Targeted Drug Delivery for the Treatment of Blood Cancers.

Blood cancers are a type of liquid tumor which means cancer is present in the body fluid. Multiple myeloma, leukemia, and lymphoma are the three common types of blood cancers. Chemotherapy is the major therapy of blood cancers by systemic administration of anticancer agents into the blood. However, a high incidence of relapse often happens, due to the low efficiency of the anticancer agents that accumulate in the tumor site, and therefore lead to a low survival rate of patients. This indicates an urgent need for a targeted drug delivery system to improve the safety and efficacy of therapeutics for blood cancers. In this review, we describe the current targeting strategies for blood cancers and recently investigated and approved drug delivery system formulations for blood cancers. In addition, we also discuss current challenges in the application of drug delivery systems for treating blood cancers.

Partition and Solubilization of Phospholipid Vesicles by Noncovalently Constructed Oligomeric-like Surfactants.

This work has investigated the interaction of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles with oligomeric surfactants noncovalently formed by sodium dodecyl sulfate (SDS) and a series of polyamines, 1,3-diaminopropane (PDA), triamine, spermidine, and spermine. The partition coefficients (P) of these surfactants between lipid bilayers and the aqueous phase are measured by isothermal titration microcalorimetry (ITC), showing that the P value increases and the Gibbs free energy of the partition becomes more negative with increasing oligomerization degree of the surfactants. This changing trend is similar to that of synthetic oligomeric surfactants regardless of the charge properties, suggesting that the polyamine and SDS molecules interact with the DOPC bilayer simultaneously. Meanwhile, the DOPC solubilization by these surfactants is evaluated by the effective surfactant-to-lipid molar ratios for the onset (Resat) and end (Resol) of the solubilization process, which are determined from the phase boundaries obtained by ITC, turbidity, and dynamic light scattering measurements. With the increment of oligomerization degree, the Resat and Resol values increase anomalously and are much larger than those of the synthetic surfactants with the same oligomerization degree, suggesting that noncovalently constructed oligomeric surfactants exhibit lower solubilization ability to phospholipid vesicles than the corresponding covalent oligomeric surfactants. Therefore, the noncovalently constructed oligomeric-like surfactants facilitate strong partition but weak solubilization to phospholipid vesicles, which may provide a useful strategy to mildly adjust the permeation and fluidity of phospholipid vesicles with solubilization delay.

Optimizing the Calibration Error of Refraction Angles in Ultrasonic Angle Beam Testing.

Ultrasonic testing is a useful approach for quantifying the flaws in mechanical components. The height of the flaws in ultrasonic angle beam testing is closely related to the calibration value of the probe refraction angle. In order to reduce the calibration error, some ignored data during the traditional calibration process are reanalyzed and fused to determine the refraction angle. Both arithmetical measurement fusion method and weighted measurement fusion method are applied and compared. Monte Carlo simulation is used to estimate the probability distribution of the refraction angle and obtain the optimal refraction angle weights. Experiments were carried out to verify the results of Monte Carlo simulation. The applicability of data fusion on refraction angles is investigated. It was found in the study that the data fused with the refraction angle is helpful for measuring the height of flaws.

Aggregation of Oligomeric Surfactant Constructed by Four-Armed Carboxylic Acid Sodium and Cationic Surfactant.

