Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling.

Use of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because of an incomplete understanding of fundamental mechanisms controlling mAb absorption from the SC site, and due to the limited translatability of preclinical studies. In this paper, we report on the development and evaluation of a whole-body physiologically-based model to predict mAb pharmacokinetics following SC administration. The circulatory model is based on the physiological processes governing mAb transport and includes two mAb-specific parameters representing differences in pinocytosis rate and the diffusive/convective transport rates among mAbs. At the SC administration site, two additional parameters are used to represent mAb differences in lymphatic capillary uptake and in pre-systemic clearance. Model development employed clinical intravenous (IV) plasma PK data from 20 mAbs and SC plasma PK data from 12 of these mAbs, as obtained from the literature. The resulting model reliably described both the IV and SC measured plasma concentration data. In addition, a metric based on the positive charge across the mAb's complementarity determining region vicinity was found to positively correlate with the model-based estimates of the mAb-specific parameter governing organ/tissue pinocytosis transport and with estimates of the mAb's SC lymphatic capillary clearance. These two relationships were incorporated into the model and accurately predicted the SC PK profiles of three out of four separate mAbs not included in model development. The whole-body physiologically-based model reported herein, provides a platform to characterize and predict the plasma disposition of monoclonal antibodies following SC administration in humans.

Natural Particulates Inspired Specific-Targeted Codelivery of siRNA and Paclitaxel for Collaborative Antitumor Therapy.

The effective combination of drugs promoting antiangiogenesis and apoptosis effects has proven to be a promising collaborative tumor antidote; and the codelivery of small interfering RNA (siRNA) and chemotherapy agents within one efficient vehicle has gained more attention over single regimen administration. Herein, vascular endothelial growth factor specific siRNA (siVEGF) and paclitaxel (PTX) were introduced as therapeutic companions and coencapsulated into naturally mimic high-density lipoproteins (rHDL/siVEGF-PTX), so that various mechanisms of treatment can occur simultaneously. The terminal nanoparticles share capacity of specific-targeting to tumor cells overexpressed scavenger receptor class B type I (SR-BI) and deliver siVEGF and PTX into cytoplasm by a nonendocytosis mechanism. By exchanging HDL core lipids with hydrophobic therapeutics, rHDL/siVEGF-PTX possessed particle size of ∼160 nm, surface potential of ∼-20 mV, and desirable long-term storage stability. In vitro results confirmed that the parallel activity of siVEGF and PTX displayed enhanced anticancer efficacy. The half-maximal inhibitory concentration (IC50) of rHDL/siVEGF-PTX toward human breast cancer MCF-7 cell is 0.26 µg/mL (PTX concentration), which presents a 14.96-fold increase in cytotoxicity by taking Taxol as comparison. Moreover, in vivo results further demonstrated that rHDL/siVEGF-PTX performed enhanced tumor growth inhibition via natural targeting pathway, accompanied by remarkable inhibition of neovascularization in situ caused by siVEGF silencing in down-regulation of VEGF proteins. On the premise of effective drug codelivery, rHDL/siVEGF-PTX demonstrated high tumor targeting for collaborative antitumor efficacy without side effects after systemic administration, and this bioinspired strategy could open an avenue for exploration of combined anticancer therapy.

Dynamic Fall Recovery Control for Legged Robots via Reinforcement Learning.

Falling is inevitable for legged robots when deployed in unstructured and unpredictable real-world scenarios, such as uneven terrain in the wild. Therefore, to recover dynamically from a fall without unintended termination of locomotion, the robot must possess the complex motor skills required for recovery maneuvers. However, this is exceptionally challenging for existing methods, since it involves multiple unspecified internal and external contacts. To go beyond the limitation of existing methods, we introduced a novel deep reinforcement learning framework to train a learning-based state estimator and a proprioceptive history policy for dynamic fall recovery under external disturbances. The proposed learning-based framework applies to different fall cases indoors and outdoors. Furthermore, we show that the learned fall recovery policies are hardware-feasible and can be implemented on real robots. The performance of the proposed approach is evaluated with extensive trials using a quadruped robot, which shows good effectiveness in recovering the robot after a fall on flat surfaces and grassland.

Effect of Bionic Crab Shell Attitude Parameters on Lift and Drag in a Flow Field.

