Chemotherapeutic loading via tailoring of drug-carrier interactions in poly (sialic acid) micelles

New methods in nanoparticle development have aimed to develop customized carriers suited for specific purposes. Micelles, due to their highly tailorable nature, are prime candidates for this customizable methodology. In order to maximize drug loading and tailor release, groups of the micelle core should be carefully selected in order to exploit inherent interactions between the selected drug and the carrier core. Small variations within the composition of these groups can greatly affect micelle characteristics (e.g., size, stability, loading and release). While covalent bonding of drug-to-carrier has enhanced drug loading, drawbacks include inhibited release and altered drug properties. As a result, drug/carrier non-covalent interactions such as hydrophobic attraction, hydrogen bonding and π-π stacking have all garnered great interest, allowing for both enhanced loading as well as bond dissociation to aid in drug release. Just as important, external composition of these micelles should be suited for specific therapeutic applications. Examples include providing stabilization, enhanced circulation times and site-specific targeting. Poly (sialic acid) (PSA), a naturally occurring polysaccharide, has been shown to exhibit all three of these properties yet remains relatively unexplored in the field of micelle-based cancer drug delivery applications. Here, we have grafted various phenyl-terminated alkyl groups (PTAGs) onto the backbone of PSA (PTAG-g-PSA), each selected in order to exploit a specific non-covalent interaction (hydrophobic attraction, hydrogen bonding and π-π stacking) between the PTAG group and the anthracycline chemotherapeutic doxorubicin (DOX) (Figure 1). Upon aqueous self-assembly, these amphiphiles formed micelles which exhibited variation in size, stability, cytotoxicity and DOX loading/release based upon the PTAG selected. For example, PTAGs selected to exploit either hydrogen bonding or π-π stacking loaded in a similar fashion yet varied greatly in release properties. Therefore, the synergistic effect of these small-scale modifications in core groups selected can greatly effect micelle characteristics and result in highly tailorable carriers

In-situ mechanical weakness of subducting sediments beneath a plate boundary décollement in the Nankai Trough

© 2018, The Author(s). The study investigates the in-situ strength of sediments across a plate boundary décollement using drilling parameters recorded when a 1180-m-deep borehole was established during International Ocean Discovery Program (IODP) Expedition 370, Temperature-Limit of the Deep Biosphere off Muroto (T-Limit). Information of the in-situ strength of the shallow portion in/around a plate boundary fault zone is critical for understanding the development of accretionary prisms and of the décollement itself. Studies using seismic reflection surveys and scientific ocean drillings have recently revealed the existence of high pore pressure zones around frontal accretionary prisms, which may reduce the effective strength of the sediments. A direct measurement of in-situ strength by experiments, however, has not been executed due to the difficulty in estimating in-situ stress conditions. In this study, we derived a depth profile for the in-situ strength of a frontal accretionary prism across a décollement from drilling parameters using the recently established equivalent strength (EST) method. At site C0023, the toe of the accretionary prism area off Cape Muroto, Japan, the EST gradually increases with depth but undergoes a sudden change at ~ 800 mbsf, corresponding to the top of the subducting sediment. At this depth, directly below the décollement zone, the EST decreases from ~ 10 to 2 MPa, with a change in the baseline. This mechanically weak zone in the subducting sediments extends over 250 m (~ 800–1050 mbsf), corresponding to the zone where the fluid influx was discovered, and high-fluid pressure was suggested by previous seismic imaging observations. Although the origin of the fluids or absolute values of the strength remain unclear, our investigations support previous studies suggesting that elevated pore pressure beneath the décollement weakens the subducting sediments. [Figure not available: see fulltext.]

Highly Porous Foam Materials for Uses in Reconstructive Orthopedic Surgery and Transcutaneous Implant Applications

High rates of infection are often associated with solid implanted devices employed for reconstructive orthopedic applications. In addition, such devices, when implanted into subcutaneous tissue, do not promote functional soft tissue attachment that is critical for the surgical reconstruction of mobile joints including knees and hips. In particular, transcutaneous implants pose a unique challenge, as wounds resulting from implantation are highly likely to contract severe deep tissue infections that require the repeated administration of antibiotics post surgery. Highly porous implants constructed of materials including inert metals, plastics, and ceramics, exhibit biocompatibility and can facilitate soft tissue in-growth, achieving functional soft tissue attachment with little to no bacterial infections. As such, these devices have become desirable for a large variety of uses in orthopedic surgery. In an effort to better understand the mechanisms of soft tissue in-growth into highly porous implants, four studies (Phase I, II, III and IV) were conducted to observe the effects of implant design parameters on promoting soft tissue in-growth. Quantitative and semi-quantitative analyses of retrieved implants were performed by the use of mechanical peel tests, histological analyses, and growth factor analyses. Phases I and II employed an in-vivo canine model, and Phases III and IV employed an in-vivo rabbit model

Increasing the stability of <i>Lumbricus terrestris</i> erythrocruorin <i>via</i> poly(acrylic acid) conjugation