A star-shaped oligomeric-like surfactant with variable oligomeric degrees has been formed with a four-arm carboxylate salt (4EOCOONa) and cationic single chain surfactant dodecyl trimethylammonium bromide (DTAB). The aggregation of the 4EOCOONa/(DTAB)n complexes has been investigated by surface tension, electrical conductivity, isothermal titration microcalorimetry, ζ potential, dynamic light scattering, 1H NMR spectroscopy, and steady-state fluorescence measurements. The calorimetric result shows that 4EOCOONa interacts strongly with DTAB and each 4EOCOONa molecule binds with six DTAB molecules, wherein four DTAB molecules electrostatically bind to one 4EOCOONa molecule and additional two DTAB molecules further bind to the 4EOCOONa/(DTAB)n complex by hydrophobic interaction. The critical micelle concentration (CMC) of the 4EOCOONa/(DTAB)n complexes is remarkably lower than the CMC of DTAB, similar to synthesized star-shaped oligomeric surfactants. The micelle properties of the DTAB/4EOCOONa mixtures depend on the component changes of the 4EOCOONa/(DTAB)n complexes. By increasing the DTAB/4EOCOONa molar ratio and/or concentration, the DTAB/4EOCOONa mixtures gradually form the complexes of 4EOCOO(DTA)13-, 4EOCOO(DTA)22-, 4EOCOO(DTA)3-, 4EOCOO(DTA)4, and 4EOCOO(DTA)62+, and the corresponding aggregates are small anionic micelles with loose molecular packing, and nearly nonionic or positively charged small micelles with more compact packing. Moreover, the positive charge of the small micelles increases with the increase of the concentration and the DTAB/4EOCOONa molar ratio. Therefore, constructing oligomeric-like surfactants by adding appropriate organic salts into conventional surfactants is a convenient method to achieve desired properties of surfactant aggregates.

Hydration lubrication and shear-induced self-healing of lipid bilayer boundary lubricants in phosphatidylcholine dispersions.

Measurements of normal and shear (frictional) forces between mica surfaces across small unilamellar vesicle (SUV) dispersions of the phosphatidylcholine (PC) lipids DMPC (14:0), DPPC (16:0) and DSPC (18:0) and POPC (16:0, 18:1), at physiologically high pressures, are reported. We have previously studied the normal and shear forces between two opposing surfaces bearing PC vesicles across pure water and showed that liposome lubrication ability improved with increasing acyl chain length, and correlated strongly with the SUV structural integrity on the substrate surface (DSPC > DPPC > DMPC). In the current study, surprisingly, we discovered that this trend is reversed when the measurements are conducted in SUV dispersions, instead of pure water. In their corresponding SUV dispersion, DMPC SUVs ruptured and formed bilayers, which were able to provide reversible and reproducible lubrication with extremely low friction (µ < 10(-4)) up to pressures of 70-90 atm. Similarly, POPC SUVs also formed bilayers which exhibited low friction (µ < 10(-4)) up to pressures as high as 160 atm. DPPC and DSPC SUVs also provided good lubrication, but with slightly higher friction coefficients (µ = 10(-3)-10(-4)). We believe these differences originate from fast self-healing of the softer surface layers (which are in their liquid disordered phase, POPC, or close to it, DMPC), which renders the robustness of the DPPC or DSPC (both in their solid ordered phase) less important in these conditions. Under these circumstances, the enhanced hydration of the less densely packed POPC and DMPC surface layers is now believed to play an important role, and allows enhanced lubrication via the hydration lubrication mechanism. Our findings may have implications for the understanding of complex biological systems such us biolubrication of synovial joints.

Aggregation behavior of sodium lauryl ether sulfate with a positively bicharged organic salt and effects of the mixture on fluorescent properties of conjugated polyelectrolytes.

The aggregation behavior of anionic single-chain surfactant sodium lauryl ether sulfate containing three ether groups (SLE3S) with positively bicharged organic salt 1,2-bis(2-benzylammoniumethoxy)ethane dichloride (BEO) has been investigated in aqueous solution, and the effects of the BEO/SLE3S aggregate transitions on the fluorescent properties of anionic conjugated polyelectrolyte MPS-PPV with a larger molecular weight and cationic conjugated oligoelectrolyte DAB have been evaluated. Without BEO, SLE3S does not affect the fluorescent properties of MPS-PPV and only affects the fluorescent properties of DAB at a higher SLE3S concentration. With the addition of BEO, SLE3S and BEO form gemini-like surfactant (SLE3S)2-BEO. When the BEO/SLE3S molar ratio is fixed at 0.25, with increasing the BEO/SLE3S concentration, the BEO/SLE3S mixture forms large, loosely arranged aggregates and then transforms to closely packed spherical aggregates and finally to long thread-like micelles. The photoluminescence (PL) intensity of MPS-PPV varies with the morphologies of the BEO/SLE3S aggregates, while the PL intensity of DAB is almost independent of the aggregate morphologies. The results demonstrate that gemini-like surfactants formed through intermolecular interactions can effectively adjust the fluorescent properties of conjugated polyelectrolytes.