Underwater bionic-legged robots encounter significant challenges in attitude, velocity, and positional control due to lift and drag in water current environments, making it difficult to balance operational efficiency with motion stability. This study delves into the hydrodynamic properties of a bionic crab robot's shell, drawing inspiration from the sea crab's motion postures. It further refines the robot's underwater locomotion strategy based on these insights. Initially, the research involved collecting attitude data from crabs during underwater movement through biological observation. Subsequently, hydrodynamic simulations and experimental validations of the bionic shell were conducted, examining the impact of attitude parameters on hydrodynamic performance. The findings reveal that the transverse angle predominantly influences lift and drag. Experiments in a test pool with a crab-like robot, altering transverse angles, demonstrated that increased transverse angles enhance the robot's underwater walking efficiency, stability, and overall performance.

Rational design and nanofabrication of gecko-inspired fibrillar adhesives.

Gecko feet integrate many intriguing functions such as strong adhesion, easy detachment, and self-cleaning. Mimicking gecko toe pad structure leads to the development of new types of fibrillar adhesives useful for various applications. In this Concept article, in addition to the design of adhesive mimics by replicating gecko geometric features, we show a new trend of rational design by adding other physical, chemical, and biological principles on to the geometric merits, for enhancing robustness, responsive control, and durability. Current challenges and future directions are highlighted in the design and nanofabrication of biomimetic fibrillar adhesives.

Physiologically Based Modeling to Predict Monoclonal Antibody Pharmacokinetics in Humans from in vitro Physiochemical Properties.

A model-based framework is presented to predict monoclonal antibody (mAb) pharmacokinetics (PK) in humans based on in vitro measures of antibody physiochemical properties. A physiologically based pharmacokinetic (PBPK) model is used to explore the predictive potential of 14 in vitro assays designed to measure various antibody physiochemical properties, including nonspecific cell-surface interactions, FcRn binding, thermal stability, hydrophobicity, and self-association. Based on the mean plasma PK time course data of 22 mAbs from humans reported in the literature, we found a significant positive correlation (R = 0.64, p = .0013) between the model parameter representing antibody-specific vascular to endothelial clearance and heparin relative retention time, an in vitro measure of nonspecific binding. We also found that antibody-specific differences in paracellular transport due to convection and diffusion could be partially explained by antibody heparin relative retention time (R = 0.52, p = .012). Other physiochemical properties, including antibody thermal stability, hydrophobicity, cross-interaction and self-association, in and of themselves were not predictive of model-based transport parameters. In contrast to other studies that have reported empirically derived expressions relating in vitro measures of antibody physiochemical properties directly to antibody clearance, the proposed PBPK model-based approach for predicting mAb PK incorporates fundamental mechanisms governing antibody transport and processing, informed by in vitro measures of antibody physiochemical properties, and can be expanded to include more descriptive representations of each of the antibody processing subsystems, as well as other antibody-specific information.

Monoclonal Antibody Pharmacokinetics in Cynomolgus Monkeys Following Subcutaneous Administration: Physiologically Based Model Predictions from Physiochemical Properties.

An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous and subcutaneous administration. Significant associations were found between subcutaneous injection site degradation rate and the antibody's local positive charge of its complementarity-determining region (R = 0.56, p = 0.0012), antibody pinocytosis rate and its overall positive charge (R = 0.59, p = 0.00063), and antibody paracellular transport and its overall charge together with hydrophobicity (R = 0.63, p = 0.00096). Based on these results, population simulations were performed to predict the relationship between bioavailability and antibody local positive charge. In addition, model simulations were conducted to calculate the relative contribution of absorption pathways (lymphatic and blood), pre-systemic degradation pathways (interstitial and lysosomal), and the influence of injection site lymph flow on antibody bioavailability and pharmacokinetics. The proposed physiologically based modeling framework integrates fundamental mechanisms governing antibody subcutaneous absorption and disposition, with structured-based physiochemical properties, to predict antibody bioavailability and pharmacokinetics in vivo.

Chain conformations and steady-shear viscosity properties of pectic polysaccharides from apple and tomato.

