Micelle Stabilization via Entropic Repulsion: Balance of Force Directionality and Geometric Packing of Subunit

Nanoparticles, 10–30 nm in size, have shown great prospects as nanocarriers for drug delivery. We designed amphiphiles based on 3-helix peptide-PEG conjugate forming 15 nm micelles (defined as “3-helix micelles”) with good in vivo stability. Here, we investigated the effect of the site of PEG conjugation on the kinetic stability and showed that the conjugation site affects the PEG chain conformation and the overall molecular architecture of the subunit. Compared to the original design where the PEG chain is located in the middle of the 3-helix bundle, micelle kinetic stability was reduced when the PEG chain was attached near the N-terminus (<i>t</i>_1/2 = 35 h) but was enhanced when the PEG chain was attached near the C-terminus (<i>t</i>_1/2 = 80 h). Quantitative structural and kinetic analysis suggest that the kinetic stability was largely dictated by the combined effects of entropic repulsion associated with PEG chain conformation and the geometric packing of the trimeric subunits. The modular design approach coupled with a variety of well-defined protein stucture and functional polymers will significantly expand the utility of these materials as nanocarriers to meet current demands in nanomedine

Numerical Calculation Method of Apparent Contact Angles on Heterogeneous Double-Roughness Surfaces

Double-roughness surfaces can be used to mimic lotus surfaces. The apparent contact angles (ACAs) of droplets on these surfaces were first calculated by Herminghaus. Then Patankar utilized the pillar model to improve the Herminghaus approach and put forward the formulas for ACAs calculation of the homogeneous double-roughness surfaces where the dual-scale structures and the bases were the same wettable materials. In this paper, we propose a numerical calculation method of ACAs on the heterogeneous double-roughness surfaces where the dual-scale structures and the bases are made of different wettable materials. This numerical calculation method has successfully enhanced the Herminghaus approach. It is promising to become a novel design approach of heterogeneous superhydrophobic surfaces, which are frequently applied in technical fields of self-cleaning, anti-icing, antifogging, and enhancing condensation heat transfer

Numerical Study for a Large-Volume Droplet on the Dual-Rough Surface: Apparent Contact Angle, Contact Angle Hysteresis, and Transition Barrier

The profile, apparent contact angle (ACA), contact angle hysteresis (CAH), and wetting state transmission energy barrier (WSTEB) are important static and dynamic properties of a large-volume droplet on the hierarchical surface. Understanding them can provide us with important insights into functional surfaces and promote the application in corresponding areas. In this paper, we establish three theoretical models (models 1–3) and the corresponding numerical methods, which were obtained by the free energy minimization and the nonlinear optimization algorithm, to predict the profile, ACA, CAH, and WSTEB of a large-volume droplet on the horizontal regular dual-rough surface. In consideration of the gravity, the energy barrier on the contact circle, the dual heterogeneous structures and their roughness on the surface, the models are more universal and accurate than the previous models. It showed that the predictions of the models were in good agreement with the results from the experiment or literature. The models are promising to become novel design approaches of functional surfaces, which are frequently applied in microfluidic chips, water self-catchment system, and dropwise condensation heat transfer system

Image 1_v1_Prediction for 2-year mortality of metastatic ovarian cancer patients based on surveillance, epidemiology, and end results database.tiff