Complex formation and aggregate transitions of sodium dodecyl sulfate with an oligomeric connecting molecule in aqueous solution.

Anionic single-tail surfactant sodium dodecyl sulfate (SDS) and a molecule with multiple amido and amine groups (Lys-12-Lys) were used as building blocks to fabricate oligomeric surfactants through intermolecular interactions. Their interactions and the resultant complex and aggregate structures were investigated by turbidity titration, isothermal titration microcalorimetry, dynamic light scattering, cryogenic transmission electron microscopy, freeze-fracture transmission electron microscopy, (1)H NMR, and 1D NOE techniques. At pH 11.0, the interaction between SDS and Lys-12-Lys is exothermic and mainly resulted from hydrogen bonding among the amido and amine groups of Lys-12-Lys and the sulfate group of SDS and hydrophobic interaction between the hydrocarbon chains of SDS and Lys-12-Lys. At pH 3.0, each Lys-12-Lys carries four positive charges and two hydrogen bonding sites. Then SDS and Lys-12-Lys form complexes Lys-12-Lys(SDS)6 and Lys-12-Lys(SDS)4 through the head groups by electrostatic attraction and hydrogen bonds assisted by hydrophobic interaction. Moreover, the complexes pack more tightly in their aggregates with the increase of the molar ratio. Especially the Lys-12-Lys(SDS)4 and Lys-12-Lys(SDS)6 complexes behave like oligomeric surfactants taking Lys-12-Lys as a spacer group, exhibiting a series of aggregates transitions with the increase of concentration, i.e., larger vesicles, smaller spherical micelles, and long threadlike micelles. Therefore, oligomeric surfactants Lys-12-Lys(SDS)4 and Lys-12-Lys(SDS)6 have been successfully fabricated by using a single chain surfactant and an oligomeric connecting molecule through noncovalent association.

Genome-Wide Association Studies to Drug: Identifying Retinoic Acid Metabolism Blocking Agents to Suppress Mechanoflammation in Osteoarthritis.

Osteoarthritis (OA) is a highly prevalent debilitating joint disease for which there are currently no licensed disease-modifying treatments. The pathogenesis of OA is complex, involving genetic, mechanical, biochemical, and environmental factors. Cartilage injury, arguably the most important driving factor in OA development, is able to activate both protective and inflammatory pathways within the tissue. Recently, >100 genetic risk variants for OA have been identified through Genome Wide Association Studies, which provide a powerful tool to validate existing putative disease pathways and discover new ones. Using such an approach, hypomorphic variants within the aldehyde dehydrogenase 1 family member A2 (ALDH1A2) gene were shown to be associated with increased risk of severe hand OA. ALDH1A2 encodes the enzyme that synthesizes all-trans retinoic acid (atRA), an intracellular signaling molecule. This review summarizes the influence of the genetic variants on expression and function of ALDH1A2 in OA cartilage, its role in the mechanical injury response of cartilage, and its potent anti-inflammatory effect after cartilage injury. In doing so it identifies atRA metabolism-blocking agents as potential treatments for suppressing mechanoflammation in OA.

A vital parameter? Systematic review of spirometry in evaluation for intensive care unit admission and intubation and ventilation for Guillain-Barré syndrome.

BACKGROUND: Patients with Guillain-Barré syndrome (GBS) may require intensive care unit (ICU) admission for intubation and ventilation (I + V). The means to predict which patients will require I + V include spirometry measures. The aims of this study were to determine, for adult patients with GBS, how effectively different spirometry parameter thresholds predict the need for ICU admission and the requirement for I + V; and what effects these different parameter thresholds have on GBS patient outcomes. METHOD: A systematic review was conducted of the databases PubMed, EMBASE, and Cochrane library in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The systematic review was registered prospectively on PROSPERO. RESULTS: Initial searches returned 1011 results, of which 8 fulfilled inclusion criteria. All included studies were observational in nature. Multiple studies suggest that a vital capacity below 60% of predicted value on admission is associated with the need for eventual I + V. No included studies evaluated peak expiratory flow rate, or interventions with different thresholds for ICU or I + V. CONCLUSIONS: There is a relationship between vital capacity and the need for I + V. However, there is limited evidence supporting specific thresholds for I + V. In addition to evaluating these factors, future research may evaluate the effect of different patient characteristics, including clinical presentation, weight, age, and respiratory comorbidities, on the effectiveness of spirometry parameters in the prediction of the need for I + V.

