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Stimuli responsive polymers are an efficient means of targeted therapy.  Compared to conventional agents, they increase bioavailability and efficacy.  In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials.  In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors.  NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH).  The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex.  When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%).  The OxNP-LDH complexes were not responsive to structurally related small molecules.  This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.

Maintaining membrane integrity is a challenge at extreme temperatures. Biochemical synthesis of membrane-spanning lipids is one adaptation that organisms such as thermophilic archaea have evolved to meet this challenge and preserve vital cellular function at high temperatures. The molecular-level details of how these tethered lipids affect membrane dynamics and function, however, remain unclear. Using synthetic monolayer-forming lipids with transmembrane tethers, here, we reveal that lipid tethering makes membrane permeation an entropically controlled process that helps to limit membrane leakage at elevated temperatures relative to bilayer-forming lipid membranes. All-atom molecular dynamics simulations support a view that permeation through membranes made of tethered lipids reduces the torsional entropy of the lipids and leads to tighter lipid packing, providing a molecular interpretation for the increased transition-state entropy of leakage.

The solubilization of lyophobic compounds in block copolymer micelles has been extensively investigated but remains only partially understood. There is a need to understand the fundamental parameters that determine the spatial distribution of the solubilized compounds within the micelles. Controlling this feature is a key aspect in the design of drug delivery systems with tailored release properties. Using Scheutjens-Fleer self-consistent field (SF-SCF) computations, we found that solubilization is regulated by a complex interplay between enthalpic and entropic contributions and that the spatial distribution can be controlled by the concentration and solubility of the guest compound in the dispersion medium. Upon solubilization, a characteristic change in size and mass of the micelles is predicted. This can be used as a fingerprint to indirectly assess the spatial distribution. Based on these findings, we developed two experimental protocols to control and assess the spatial distribution of lyophobic compounds within block copolymer micelles.

Data from wearable technology may correlate with patient-reported outcome measures (PROMs). The objective of this prospective pilot study of 22 total joint arthroplasty patients was to determine if sensor-generated data are predictive of short-term PROMs in total joint arthroplasty. Data on "average daily step count" and "average daily minutes active" were generated by the provided wearable sensor preoperatively and up to 6 weeks postoperatively. PROMs were collected preoperatively and at 6 weeks postoperatively. Changes in PROMs were calculated as "Δ". Linear regression of the sensor data and PROMs generated R2 values. Changes in the average daily step count from preop to 6-week postop strongly associated with changes in Veterans Rand 12 Physical Component Score (R2 = 0.4532) from preop to 6 weeks. Changes in average daily minutes active from preop to 6-weeks postop were strongly associated with ΔHOOS/KOOS (R2 = 0.4858).

Purpose: To determine the interobserver reliability of perceived displacement (PD) ≥ 1 cm of lateral compression type 1 (LC1) pelvic ring fractures and to determine if PD correlated with published methods of measuring fracture displacement and adverse events. Methods: The injury and follow-up radiographs of 10 patients with nonoperative minimally displaced LC1 injuries were reviewed by 27 orthopaedic trauma surgeons to determine if they perceived an interval fracture displacement ≥ 1 cm. Perceived displacement (PD) was compared to 11 measurements of displacement: the difference in heights of iliac crests (IC), sourcils, and ischial tuberosities on AP/outlet radiographs; the distance from femoral head (FH) to the sacral midline and the distance between the radiographic teardrops (TD) on the AP; the distance from the TD to sacral midline and the difference in distances between the SI joints and the contralateral TD on the inlet. The interobserver reliability and correlation of PD and measured displacement was calculated. The association between PD and adverse events was also evaluated. Results: PD had weak interobserver reliability (kappa = 0.46). Many of the measurements of displacement were poorly sensitive for PD. The magnification-corrected AP TD measurement had the highest sensitivity (100%) for PD and excellent interobserver reliability (Intraclass correlation 0.97), but had a low specificity (57.1%). All three patients with PD had adverse events while patients without PD had uneventful recoveries (p = 0.008). Conclusions: The AP TD measurement detected all cases of PD and had excellent reliability. PD was associated with adverse events, suggesting that accurate and reliable measurements of displacement are warranted. Level of evidence III: Diagnostic. [ABSTRACT FROM AUTHOR]