AimTo establish prediction models for 2-year overall survival of ovarian cancer patients with metastasis.MethodsIn total, 4,929 participants from Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into the training set (n = 3,451) and the testing set (n = 1,478). Univariate and multivariable regression were conducted in the training set to identify predictors for 2-year overall survival of metastatic ovarian cancer patients. The C-index was calculated for assessing the performance of the models. The nomogram for the model was plotted. The prediction value of the model was validated in the testing set. Subgroup analysis were performed concerning surgery and chemotherapy status of patients and the metastatic site of ovarian cancer in the testing set. The calibration curves were plotted and the decision curve analysis (DCA) were conducted.ResultsAt the end of follow-up, 2,587 patients were survived and 2,342 patients were dead within 2 years. The 2-year survival rate was 52.5%. The prediction models were constructed based on predictors including age, radiation, surgery and chemotherapy, CA125, and bone, liver, and lung metastasis. The prediction model for 2-year overall survival of ovarian cancer patients with metastasis showed good predictive ability with the C-index of the model of 0.719 (95% CI: 0.706–0.731) in the training set and 0.718 (95% CI: 0.698–0.737) in the testing set. In terms of patients with bone metastasis, the C-index was 0.740 (95% CI: 0.652–0.828) for predicting the 2-year overall survival of ovarian cancer patients. The C-index was 0.836 (95% CI: 0.694–0.979) in patients with brain metastasis, 0.755 (95% CI: 0.721–0.788) in patients with liver metastasis and 0.725 (95% CI: 0.686–0.764) in those with lung metastasis for predicting the 2-year overall survival of ovarian cancer patients.ConclusionThe models showed good predictive performance for 2-year overall survival of metastatic ovarian cancer patients.</p

Chemo-enzymatic Routes to Lipopeptides and Their Colloidal Properties

A unique chemo-enzymatic route to lipopeptides was demonstrated herein that, relative to alternative methods such as solid-phase peptide synthesis (SPPS) and microbial synthesis, is simple, efficient, and scalable. Homo- and co-oligopeptides were synthesized from amino acid ethyl esters via protease catalysis in an aqueous media, followed by chemical coupling to fatty acids to generate a library of lipopeptides. Synthesized lipopeptides were built from hydrophobic moieties with chain lengths ranging from 8 to 18 and peptides consisting of oligo­(l-Glu) or oligo­(l-Glu-<i>co</i>-l-Leu) with an average of seven to eight repeating units. The chemical structures of the lipopeptides were characterized and confirmed by NMR and matrix-assisted laser desorption/ionization (MALDI). The colloidal and interfacial properties of these lipopeptides were characterized and compared in terms of the hydrophobic chain length, oligopeptide composition, and solution pH. The results showed correlation between the interfacial activity of the lipopeptides and the hydrophobicity of the fatty acid and oligopeptide headgroup, the effects of which have been semiquantitatively described in the manuscript. Results from these studies provide insights into design principles that can be further expanded in future work to access lipopeptides from protease-catalysis with improved control over sequence and exploring a wider range of peptide and lipid compositions to further tune lipopeptide biochemical and physical properties

HHRR results of three genetic loci in 241 trios.

<p>HHRR results of three genetic loci in 241 trios.</p

3-Helix Micelles Stabilized by Polymer Springs

Despite increasing demands to employ amphiphilic micelles as nanocarriers and nanoreactors, it remains a significant challenge to simultaneously reduce the particle size and enhance the particle stability. Complementary to covalent chemical bonding and attractive intermolecular interactions, entropic repulsion can be incorporated by rational design in the headgroup of an amphiphile to generate small micelles with enhanced stability. A new family of amphiphilic peptide–polymer conjugates is presented where the hydrophilic headgroup is composed of a 3-helix coiled coil with poly­(ethylene glycol) attached to the exterior of the helix bundle. When micelles form, the PEG chains are confined in close proximity and are compressed to act as a spring to generate lateral pressure. The formation of 3-helix bundles determines the location and the directionalities of the force vector of each PEG elastic spring so as to slow down amphiphile desorption. Since each component of the amphiphile can be readily tailored, these micelles provide numerous opportunities to meet current demands for organic nanocarriers with tunable stability in life science and energy science. Furthermore, present studies open new avenues to use energy arising from entropic polymer chain deformation to self-assemble energetically stable, single nanoscopic objects, much like repulsion that stabilizes bulk assemblies of colloidal particles

Dual Switching in Both RAFT and ROP for Generation of Asymmetric A²A¹B¹B² Type Tetrablock Quaterpolymers

