP2, respectively). After administration of a single dose in mice, the accumulation of ATB-loaded CP1 micelles in the tumor and lungs, respectively, was 15.31-fold and 9.49-fold as high as that of free ATB. A549 xenograft tumor mice treated with ATB-loaded CP1 micelles for 21 d showed the smallest tumor volume (one-fourth of that in the control group) and the highest inhibition rate (85.6%) among all the treatment groups. After 21-d treatment, no significant pathological changes were observed in hearts and other main tissues. In summary, ATB may serve as a promising antitumor chemotherapeutic agent for lung cancer, and its antitumor efficacy was significantly improved by CP micelles, with lower adverse effects.

Ceramide and N,N,N-Trimethylphytosphingosine-Iodide (TMP-I)-Based Lipid Nanoparticles for Cancer Therapy.

PURPOSE: To evaluate the anti-tumor effect of ceramide or trimethylphytosphingosine-iodide (TMP-I) containing solid lipid nanoparticles (SLNs) prepared using trymyristin, phosphatidylcholine (PC), and Pluronic P85 (P85) for intravenous delivery of docetaxel. METHODS: Docetaxel-loaded SLNs using ceramide or TMP-I at 3.22% (w/w) with a mean diameter of 89-137 nm were successfully prepared by high pressure homogenization. The prepared nanoparticles were characterized by particle size, zeta potential, drug content, and TEM analysis. Cellular uptake and cytotoxicity were studied using adriamycin-resistant breast cancer (MCF-7/ADR) cells. The optimized formulation's dissolution profile, pharmacokinetics, and antitumor effect in mice tumor model were compared with that of control (Taxotere(®)). RESULTS: The drug release rate of docetaxel from SLNs was lower than that of control (Taxotere(®)). The prepared SLNs showed higher cellular uptake of docetaxel compared to that of Taxotere(®) in MCF-7/ADR cell lines, which was further confirmed by the confocal laser scanning microscopy (CLSM) study using coumarin 6 (C6). Prepared SLNs exhibited significantly increased antitumor efficacy, compared to Taxotere(®), in MCF-7/ADR cells. In vivo pharmacokinetic study in rats (at 10 mg/kg dose) showed that the SLNs significantly reduced in vivo clearance of drug than Taxotere(®). Interestingly, ceramide and TMP-I SLNs efficiently inhibited the tumor growth compared to Taxotere(®) in MCF-7/ADR tumor xenografted mouse model. CONCLUSION: This work showed that TMP-I and ceramide SLNs not only significantly enhanced systemic exposure of drug, but also increased antitumor efficacy compared to Taxotere(®) and control SLN.

Human metapneumovirus virus-like particles induce protective B and T cell responses in a mouse model.

UNLABELLED: Human metapneumovirus (HMPV) is a leading cause of respiratory disease in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach because of reduced safety concerns compared with live vaccines. We generated HMPV VLPs by expressing viral proteins in suspension-adapted human embryonic kidney epithelial (293-F) cells and found that the viral matrix (M) and fusion (F) proteins were sufficient to form VLPs. We previously reported that the VLPs resemble virus morphology and incorporate fusion-competent F protein (R. G. Cox, S. B. Livesay, M. Johnson, M. D. Ohi, and J. V. Williams, J. Virol. 86:12148-12160, 2012), which we hypothesized would elicit F-specific antibody and T cell responses. In this study, we tested whether VLP immunization could induce protective immunity to HMPV by using a mouse model. C57BL/6 mice were injected twice intraperitoneally with VLPs alone or with adjuvant and subsequently challenged with HMPV. Mice were euthanized 5 days postinfection, and virus titers, levels of neutralizing antibodies, and numbers of CD3(+) T cells were quantified. Mice immunized with VLPs mounted an F-specific antibody response and generated CD8(+) T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant, though adjuvant reduced cellular immune responses. Two doses of VLPs conferred complete protection from HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV. IMPORTANCE: Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection in infants, children, and the elderly worldwide, yet no licensed vaccines exist. Live-attenuated vaccines present safety challenges, and protein subunit vaccines induce primarily antibody responses. Virus-like particles (VLPs) are an attractive alternative vaccine approach. We generated HMPV VLPs by expressing the viral matrix (M) and fusion (F) proteins in mammalian cells. We found that mice immunized with VLPs mounted an F-specific antibody response and generated CD8(+) T cells recognizing an F protein-derived epitope. VLP immunization induced a neutralizing-antibody response that was enhanced by the addition of either TiterMax Gold or α-galactosylceramide adjuvant. Two doses of VLPs conferred complete protection against HMPV replication in the lungs of mice and were not associated with a Th2-skewed cytokine response. These results suggest that nonreplicating VLPs are a promising vaccine candidate for HMPV.

Effects of Bile Salt Sodium Glycodeoxycholate on the Self-Assembly of PEO-PPO-PEO Triblock Copolymer P123 in Aqueous Solution.