Association behaviors of dodecyltrimethylammonium bromide with double hydrophilic block co-polymer poly(ethylene glycol)-block-poly(glutamate sodium).

The association behaviors of single-chain surfactant dodecyltrimethylammonium bromide (DTAB) with double hydrophilic block co-polymers poly(ethylene glycol)-b-poly(sodium glutamate) (PEG(113)-PGlu(50) or PEG(113)-PGlu(100)) were investigated using isothermal titration microcalorimetry, cryogenic transmission electron microscopy, circular dichroism, ζ potential, and particle size measurements. The electrostatic interaction between DTAB and the oppositely charged carboxylate groups of PEG-PGlu induces the formation of super-amphiphiles, which further self-assemble into ordered aggregates. Dependent upon the charge ratios between DTAB and the glutamic acid residue of the co-polymer, the mixture solutions can change from transparent to opalescent without precipitation. Dependent upon the chain length of the PGlu block, the mixture of DTAB and PEG-PGlu diblocks can form two different aggregates at their corresponding electroneutral point. Spherical and rod-like aggregates are formed in the PEG(113)-PGlu(50)/DTAB mixture, while the vesicular aggregates are observed in the PEG(113)-PGlu(100)/DTAB mixture solution. Because the PEG(113)-PGlu(100)/DTAB super-amphiphile has more hydrophobic components than that of the PEG(113)-PGlu(50)/DTAB super-amphiphile, the former prefers forming the ordered aggregates with higher curvature, such as spherical and rod aggregates, but the latter prefers forming vesicular aggregates with lower curvature.

Role of Ciliary Protein Intraflagellar Transport Protein 88 in the Regulation of Cartilage Thickness and Osteoarthritis Development in Mice.

OBJECTIVE: Mechanical and biologic cues drive cellular signaling in cartilage development, health, and disease. Primary cilia proteins, which are implicated in the transduction of biologic and physiochemical signals, control cartilage formation during skeletal development. This study was undertaken to assess the influence of the ciliary protein intraflagellar transport protein 88 (IFT88) on postnatal cartilage from mice with conditional knockout of the Ift88 gene (Ift88-KO). METHODS: Ift88fl/fl and aggrecanCreERT2 mice were crossed to create a strain of cartilage-specific Ift88-KO mice (aggrecanCreERT2 ;Ift88fl/fl ). In these Ift88-KO mice and Ift88fl/fl control mice, tibial articular cartilage thickness was assessed by histomorphometry, and the integrity of the cartilage was assessed using Osteoarthritis Research Society International (OARSI) damage scores, from adolescence through adulthood. In situ mechanisms of cartilage damage were investigated in the microdissected cartilage sections using immunohistochemistry, RNAScope analysis, and quantitative polymerase chain reaction. Osteoarthritis (OA) was induced in aggrecanCreERT2 ;Ift88fl/fl mice and Ift88fl/fl control mice using surgical destabilization of the medial meniscus (DMM). Following tamoxifen injection and DMM surgery, the mice were given free access to exercise on a wheel. RESULTS: Deletion of Ift88 resulted in progressive reduction in the thickness of the medial tibial cartilage in adolescent mice, as well as marked atrophy of the cartilage in mice during adulthood. In aggrecanCreERT2 ;Ift88fl/fl mice at age 34 weeks, the median thickness of the medial tibial cartilage was 89.42 µm (95% confidence interval [95% CI] 84.00-93.49), whereas in Ift88fl/fl controls at the same age, the median cartilage thickness was 104.00 µm (95% CI 100.30-110.50; P < 0.0001). At all time points, the median thickness of the calcified cartilage was reduced. In some mice, atrophy of the medial tibial cartilage was associated with complete, spontaneous degradation of the cartilage. Following DMM, aggrecanCreERT2 ;Ift88fl/fl mice were found to have increased OARSI scores of cartilage damage. In articular cartilage from maturing mice, atrophy was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy. Of the 44 candidate genes analyzed, only Tcf7l2 expression levels correlated with Ift88 expression levels in the microdissected cartilage. However, RNAScope analysis revealed that increased hedgehog (Hh) signaling (as indicated by increased expression of Gli1) was associated with the reductions in Ift88 expression in the tibial cartilage from Ift88-deficient mice. Wheel exercise restored both the articular cartilage thickness and levels of Hh signaling in these mice. CONCLUSION: Our results in a mouse model of OA demonstrate that IFT88 performs a chondroprotective role in articular cartilage by controlling the calcification of cartilage via maintenance of a threshold of Hh signaling during physiologic loading.

Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Identifying typologies of quality of life in patients with moderate to severe hand trauma based on patient-reported outcomes.

BACKGROUND: This study sought to classify the level of quality of life in patients with moderate to severe hand trauma, and explore differences in their potential profile characteristics based on the Patient-Reported Outcomes Measurement Information System (PROMIS). METHODS: This was a survey research. A convenience sampling method was used to investigate 296 patients with moderate to severe hand trauma. A general information questionnaire (which was used to gather general demographic data and disease-related data) and PROMIS-57 were administered form November 2020 to May 2021. A latent profile analysis and Chi square test were conducted to analyze the data. RESULTS: Based on quality of life, patients with moderate to severe hand trauma were divided into the following 3 groups: (I) Group C1: the psychosocial-pain low-impact group (38.9%); (II) Group C2: the psychosocial-moderate-impact severe-pain group (43.9%); and (III) Group C3: the psychosocial-pain high-impact group (17.2%). There were significant differences in the distribution of age, educational level, marital status, occupation, monthly income, medical insurance type, family role, subsequent financial resources, cause of the injury, satisfaction with the appearance of the hand, degree of the injury, and impact of the injury on daily life among patients in the different groups (P<0.05). CONCLUSIONS: The quality of life in patients with moderate to severe hand trauma can be identified to provide precise care.

TSG-6 Is Weakly Chondroprotective in Murine OA but Does not Account for FGF2-Mediated Joint Protection.

OBJECTIVE: Tumor necrosis factor α-stimulated gene 6 (TSG-6) is an anti-inflammatory protein highly expressed in osteoarthritis (OA), but its influence on the course of OA is unknown. METHODS: Cartilage injury was assessed by murine hip avulsion or by recutting rested explants. Forty-two previously validated injury genes were quantified by real-time polymerase chain reaction in whole joints following destabilization of the medial meniscus (DMM) (6 hours and 7 days). Joint pathology was assessed at 8 and 12 weeks following DMM in 10-week-old male and female fibroblast growth factor 2 (FGF2)-/- , TSG-6-/- , TSG-6tg (overexpressing), FGF2-/- ;TSG-6tg (8 weeks only) mice, as well as strain-matched, wild-type controls. In vivo cartilage repair was assessed 8 weeks following focal cartilage injury in TSG-6tg and control mice. FGF2 release following cartilage injury was measured by enzyme-linked immunosorbent assay. RESULTS: TSG-6 messenger RNA upregulation was strongly FGF2-dependent upon injury in vitro and in vivo. Fifteeen inflammatory genes were significantly increased in TSG-6-/- joints, including IL1α, Ccl2, and Adamts5 compared with wild type. Six genes were significantly suppressed in TSG-6-/- joints including Timp1, Inhibin ßA, and podoplanin (known FGF2 target genes). FGF2 release upon cartilage injury was not influenced by levels of TSG-6. Cartilage degradation was significantly increased at 12 weeks post-DMM in male TSG-6-/- mice, with a nonsignificant 30% reduction in disease seen in TSG-6tg mice. No differences were observed in cartilage repair between genotypes. TSG-6 overexpression was unable to prevent accelerated OA in FGF2-/- mice. CONCLUSION: TSG-6 influences early gene regulation in the destabilized joint and exerts a modest late chondroprotective effect. Although strongly FGF2 dependent, TSG-6 does not explain the strong chondroprotective effect of FGF2.