The intrinsic properties of nanomaterials offer promise for technological revolutions in many fields, including transportation, soft robotics, and energy. Unfortunately, the exploitation of such properties in polymer nanocomposites is extremely challenging due to the lack of viable dispersion routes when the filler content is high. We usually face a dichotomy between the degree of nanofiller loading and the degree of dispersion (and, thus, performance) because dispersion quality decreases with loading. Here, we demonstrate a potentially scalable pressing-and-folding method (P & F), inspired by the art of croissant-making, to efficiently disperse ultrahigh loadings of nanofillers in polymer matrices. A desired nanofiller dispersion can be achieved simply by selecting a sufficient number of P & F cycles. Because of the fine microstructural control enabled by P & F, mechanical reinforcements close to the theoretical maximum and independent of nanofiller loading (up to 74 vol %) were obtained. We propose a universal model for the P & F dispersion process that is parametrized on an experimentally quantifiable " D factor". The model represents a general guideline for the optimization of nanocomposites with enhanced functionalities including sensing, heat management, and energy storage.

Researchers report the synthesis of a new archaea-inspired tetraether lipid and study the mechanical elastic properties of membranes made from this bolalipid. To access structural diversity in the hydrophobic moiety of the lipids and to tune membrane properties, they have used used Huisgen 1,3-dipolar cycloaddition strategy to design and synthesize a tetraether lipid incorporating phytanyl side chains and polar 1,4 triazole rings known to change lipid packing. The researchers demonstrate the first example of the synthesis of phytanyl side chain incorporated tetraether lipids with 1,4-triazole rings. They also confirm the ability of lipids incorporating 1,4-triazole rings to form stable small and giant vesicles and examined their physical and mechanical properties using a micropipette aspiration technique.

Morphology plays an essential role in chemistry through the segregation of atoms and/or molecules into different phases, delineated by interfaces. This is a general process in materials synthesis and exploited in many fields including colloid chemistry, heterogeneous catalysis, and functional molecular systems. To rationally design complex materials, we must understand and control morphology evolution. Toward this goal, we utilize cryogenic transmission electron microscopy (cryoTEM), which can track the structural evolution of materials in solution with nanometer spatial resolution and a temporal resolution of

The passive leakage of small molecules across membranes is a major limitation of liposomal drug formulations. Here, we evaluate the leakage of 3 clinically used chemotherapeutic agents (cytarabine, methotrexate and vincristine) encapsulated in liposomes comprised of a synthetic, archaea-inspired, membrane-spanning tetraether lipid. Liposomes comprised of the pure tetraether lipid exhibited superior retention of both a neutrally and positively charged drug (up to an ∼9-fold decrease in the rate of drug leakage) compared to liposomes formed from a commercial diacyl lipid, while exhibiting a similar retention of a negatively charged drug that did not appreciably leak from either type of liposome. We also demonstrate that liposomes made of the archaea-inspired lipid can be used for the delivery of encapsulated small molecules into living cells.

Polymerization‐induced self‐assembly (PISA) has emerged as a scalable one‐pot technique to prepare block copolymer (BCP) nanoparticles. Recently, a PISA process, that results in poly(l‐lactide)‐b‐poly(ethylene glycol) BCP nanoparticles coined ring‐opening polymerization (ROP)‐induced crystallization‐driven self‐assembly (ROPI‐CDSA), was developed. The resulting nanorods demonstrate a strong propensity for aggregation, resulting in the formation of 2D sheets and 3D networks. This article reports the synthesis of poly(N,N‐dimethyl acrylamide)‐b‐poly(l)‐lactide BCP nanoparticles by ROPI‐CDSA, utilizing a two‐step, one‐pot approach. A dual‐functionalized photoiniferter is first used for controlled radical polymerization of the acrylamido‐based monomer, and the resulting polymer serves as a macroinitiator for organocatalyzed ROP to form the solvophobic polyester block. The resulting nanorods are highly stable and display anisotropy at higher molecular weights (>12k Da) and concentrations (>20% solids) than the previous report. This development expands the chemical scope of ROPI‐CDSA BCPs and provides readily accessible nanorods made with biocompatible materials. [ABSTRACT FROM AUTHOR]

A Gd3+-coordinated polymerizable analogue of the MRI contrast agent Gd-DOTA was used to prepare amphiphilic block copolymers, with hydrophilic blocks composed entirely of the polymerized contrast agent. The resulting amphiphilic block copolymers assemble into nanoparticles (NPs) of spherical- or fibril-shape, each demonstrating enhanced relaxivity over Gd-DOTA. As an initial examination of their behavior in vivo, intraperitoneal (IP) injection of NPs into live mice was performed, showing long IP residence times, observed by MRI. Extended residence times for particles of well-defined morphology may represent a valuable design paradigm for treatment or diagnosis of peritoneal malignances.

