Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients.

After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein-protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

Effects of Reductive Soil Disinfestation Combined with Liquid-Readily Decomposable Compounds and Solid Plant Residues on the Bacterial Community and Functional Composition.

Reductive soil disinfestation (RSD) incorporated with sole plant residues or liquid-readily decomposable compounds is an effective management strategy to improve soil health. However, the synthetic effects of RSD incorporated with liquid-readily decomposable compounds and solid plant residues on soil ecosystem services remain unclear. Field experiments were carried out to investigate the effects of untreated soil (CK), RSD incorporated with sawdust (SA), molasses (MO), and their combinations (SA + MO) on the bacterial community and functional composition. The results showed that RSD treatments significantly altered soil bacterial community structure compared to CK treatment. The bacterial community structure and composition in MO and SA + MO treatments were clustered compared to SA treatment. This was mainly attributed to the readily decomposable carbon sources in molasses having a stronger driving force to reshape the soil microbial community during the RSD process. Furthermore, the functional compositions, such as the disinfestation efficiency of F. oxysporum (96.4 - 99.1%), abundances of nitrogen functional genes, soil metabolic activity, and functional diversity, were significantly increased in all of the RSD treatments. The highest disinfestation efficiency and abundances of denitrification (nirS and nrfA) and nitrogen fixation (nifH) genes were observed in SA + MO treatment. Specifically, SA + MO treatment enriched more abundant beneficial genera, e.g., Oxobacter, Paenibacillus, Cohnella, Rummeliibacillus, and Streptomyces, which were significantly and positively linked to disinfestation efficiency, soil metabolic activity, and denitrification processes. Our results indicated that combining RSD practices with liquid-readily decomposable compounds and solid plant residues could effectively improve soil microbial community and functional composition.

Nanoemulsions of Hydroxysafflor Yellow A for Enhancing Physicochemical and In Vivo Performance.

Stroke was always a disease that threatened human life and health worldwide. We reported the synthesis of a new type of hyaluronic acid-modified multi-walled carbon nanotube. Then, we produced hydroxysafflor yellow A-hydroxypropyl-ß-cyclodextrin phospholipid complex water-in-oil nanoemulsion with hyaluronic acid-modified multi-walled carbon nanotubes and chitosan (HC@HMC) for oral treatment of an ischemic stroke. We measured the intestinal absorption and pharmacokinetics of HC@HMC in rats. We found that the intestinal absorption and the pharmacokinetic behavior of HC@HMC was superior to that of HYA. We measured intracerebral concentrations after oral administration of HC@HMC and found that more HYA crossed the blood-brain barrier (BBB) in mice. Finally, we evaluated the efficacy of HC@HMC in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice. In MCAO/R mice, oral administration of HC@HMC demonstrated significant protection against cerebral ischemia-reperfusion injury (CIRI). Furthermore, we found HC@HMC may exert a protective effect on cerebral ischemia-reperfusion injury through the COX2/PGD2/DPs pathway. These results suggest that oral administration of HC@HMC may be a potential therapeutic strategy for the treatment of stroke.

Biomimetic lipidic nanovectors for effective asparaginase supramolecule delivery.

Effectiveness of enzyme therapy is limited by enzyme drawbacks such as short half-life, low bioavailability and high immunogenicity. We loaded asparaginase (Aase) into hydroxypropyl- or sulfonbutylether-beta cyclodextrin to form supramolecular amphiphilic molecules by self-assembly followed by entrapment inside the cores of two biomimetic lipidic nanovectors (AS-XLNs). Supramolecular structure was simulated by molecular docking. AS-XLNs maintained superior activity through isolating Aase from external environment due to docking with cyclodextrin and coating with biomimetic membrane. Fluorescent probes and computational simulations were used to reveal possible interactions between serum albumin/trypsin and Aase/nanovector membrane components which were partly responsible for enhanced bioavailability and bioactivity of AS-XLNs compared to Aase. AS-XLNs significantly increased cytotoxicity against pulmonary tumor cells due to synergistic effects of Aase and nanovector membrane components (killing tumor cells through apoptosis induced by asparagine depletion and autophagy inhibition or via targets such as vascular endothelial growth factor A, alpha-amylase, p-selectin or androgen receptor).

Bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles for enhancing photothermal and hypoxia-activated chemotherapy of bone invasion by OSCC.

BACKGROUND: Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. RESULTS: We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. CONCLUSIONS: Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion.

Biomimetic microbioreactor-supramolecular nanovesicles improve enzyme therapy of hepatic cancer.