In this study, apple pectin (AP) and tomato pectin (TP) were demonstrated to be a high-ester (74.8%) polysaccharide with the weight-average molecular weight (Mw ) of âˆ¼ 243 kDa and a low-ester (45.9%) polysaccharide with the Mw of âˆ¼ 19 kDa, respectively. The semi-rigid chain conformations of pectic polysaccharides in NaNO3 aqueous solution were deduced according to the Smidsrød "B values" of AP (0.025) and TP (0.029), while AP and TP exhibited higher stiffness in water due to the electric repulsion of carboxyl groups, which was visually observed by AFM images. Under steady shear, the shear-thickening behaviors of AP and TP in NaNO3 aqueous solutions were observed in the shear rate range of < 1 s-1, which were attributed to the disruption of the ordered arrangement induced by semi-rigid pectin chains into randomly entangled structure by weak shear force. AP exhibited stronger shear-thickening behavior due to the formation of more entanglements resulted from the higher Mw and longer side chains highly branched at rhamngalacturonan region. This study provides the scientific basis for the construction of the relationship of steady-shear property with chain conformation and molecular weight of pectin.

An Analysis of Glucose Effectiveness in Subjects With or Without Type 2 Diabetes via Hierarchical Modeling.

Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production, is an important mechanism maintaining normoglycemia. We conducted a minimal modeling analysis of glucose effectiveness at zero insulin (GEZI) using intravenous glucose tolerance test data from subjects with type 2 diabetes (T2D, n=154) and non-diabetic (ND) subjects (n=343). A hierarchical statistical analysis was performed, which provided a formal mechanism for pooling the data from all study subjects, to yield a single composite population model that quantifies the role of subject specific characteristics such as weight, height, age, sex, and glucose tolerance. Based on the resulting composite population model, GEZI was reduced from 0.021 min-1 (standard error - 0.00078 min-1) in the ND population to 0.011 min-1 (standard error - 0.00045 min-1) in T2D. The resulting model was also employed to calculate the proportion of the non-insulin-dependent net glucose uptake in each subject receiving an intravenous glucose load. Based on individual parameter estimates, the fraction of total glucose disposal independent of insulin was 72.8% ± 12.0% in the 238 ND subjects over the course of the experiment, indicating the major contribution to the whole-body glucose clearance under non-diabetic conditions. This fraction was significantly reduced to 48.8% ± 16.9% in the 30 T2D subjects, although still accounting for approximately half of the total in the T2D population based on our modeling analysis. Given the potential application of glucose effectiveness as a predictor of glucose intolerance and as a potential therapeutic target for treating diabetes, more investigations of glucose effectiveness in other disease conditions can be conducted using the hierarchical modeling framework reported herein.

Construction of physical-crosslink chitosan/PVA double-network hydrogel with surface mineralization for bone repair.

Weak mechanical properties, lack biocompatibility and relatively bioinert are formidable obstruct in application of bone repair materials. Multifunctional composite materials have been considered as a viable solution to this problem. Here, a new double network (DN) hydrogel was constructed by physical cross-linking of medical grade poly (vinyl alcohol) (PVA) and chitosan in KOH/urea dissolution system. The obtained hydrogel demonstrated excellent tensile strength (0.24 MPa), elongation at break (286%), and high compressive strength (0.11 MPa on the strain of 60%). Our studies showed that the prepared hydrogel had excellent biocompatibility in vitro and the introduction of hydroxyapatite (HAp) by surface mineralization imparted hydrogel the ability to induce rat bone marrow stem cells (rBMSCs) differentiation. The in vivo experiments revealed that the surface mineralized double network hydrogel significantly accelerated simultaneous regeneration of bone defects in a rabbit bone defect model. All the results indicated that this hydrogel has the potential as a bone repair material.

Why do very unattractive workers earn so much?

Kanazawa and Still (2018) showed that very unattractive workers earned more than unattractive workers, sometimes more than average-looking or attractive workers, because they had higher levels of intelligence and education, but they did not explain why very unattractive workers had higher intelligence and education. There are both theoretical and empirical reasons to expect that some intelligent men may prefer to marry very unattractive women. The analysis of the National Longitudinal Study of Adolescent Health (Add Health) shows that very unattractive women were significantly more likely to be married at Age 29 than unattractive or average-looking women, and their spouses or partners earned significantly more than those of unattractive or average-looking women. If intelligent men have historically preferred to marry very unattractive women generation after generation, then, because both general intelligence and physical attractiveness are highly heritable, this can explain why very unattractive workers are more intelligent and achieve higher education, thereby earning more. It can also explain why the positive correlation between intelligence and physical attractiveness is not larger despite assortative mating of intelligent men of higher status and physically attractive women over many generations.