A comprehensive experimental study on the interaction between the PEO-PPO-PEO block copolymer P123 (EO20PO68EO20) and the anionic bile salt sodium glycodeoxycholate (NaGDC) in water has been performed. The work was aimed at investigating the suitability of using P123 as bile salt sequestrant beside the fundamental aspects of PEO-PPO-PEO block copolymer-bile salt interactions. Various experimental techniques including dynamic and static light scattering, small-angle X-ray scattering, and differential scanning calorimetry (DSC) were employed in combination with electrophoretic mobility measurements. The system was investigated at a constant P123 concentration of 1.74 mM and with varying bile salt concentrations up to approximately 250 mM NaGDC (or a molar ratio n(NaGDC)/n(P123) = 144). In the mixed P123-NaGDC solutions, the endothermic process related to the self-assembly of P123 was observed to gradually decrease in enthalpy and shift to higher temperatures upon progressive addition of NaGDC. To explain this effect, the formation of NaGDC micelles carrying partly dehydrated P123 unimers was proposed and translated into a stoichiometric model, which was able to fit the experimental DSC data. In the mixtures at low molar ratios, NaGDC monomers associated with the P123 micelle forming a charged "P123 micelle-NaGDC" complex with a dehydrated PPO core. These complexes disintegrated upon increasing NaGDC concentration to form small "NaGDC-P123" complexes visualized as bile salt micelles including one or a few P123 copolymer chains.

Effect of a Pluronic(®) P123 formulation on the nitric oxide-generating drug JS-K.

PURPOSE: O(2)-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] or JS-K is a nitric oxide-producing prodrug of the arylated diazeniumdiolate class with promising anti-tumor activity. JS-K has challenging solubility and stability properties. We aimed to characterize and compare Pluronic(®) P123-formulated JS-K (P123/JS-K) with free JS-K. METHODS: We determined micelle size, shape, and critical micelle concentration of Pluronic(®) P123. Efficacy was evaluated in vitro using HL-60 and U937 cells and in vivo in a xenograft in NOD/SCID IL2Rγ (null) mice using HL-60 cells. We compared JS-K and P123/JS-K stability in different media. We also compared plasma protein binding of JS-K and P123/JS-K. We determined the binding and Stern Volmer constants, and thermodynamic parameters. RESULTS: Spherical P123/JS-K micelles were smaller than blank P123. P123/JS-K formulation was more stable in buffered saline, whole blood, plasma and RPMI media as compared to free JS-K. P123 affected the protein binding properties of JS-K. In vitro it was as efficacious as JS-K alone when tested in HL-60 and U937 cells and in vivo greater tumor regression was observed for P123/JS-K treated NOD/SCID IL2Rγ (null) mice when compared to free JS-K-treated NOD/SCID IL2Rγ (null) mice. CONCLUSIONS: Pluronic(®) P123 solubilizes, stabilizes and affects the protein binding characteristics of JS-K. P123/JS-K showed more in vivo anti-tumor activity than free JS-K.

How does bile salt penetration affect the self-assembled architecture of pluronic P123 micelles?--light scattering and spectroscopic investigations.

The triblock copolymer of the type (PEO)20-(PPO)70-(PEO)20 (P123) forms a mixed supramolecular aggregate with different bile salts, sodium deoxycholate (NaDC) and sodium taurocholate (NaTC), having different hydrophobicity. These mixed micellar systems have been investigated through dynamic light scattering (DLS) and other various spectroscopic techniques. DLS measurements reveal that the bile salts penetrate into the core-corona region of the P123 micelle and further addition of bile salts causes formation of a new supramolecular aggregate. Further CONTIN analysis confirms existence of two types of complexes at higher molar ratios of bile salt-P123 (>1 : 3). Due to the bile salt penetration, the polarity of the core-corona region of bile salt-P123 mixed micelle increases which results in red shift in the absorption and emission spectra of coumarin 153 (C153) and coumarin 480 (C480). The rotational diffusion of the hydrophobic probe C153 and a hydrophilic probe C480 has been investigated in these bile salt-P123 mixed systems and for both the probes a decrease in the average reorientation time has been observed. The reason behind this decrease in the average reorientation time is the increase in both polarity and hydration of the core-corona region in these mixed micelles. Moreover, these bile salt-P123 mixed micelles are characterized by fluorescence correlation spectroscopy (FCS) techniques. As hydrophobic solute 4-(dicyanomethylene)-2-methyl-6-(p-dimethylamino-styryl)-4H-pyran (DCM) resides in the core region of the bile salt-P123 mixed micelles, the translational diffusion of DCM becomes faster in these mixed micelles compared to that in pure P123 micelle. However, for cationic probe rhodamine 6G perchlorate (R6G), a totally opposite trend in the translational diffusion coefficients has been observed. Both anisotropy and FCS measurements confirm that bile salts affect the core region of the P123 micelle more than the corona region. Besides, all these characterizations confirm that more hydrophobic NaDC interacts in a better way than NaTC with the P123 micelle.

An interface-directed coassembly approach to synthesize uniform large-pore mesoporous silica spheres.