Liquid cell transmission electron microscopy (LCTEM) provides a unique insight into the dynamics of nanomaterials in solution. Controlling the addition of multiple solutions to the liquid cell remains a key hurdle in our ability to increase throughput and to study processes dependent on solution mixing including chemical reactions. Here, we report that a piezo dispensing technique allows for mixing of multiple solutions directly within the viewing area. This technique permits deposition of 50 pL droplets of various aqueous solutions onto the liquid cell window, before assembly of the cell in a fully controlled manner. This proof-of-concept study highlights the great potential of picoliter dispensing in combination with LCTEM for observing nanoparticle mixing in the solution phase and the creation of chemical gradients.

Direct polymerization of an oxaliplatin analogue was used to reproducibly generate amphiphiles in one pot, which consistently and spontaneously self-assemble into well-defined nanoparticles (NPs). Despite inefficient drug leakage in cell-free assays, the NPs were observed to be as cytotoxic as free oxaliplatin in cell culture experiments. We investigated this phenomenon by super-resolution fluorescence structured illumination microscopy (SIM) and nanoscale secondary ion mass spectrometry (NanoSIMS). In combination, these techniques revealed NPs are taken up via endocytic pathways before intracellular release of their cytotoxic cargo. As with other drug-carrying nanomaterials, these systems have potential as cellular delivery vehicles. However, high-resolution methods to track nanocarriers and their cargo at the micro- and nanoscale have been underutilized in general, limiting our understanding of their interactions with cells and tissues. We contend this type of combined optical and isotopic imaging strategy represents a powerful and potentially generalizable methodology for cellular tracking of nanocarriers and their cargo.

Amphiphilic block copolymers can assemble into a variety of structures on the nanoscale in selective solvent. The micelle blending protocol offers a simple unique route to reproducibly produce polymer nanostructures. Here we expand this blending protocol to a range of polymer micelle systems and self-assembly routes. We found by exploring a range of variables that the systems must be able to reach global equilibrium at some point for the blending protocol to be successful. Our results demonstrate the kinetics requirements, specifically core block glass transition temperature, Tg, and length of the block limiting the exchange rates, for the blending protocol which can then be applied to a wide range of polymer systems to access this simple protocol for polymer self-assembly.

Amphiphilic triblock copolymers containing Fe(III) -catecholate complexes formulated as spherical- or cylindrical-shaped micellar nanoparticles (SMN and CMN, respectively) are described as new T1-weighted agents with high relaxivity, low cytotoxicity, and long-term stability in biological fluids. Relaxivities of both SMN and CMN exceed those of established gadolinium chelates across a wide range of magnetic field strengths. Interestingly, shape-dependent behavior is observed in terms of the particles' interactions with HeLa cells, with CMN exhibiting enhanced uptake and contrast via magnetic resonance imaging (MRI) compared with SMN. These results suggest that control over soft nanoparticle shape will provide an avenue for optimization of particle-based contrast agents as biodiagnostics. The polycatechol nanoparticles are proposed as suitable for preclinical investigations into their viability as gadolinium-free, safe, and effective imaging agents for MRI contrast enhancement.

The composition and surface properties of atmospheric aerosol particles largely control their impact on climate by affecting their ability to uptake water, react heterogeneously, and nucleate ice in clouds. However, in the vacuum of a conventional electron microscope, the native surface and internal structure often undergo physicochemical rearrangement resulting in surfaces that are quite different from their atmospheric configurations. Herein, we report the development of cryogenic transmission electron microscopy where laboratory generated sea spray aerosol particles are flash frozen in their native state with iterative and controlled thermal and/or pressure exposures and then probed by electron microscopy. This unique approach allows for the detection of not only mixed salts, but also soft materials including whole hydrated bacteria, diatoms, virus particles, marine vesicles, as well as gel networks within hydrated salt droplets-all of which will have distinct biological, chemical, and physical processes. We anticipate this method will open up a new avenue of analysis for aerosol particles, not only for ocean-derived aerosols, but for those produced from other sources where there is interest in the transfer of organic or biological species from the biosphere to the atmosphere.