In reversible addition–fragmentation chain transfer (RAFT) polymerization, monomers are divided into “more-activated” monomers (type-A¹ monomer) and “less-activated” monomers (type-A² monomer). In ring-opening polymerization (ROP), monomers are considered to fall into electrophilically polymerizable monomers (lactones and carbonates, type-B¹ monomer) and nucleophilically polymerizable monomers (lactides and carbonates, type-B² monomer). Developing a strategy to copolymerize the four kinds of monomers for formation of asymmetric A²A¹B¹B² type tetrablock quaterpolymers by one-pot sequential ROP and RAFT polymerization is a challenge. Herein, we designed and synthesized a molecule, 2-hydroxyethyl 2-(methyl­(pyridin-4-yl)­carbamo­thioylthio)­propanoate, which functioned as a trifunctional initiator, to initiate ROPs and to modulate RAFT polymerizations sequentially in one-pot. We proposed a dual “acid/base switch” strategy in both RAFT polymerizations and ROPs for one-pot generation of asymmetric A²A¹B¹B² type tetrablock quaterpolymers. A series of di-, tri-, and tetrablock copolymers were synthesized and showed predicted molar mass and narrow dispersities, manifesting that the ROPs and RAFT polymerizations proceeded independently in controlled manners. The dual “acid/base switch” strategy paved a new avenue to combine RAFT polymerizations and ROPs for synthesis of designed copolymers with advanced functionalities and architectures

Making 2‐D Materials Mechanochemically by Twin‐Screw Extrusion: Continuous Exfoliation of Graphite to Multi‐Layered Graphene

Mechanochemistry has developed rapidly in recent years for efficient chemicals and materials synthesis. Twin screw extrusion (TSE) is a particularly promising technique in this regard because of its continuous and scalable nature. A key aspect of TSE is that it provides high shear and mixing. Because of the high shear, it potentially also offers a way to delaminate 2‐D materials. Indeed, the synthesis of 2‐D materials in a scalable and continuous manor remains a challenge in their industrialization. Here, as a proof‐of‐principle, the automated, continuous mechanochemical exfoliation of graphite to give multi‐layer graphene (MLG, ≈6 layers) by TSE is demonstrated. To achieve this, a solid‐and‐liquid‐assisted extrusion (SLAE) process is developed in which organic additives such as pyrene are rendered liquid due to the high temperatures used, to assist with the exfoliation, and simultaneously solid sodium chloride is used as a grinding aid. This gave MLG in high yield (25 wt%) with a short residence time (8 min) and notably with negligible evidence for structural deterioration (defects or oxidation).</p

Effect of Alkyl Length of Peptide–Polymer Amphiphile on Cargo Encapsulation Stability and Pharmacokinetics of 3‑Helix Micelles

3-Helix micelles have demonstrated excellent <i>in vitro</i> and <i>in vivo</i> stability. Previous studies showed that the unique design of the peptide–polymer conjugate based on protein tertiary structure as the headgroup is the main design factor to achieve high kinetic stability. In this contribution, using amphiphiles with different alkyl tails, namely, C16 and C18, we quantified the effect of alkyl length on the stability of 3-helix micelles to delineate the contribution of the micellar core and shell on the micelle stability. Both amphiphiles form well-defined micelles, <20 nm in size, and show good stability, which can be attributed to the headgroup design. C18-micelles exhibit slightly higher kinetic stability in the presence of serum proteins at 37 °C, where the rate constant of subunit exchange is 0.20 h^–1 for C18-micelles vs 0.22 h^–1 for C16-micelles. The diffusion constant for drug release from C18-micelles is approximately half of that for C16-micelles. The differences between the two micelles are significantly more pronounced in terms of <i>in vivo</i> stability and extent of tumor accumulation. C18-micelles exhibit significantly longer blood circulation time of 29.5 h, whereas C16-micelles have a circulation time of 16.1 h. The extent of tumor accumulation at 48 h after injection is ∼43% higher for C18-micelles. The present studies underscore the importance of core composition on the biological behavior of 3-helix micelles. The quantification of the effect of this key design parameter on the stability of 3-helix micelles provides important guidelines for carrier selection and use in complex environment