Different chemical groups modification on the surface of chitosan nonwoven dressing and the hemostatic properties.

The hemostatic properties of surface modified chitosan nonwoven had been investigated. The succinyl groups, carboxymethyl groups and quaternary ammonium groups were introduced into the surface of chitosan nonwoven (obtained NSCS, CMCS and TMCS nonwoven, respectively). For blood clotting, absorbance value (0.105±0.03) of NSCS1 nonwoven was the smallest (CS 0.307±0.002, NSCS2 0.148±0.002, CMCS1 0.195±0.02, CMCS2 0.233±0.001, TMCS1 0.191±0.002, TMCS2 0.345±0.002), which indicated the stronger hemostatic potential. For platelet aggregation, adenosine diphosphate agonist was added to induce the nonwoven to adhered platelets. The aggregation of platelet with TMCS2 nonwoven was highest (10.97±0.16%). Further research of blood coagulation mechanism was discussed, which indicated NSCS and CMCS nonwoven could activate the intrinsic pathway of coagulation to accelerate blood coagulation. NSCS1 nonwoven showed the shortest hemostatic time (147±3.7s) and the lowest blood loss (0.23±0.05g) in a rabbit ear artery injury model. These results demonstrated that these surface modified chitosan nonwoven dressings could use as a promising hemostatic intervention, especially NSCS nonwoven dressing.

The green and stable dissolving system based on KOH/urea for homogeneous chemical modification of chitosan.

The novel solvent (0.25 M KOH/0.01 M urea alkaline solution) was used to successfully dissolve chitosan without freezing-thawing cycles, for the first time. The results from XRD, FTIR, and 13CNRM proved that KOH/urea solution could destroy the hydrogen bonds between chitosan chains more efficiently than NaOH/urea solution. The dynamic light scattering, rheology, viscosity and elemental analysis confirmed that the KOH/urea hydrogen-bonded chitosan complex had a better thermal stability at 40 °C, and no obvious deacetylation and degradation appeared in dissolution process. Subsequently, the homogeneous chemical modification of chitosan based on KOH/urea dissolution system solution was conducted at 25 °C. The FTIR and microscopic observation indicated that the carboxymethyl chitosan, N,N,N-trimethyl chitosan and hydroxyl butyl chitosan were synthetized successfully. This work provided a green and stable solvent for homogeneous chemical modification of chitosan.

pH-Activated nanoparticles with targeting for the treatment of oral plaque biofilm.

Oral plaque biofilms are highly resilient microbial assemblies that are challenging to eradicate. Herein, we describe the synthesis and study of pH-positive, doxycycline (DOX)-loaded nanocarriers to combat pathogenic biofilms. The mixed shell-core nanoparticles consisted of quaternary ammonium chitosan (TMC) as a positively charged section, which targeted nanoparticles to negatively charged biofilm surfaces. In addition liposomes were used as a DOX loading tool to eradicate the multidrug-resistant biofilm. In a drug release test, DOX release was pH-dependent with t1/2 = 0.75 h and 2.3 h for release at pH 4.5 and 6.8, respectively. Furthermore, TMC-Lip-DOX NPs could adhere to the biofilm and efficiently remove the biofilm from the hydroxyapatite (HA) surface. Furthermore, TMC-Lip-DOX NPs had biocomaptible properties and were non-toxic to MC3T3-E1 cells. This constitutes a highly effective pathway to control oral plaque biofilms and has a good potential use for dental biofilm therapies.

Preparation of composite hydroxybutyl chitosan sponge and its role in promoting wound healing.