Functional Characterization of the Osteoarthritis Genetic Risk Residing at ALDH1A2 Identifies rs12915901 as a Key Target Variant.

OBJECTIVE: To identify the functional single-nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene. METHODS: Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA-sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription-polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which, among 62 highly correlated SNPs, could account for the association at the locus. RESULTS: ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non-diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of a number of chondrogenic markers, including SOX9. In addition, reduced expression of the OA risk-conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the Ets transcription factors were identified as potential mediators of this effect. CONCLUSION: The ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk.

Ultra-low friction between boundary layers of hyaluronan-phosphatidylcholine complexes.

The boundary layers coating articular cartilage in synovial joints constitute unique biomaterials, providing lubricity at levels unmatched by any human-made materials. The underlying molecular mechanism of this lubricity, essential to joint function, is not well understood. Here we study the interactions between surfaces bearing attached hyaluronan (hyaluronic acid, or HA) to which different phosphatidylcholine (PC) lipids had been added, in the form of small unilamellar vesicles (SUVs or liposomes), using a surface force balance, to shed light on possible cartilage boundary lubrication by such complexes. Surface-attached HA was complexed with different PC lipids (hydrogenated soy PC (HSPC), 1,2-dimyristoyl-sn-glycero-3-PC (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-PC (POPC)), followed by rinsing. Atomic force microscopy (AFM) and cryo-scanning electron microscopy (Cryo-SEM) were used to image the HA-PC surface complexes following addition of the SUVs. HA-HSPC complexes provide very efficient lubrication, with friction coefficients as low as µâˆ¼0.001 at physiological pressures P≈150atm, while HA-DMPC and HA-POPC complexes are efficient only at low P (up to 10-20atm). The friction reduction in all cases is attributed to hydration lubrication by highly-hydrated phosphocholine groups exposed by the PC-HA complexes. The greater robustness at high P of the HSPC (C16(15%),C18(85%)) complexes relative to the DMPC ((C14)2) or POPC (C16, C18:1) complexes is attributed to the stronger van der Waals attraction between the HSPC acyl tails, relative to the shorter or un-saturated tails of the other two lipids. Our results shed light on possible lubrication mechanisms at the articular cartilage surface in joints. STATEMENT OF SIGNIFICANCE: Can designed biomaterials emulate the unique lubrication ability of articular cartilage, and thus provide potential alleviation to friction-related joint diseases? This is the motivation behind the present study. The principles of cartilage lubrication have attracted considerable attention for decades, and several models have been proposed to elucidate it, however, the mechanism of this ultralow friction is still not clear. In this paper we explore the recent suggestion that its efficient lubrication arises from boundary layers of hyaluronan-lipid complexes at its surface, in particular exploring a range of different phosphatidylcholines (PCs) mimicking the wide range of PCs in synovial joints. The present study suggests a synergistic lubricating behavior of the different lipids in living joints, and potential treatment directions using such biomaterial complexes for widespread cartilage-friction-related diseases such as osteoarthritis.

Supramolecular synergy in the boundary lubrication of synovial joints.

Hyaluronan, lubricin and phospholipids, molecules ubiquitous in synovial joints, such as hips and knees, have separately been invoked as the lubricants responsible for the remarkable lubrication of articular cartilage; but alone, these molecules cannot explain the extremely low friction at the high pressures of such joints. We find that surface-anchored hyaluronan molecules complex synergistically with phosphatidylcholine lipids present in joints to form a boundary lubricating layer, which, with coefficient of friction µ≈0.001 at pressures to over 100 atm, has a frictional behaviour resembling that of articular cartilage in the major joints. Our findings point to a scenario where each of the molecules has a different role but must act together with the others: hyaluronan, anchored at the outer surface of articular cartilage by lubricin molecules, complexes with joint phosphatidylcholines to provide the extreme lubrication of synovial joints via the hydration-lubrication mechanism.

Disaggregation ability of different chelating molecules on copper ion-triggered amyloid fibers.