A facile and controllable interface-directed coassembly (IDCA) approach is developed for the first time to synthesize uniform discrete mesoporous silica particles with a large pore size (ca. 8 nm) by using 3-dimensional macroporous carbon (3DOMC) as the nanoreactor for the confined coassembly of template molecules and silica source. By controlling the amount of the precursor solution and using Pluronic templates with different compositions, we can synthesize mesoporous silica particles with diverse morphologies (spheres, hollow spheres, and hemispheres) and different mesostructure (e.g., 2-D hexagonal and 3D face centered cubic symmetry), high surface area of about 790 m(2)/g, and large pore volume (0.98 cm(3)/g). The particle size can be tunable from submicrometer to micrometer regimes by changing the macropore diameter of 3DOMC. Importantly, this synthesis concept can be extended to fabricate multifunctional mesoporous composite spheres with a magnetic core and a mesoporous silica shell, large saturated magnetization (23.5 emu/g), and high surface area (280 m(2)/g). With the use of the magnetic mesoporous silica spheres as a magnetically recyclable absorbent, a fast and efficient removal of microcystin from water is achieved, and they can be recycled for 10 times without a significant decrease of removal efficiency for microcystin.

Oleochemical-tethered SBA-15-type silicates with tunable nanoscopic order, carboxylic surface, and hydrophobic framework: cellular toxicity, hemolysis, and antibacterial activity.

Novel silicates were prepared by using silylated natural fatty acids (derived from triglyceride renewable oils) as co-condensing reagents in presence of tetraethyl orthosilicate (TEOS) and the triblock copolymer, pluronic P123, as a structure directing agent. A series of carboxylic acid functionalized SBA-15-type mesoporous silicates were obtained with tunable nanoscopic order and reactive functional groups that allow the conjugation of amino probes by peptide coupling. Photophysical studies of the covalently linked aminopyrene substantiated that the internal framework of these materials have pronounced hydrophobicity. Moreover, phase separation that can emanate from the bulkiness of the starting fatty silanes has been ruled out owing to the absence of excimers after aminopyrene grafting. The hemotoxicity, cytotoxicity, and antimicrobial activity of these novel silicates were then evaluated. Without discrimination, the functionalized silicates show a significant decrease of red blood cell hemolysis as compared to bare SBA-15-silica material. Within the modified silicate series, germanium-free mesoporous silicates induce only a slight decrease in cell viability and, more interestingly, they exhibit negligible hemolytic effect. Moreover, increasing their concentration in the medium reduces the concentration of released hemoglobin as a result of Hb adsorption. Promising antimicrobial properties were also observed for these silicates with a slight dependency on whether phenylgermanium fragments were present within the silicate framework.

The effect of Pluronic P123 on shape memory of cross-linked polyurethane/poly(l-lactide) biocomposite.

Polyurethane (PU) and poly(l-lactide) (PLLA) have attracted increasing attention in the development of shape memory polymers (SMPs) due to their good biocompatibility and degradability. Although Pluronic P123 can be used to tune polymeric surface hydrophilicity, its effect on SM performance is a mystery. In this study, a soluble cross-linked PU is synthesized as the switching phase and combined with PLLA and P123 to construct a hydrothermally responsive SM composite. The water contact angle of PU/PLLA/P123 decreases from 22.7° to 5.1° within 2 min. PU and P123 form the switching group, which enhances the SM behavior of the composite. The shape fixity (Rf) and shape recovery (Rr) of PU/PLLA/P123 are 94.4 % and 98 % in 55 °C water, respectively, and the shape recovery time is only 10 s. P123 plays the role of "turbine" in the SM process. PU/PLLA/P123 exhibits a balance between stiffness and elasticity, and good degradability. Furthermore, PU/PLLA/P123 is also biocompatible and beneficial to cell proliferation and growth. Therefore, it offers an alternative approach to developing hydrothermally responsive SM biocomposites based on P123, PU and PLLA for biomedical applications.

Pluronic P123/DMSO Lyotropic Liquid Crystal for Incorporating Bioactive Substances for Topical Application.

Lyotropic liquid crystals (LLCs) have attracted considerably growing interest in drug delivery applications over the last years. The structure of LLC matrices is complementary to cell membranes and provides an efficient, controlled, and selective release of drugs. In this work, a complex of experimental methods was used to characterize binary LLCs Pluronic P123/DMSO and triple LLC systems Pluronic P123/DMSO/Ibuprofen, which are interesting as transdermal drug delivery systems. Liquid crystalline, thermal, and rheological properties of LLCs were studied. Concentration and temperature areas of the lyomesophase existence were found, and phase transition enthalpies were evaluated. Intermolecular interactions among the components were studied by infrared (IR) spectroscopy. In vitro studies of Ibuprofen (Ibu) release from various LLCs allow differentiation of its release depending on the polymer content. Atomic force microscopy and contact angle methods were used to characterize the surface morphology of the hydrophobic membrane, which was used as a stratum corneum model, and also evaluate the adhesion work of the LLCs. A complex analysis of the results provided by these experimental methods allowed revealing correlations between the phase behavior and rheological characteristics of the LLCs and release kinetics of ibuprofen. The proposed biocompatible systems have considerable potential for a transdermal delivery of bioactive substances.