In this work, a composite sponge was produced by physically mixing hydroxybutyl chitosan with chitosan to form a porous spongy material through vacuum freeze-drying. Hydrophilic and macroporous composite hydroxybutyl chitosan sponge was developed via the incorporation of chitosan into hydroxybutyl chitosan. The composite sponge showed higher porosity (about 85%), greater water absorption (about 25 times), better softness and lower blood-clotting index (BCI) than those of chitosan sponge and hydroxybutyl chitosan sponge. The composite sponge with good hydrophilic could absorb the moisture in the blood to increase blood concentration and viscosity, and become a semi-swelling viscous colloid to clog the capillaries. Cytocompatibility tests with L929 cells and HUVEC cells demonstrated that composite sponge were no cytotoxicity, and could promote the growth of fibroblasts. It made up for the shortcomings of hydroxybutyl chitosan with unfavorable antibacterial effect to achieve a higher level of antibacterial (>99.99% reduction). Eventually, the vivo evaluations in Sprague-Dawley rats revealed that epithelial cells attached to the composite sponge and penetrated into the interior, in addition to this, it was also proved that the composite sponge (HC-1) had a better ability to promote wound healing and helped for faster formation of skin glands and re-epithelialization. The obtained data encourage the use of this composite sponge for wound dressings.

Chitosan-Based Thermo/pH Double Sensitive Hydrogel for Controlled Drug Delivery.

A series of thermo/pH sensitive N-succinyl hydroxybutyl chitosan (NSHBC) hydrogels with different substitution degrees of succinyl are prepared for drug delivery. Rheology analysis shows that the gelation temperature of NSHBC hydrogels is 3.8 °C higher than that of hydroxybutyl chitosan (HBC) hydrogels. A model drug bovine serum albumin (BSA) is successfully loaded and released. NSHBC hydrogels show excellent pH sensitivity drug release behaviors. After incubation for 24 h, 93.7% of BSA is released from NSHBC hydrogels in phosphate buffer saline (PBS) (pH 7.4), which is significantly greater than that of 24.6% at pH 3.0. In contrast, the release rate of BSA from HBC is about 70.0% at pH 3.0 and 7.4. Thus, these novel hydrogels have the prominent merits of high adaptability to soluble drugs and pH sensitivity triggered release, indicating that NSHBC hydrogels have promising applications in oral drug delivery.

Tough chitosan hydrogel based on purified regeneration and alkaline solvent as biomaterials for tissue engineering applications.

The chitosan based on purified regeneration could be dissolved in 6wt% aqueous NaOH without freeze-thawing cycles and acetylation processing, and such a solution system was effective and different from other dissolving methods Upon heating, a tough hydrogel was constructed from the chitosan (purified regeneration) alkaline solution. The results of XRD, TEM, SEM and rheology analysis proved that chitosan easily aggregated in the solution and formed a nanofibers network to gelate at elevated temperature and concentration. The merely chitosan hydrogel had a uniform network structure and its (5wt%) compressive fracture stress could reach 0.2MPa. Furthermore, the hydrogels exhibited excellent biodegradability, blood compatibility and cellular compatibility. Therefore, the tough chitosan hydrogels may have a wide range of applications in biomedicine.

Nanoparticles/thermosensitive hydrogel reinforced with chitin whiskers as a wound dressing for treating chronic wounds.

Cutaneous chronic wounds are characterized by impaired wound healing which may lead to infection and even amputation. To surmount this problem, we developed a chitin whisker (CW)/carboxymethyl chitosan nanoparticles (CMCS NPs)/thermosensitive hydroxybutyl chitosan (HBC) composite hydrogel (CW/NPs/HBC-HG) as a wound dressing for treating chronic wounds. Upon introduction of CWs, the composite hydrogel exhibited a significant decrease in gelation temperature and enhanced mechanical properties. The storage modulus (G') of the CW/NPs/HBC-HG was 3.6 times that of the NPs/HBC-HG at 37 °C and the ex vivo rat skin test also showed that the mechanical properties were significantly improved. Linezolid, a wide-spectrum antibiotic, was dissolved directly in the water phase of the composite hydrogel, and the antibacterial activity of the composite hydrogel against Escherichia coli and Staphylococcus aureus was up to 99% until 7 days. When recombinant human epidermal growth factor (rhEGF) was encapsulated into the NPs, the CW/NPs/HBC-HG offered prolonged cell proliferation activity up to 5 days. More importantly, the in vivo chronic wound healing model evaluation in diabetic rats revealed that the CW/NPs/HBC-HG dressing promoted wound healing and accelerated reepithelialization, collagen deposition and angiogenesis. These findings demonstrated that CW/NPs/HBC-HG is a promising dressing for chronic wounds.

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.

The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719-31. ©2016 AACR.