Dysfunctional interaction of amyloid-ß (Aß) with excess metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal-binding compounds to reverse metal-triggered Aß aggregation has become one of the potential therapies for AD. In this study, the ability of a carboxylic acid gemini surfactant (SDUC), a widely used metal chelator (EDTA), and an antifungal drug clioquinol (CQ) in reversing the Cu(2+)-triggered Aß(1-40) fibers have been systematically studied by using turbidity essay, BCA essay, atomic force microscopy, transmission electron microscopy, and isothermal titration microcalorimetry. The results show that the binding affinity of Cu(2+) with CQ, SDUC, and EDTA is in the order of CQ > EDTA > SDUC, while the disaggregation ability to Cu(2+)-triggered Aß(1-40) fibers is in the order of CQ > SDUC > EDTA. Therefore, the disaggregation ability of chelators to the Aß(1-40) fibers does not only depend on the binding affinity of the chelators with Cu(2+). Strong self-assembly ability of SDUC and π-π interaction of the conjugate group of CQ also contributes toward the disaggregation of the Cu(2+)-triggered Aß(1-40) fibers and result in the formation of mixed small aggregates.

Modulation of Aß(1-40) peptide fibrillar architectures by Aß-based peptide amphiphiles.

Modulation of the fibrillogenesis of amyloid peptide Aß(1-40) with two Aß-based peptide amphiphiles has been studied. Both peptide amphiphiles contain two alkyl chains but in different positions. The two alkyl chains of 2C12-Aß(11-17) are attached to the same terminus of Aß(11-17), while those of C12-Aß(11-17)-C12 are separately attached to opposite termini of Aß(11-17). Thioflavin T fluorescence spectroscopy shows that all the peptide amphiphiles promote the formation of the cross-ß-sheet structure of Aß(1-40) and the aggregation of Aß(1-40), while 2C12-Aß(11-17) does this more efficiently. The atom force microscopy images indicate that the modulations of these two peptide amphiphiles on the Aß(1-40) aggregation experience two distinct pathways. 2C12-Aß(11-17) leads to amorphous aggregates, whereas C12-Aß(11-17)-C12 generates short rodlike fibrils. However, Fourier transform infrared spectroscopy suggests that the amorphous aggregates and rodlike fibrils display similar secondary structures. This work suggests that the aggregation ability and the aggregate structures of the peptide amphiphiles significantly affect their interactions with Aß(1-40) and lead to different morphologies of the Aß(1-40) aggregates.

Aggregate transitions in mixtures of anionic sulfonate gemini surfactant with cationic ammonium single-chain surfactant.

Aggregation behaviors in mixtures of an anionic gemini surfactant 1,3-bis(N-dodecyl-N-propanesulfonate sodium)-propane (C(12)C(3)C(12)(SO(3))(2)) and a cationic single-chain surfactant cetyltrimethylammonium bromide (CTAB) have been investigated in aqueous solutions at pH 9.5 by turbidity, rheology, isothermal titration microcalorimetry (ITC), cryogenic transmission electron microscopy, and dynamic light scattering. Reversible aggregate transitions from spherical micelles to wormlike micelles, vesicles, and back to wormlike micelles and spherical micelles are successfully realized through fine regulation over the mixing ratio of surfactants, i.e., the anionic/cationic charge ratio. The five aggregate regions display distinguished phase boundaries so that the aggregate regions can be well controlled. From thermodynamic aspect, the ITC curves clearly reflect all the aggregate transitions and the related interaction mechanism. The self-assembling ability of the C(12)C(3)C(12)(SO(3))(2)/CTAB mixtures are significantly improved compared with both individual surfactants. Micelle growth from spherical to long wormlike micelles takes place at a relative low total concentration, i.e., 2.0 mM. The wormlike micelle solution at 10 mM or higher shows high viscosity and shear thinning property. Moreover, the C(12)C(3)C(12)(SO(3))(2)/CTAB mixtures do not precipitate even at 1:1 charge ratio and relative high concentration. It suggests that applying gemini surfactant should be an effective approach to improve the solubility of anionic/cationic surfactant mixtures and in turn may promote applications of the surfactant mixtures.