<p>Since donated red blood cells must be constantly refrigerated, they are often unavailable in remote areas and battlefields. The goal of this study was to synthesize a highly stable blood substitute that does not require refrigeration. Specifically, the extracellular haemoglobin (a.k.a. erythrocruorin, Ec) of the earthworm <i>Lumbricus terrestris</i> erythrocruororin (LtEc) was cross-linked with poly(acrylic acid) (PAA) and ethylene diamine (EDA). PAGE analysis of the LtEc nanoparticles reveals cross-linking between subunits, while dynamic light scattering and scanning electron microscopy show that cross-linking significantly increases the size of the LtEc nanoparticles (164 ± 13.9 nm). Cross-linking also significantly increased the thermal stability of the LtEc nanoparticles by 10 °C (<i>T</i>_m = 72 ± 0.84 °C) relative to native LtEc (<i>T</i>_m = 62 ± 0.6 °C). In addition, while native LtEc rapidly dissociates at pH 9, the LtEc nanoparticles resist subunit dissociation up to pH 10. The oxygen affinity of the LtEc nanoparticles (P₅₀ = 6.85 ± 0.13 mm Hg) is much higher than native LtEc (P₅₀ = 26.67 ± 0.4 mm Hg), but the cooperativity (<i>n</i> = 2.43 ± 0.12) is not affected. Altogether, these results show that cross-linking LtEc with PAA and EDA provides a potential blood substitute with increased stability and oxygen affinity.</p

Expedition 370 Preliminary Report: Temperature Limit of the Deep Biosphere off Muroto.

International Ocean Discovery Program (IODP) Expedition 370 aimed to explore the limits of life in the deep subseafloor biosphere at a location where temperature increases with depth at an intermediate rate and exceeds the known temperature maximum of microbial life (~120°C) at the sediment/basement interface ~1.2 km below the seafloor. Drilling Site C0023 is located in the vicinity of Ocean Drilling Program (ODP) Sites 808 and 1174 at the protothrust zone in the Nankai Trough off Cape Muroto at a water depth of 4776 m. ODP Leg 190 in 2000, revealed the presence of microbial cells at Site 1174 to a depth of ~600 meters below seafloor (mbsf), which corresponds to an estimated temperature of ~70°C, and reliably identified a single zone of higher cell concentrations just above the décollement at around 800 mbsf, where temperature presumably reached 90°C; no cell count data was reported for other sediment layers in the 70°–120°C range, because the limit of manual cell count for low-biomass samples was not high enough. With the establishment of Site C0023, we aimed to detect and investigate the presence or absence of life and biological processes at the biotic–abiotic transition with unprecedented analytical sensitivity and precision. Expedition 370 was the first expedition dedicated to subseafloor microbiology that achieved time-critical processing and analyses of deep biosphere samples by simultaneous shipboard and shore-based investigations. Our primary objectives during Expedition 370 were to study the relationship between the deep subseafloor biosphere and temperature. We aimed to comprehensively study the factors that control biomass, activity, and diversity of microbial communities in a subseafloor environment where temperatures increase from ~2°C at the seafloor to ~120°C at the sediment/basement interface and thus likely encompasses the biotic–abiotic transition zone. We also aimed to determine geochemical, geophysical, and hydrogeological characteristics in sediment and the underlying basaltic basement and elucidate if the supply of fluids containing thermogenic and/or geogenic nutrient and energy substrates may support subseafloor microbial communities in the Nankai accretionary complex. To address these primary scientific objectives and questions, we penetrated 1180 m and recovered 112 cores across the sediment/basalt interface. More than 13,000 samples were collected, and selected samples were transferred to the Kochi Core Center by helicopter for simultaneous microbiological sampling and analysis in laboratories with a super-clean environment. Following the coring operations, a temperature observatory with 13 thermistor sensors was installed in the borehole to 863 mbsf

A New Method for Quality Control of Geological Cores by X-Ray Computed Tomography: Application in IODP Expedition 370

X-ray computed tomography (XCT) can be used to identify lithologies and deformation structures within geological core, with the potential for the identification processes to be applied automatically. However, because of drilling disturbance and other artifacts, the use of large XCT-datasets in automated processes requires methods of quality control that can be applied systematically. We propose a new systematic method for quality control of XCT data that applies numerical measures to CT slices, and from this obtains data reflective of core quality. Because the measures are numerical they can be applied quickly and consistently between different sections and cores. This quality control processing protocol produces downhole radiodensity profiles from mean CT-values that can be used for geological interpretation. The application of this quality control protocols was applied to XCT data from International Ocean Discovery Program (IODP) Expedition 370 Site C0023 located at the toe of the Nankai accretionary complex. The evaluation of core quality based on this protocol was found to be a good fit to standard-evaluations based on the visual description of core, and could be used to select samples free from drilling disturbance or contamination. The quality-controlled downhole mean CT-value profile has features that can be used to identify lithologies within a formation, the presence and type of deformation structures and to distinguish formations