A novel biomimetic nanovesicle-loaded supramolecular enzyme-based therapeutics has been developed. Here, using a biomimetic lipid-D-α-tocopherol polyethylene glycol succinate (TPGS) hybrid semi-permeable membrane, cyclodextrin supramolecular docking, metal-ion-aided coordination complexing, we combined multiple functional motifs into a single biomimetic microbioreactor-supramolecular nanovesicle (MiSuNv) that allowed effective transport of arginine deiminase (ADI) to hepatic tumor cells to enhance arginine depletion. We compared two intercalated enzyme-carrying supermolecular motifs mainly comprising of 2-hydroxypropyl-ß-cyclodextrin and sulfobutyl-ether-ß-cyclodextrin, the only two cyclodextrin derivatives approved for injection by the United States Food and Drug Administration. The ADI-specific antitumor effects were enhanced by TPGS (one constituent of MiSuNv, having synergistic antitumor effects), as ADI was separated from adverse external environment by a semi-permeable membrane and sequestered in a favorable internal microenvironment with an optimal pH and metal-ion combination. ADI@MiSuNv contributed to cell cycle arrest, apoptosis and autophagy through the enhanced efficacy of enzyme treatment against Hep3B xenograft tumors in rats.

[Preparation, Characterization and Pharmacokinetic Study of Arginine Deiminase Lipid Nanoparticles].

OBJECTIVE: To prepare and characterize D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified arginine deiminase (ADI) sulfobutyl-ß-Cyclodextrin liposome nanoparticles (ATCL), and to investigate the pharmacokinetic characteristics of ATCL in animals. METHODS: The reverse evaporation method was used to prepare ATCL, and the particle size and Zeta potential of ATCL were measured. Thiosemicarbazone-diacetylmonooxime colorimetric method was used to measure the activity of ADI. After intravenous administration, blood was drawn at set intervals of time and the enzyme activity in the plasma was measured. Enzyme activity-time curve was drawn subsequently and Debris Assessment Software (DAS) 2.1.1 was used to analyze the pharmacokinetic characteristics. RESULTS: The particle size and the potential of ATCL were (216.1±13.6) nm and (-19.4±2.1) mV, respectively. The optimal temperature and optimal pH for the catalytic reaction of ADI and ATCL were the same, both being 37 ℃ and pH6.5. Results of the analysis showed that the AUC (0-168 h), MRT (0-168 h), C max, T max, and t 1/2 of ATCL were 3.99, 2.56, 1.58, 3.2, and 9.88 times those of free ADI, respectively. Compared with ADI, the bioavailability of ATCL increased by 298.54%. CONCLUSION: ATCL prepared in the study can effectively improve the enzyme activity and bioavailability of ADI in Sprague-Dawley rats.

Toward a better understanding of metabolic and pharmacokinetic characteristics of low-solubility, low-permeability natural medicines.

Today, it is very challenging to develop new active pharmaceutical ingredients. Developing good preparations of well-recognized natural medicines is certainly a practical and economic strategy. Low-solubility, low-permeability natural medicines (LLNMs) possess valuable advantages such as effectiveness, relative low cost and low toxicity, which is shown by the presence of popular products on the market. Understanding the in vivo metabolic and pharmacokinetic characteristics of LLNMs contributes to overcoming their associated problems, such as low absorption and low bioavailability. In this review, the structure-based metabolic reactions of LLNMs and related enzymatic systems, cellular and bodily pharmacological effects and metabolic influences, drug-drug interactions involved in metabolism and microenvironmental changes, and pharmacokinetics and dose-dependent/linear pharmacokinetic models are comprehensively evaluated. This review suggests that better pharmacological activity and pharmacokinetic behaviors may be achieved by modifying the metabolism through using nanotechnology and nanosystem in combination with the suitable administration route and dosage. It is noteworthy that novel nanosystems, such as triggered-release liposomes, nucleic acid polymer nanosystems and PEGylated dendrimers, in addition to prodrug and intestinal penetration enhancer, demonstrate encouraging performance. Insights into the metabolic and pharmacokinetic characteristics of LLNMs may help pharmacists to identify new LLNM formulations with high bioavailability and amazing efficacy and help physicians carry out LLNM-based precision medicine and individualized therapies.

Oral administration of natural polyphenol-loaded natural polysaccharide-cloaked lipidic nanocarriers to improve efficacy against small-cell lung cancer.

Oral administration shows good tolerance in patients. Botanic anticancer drugs without serious side effects have attracted increased attention worldwide. However, oral delivery of natural anticancer drugs faces great challenges due to low solubility, gastrointestinal side effects, first-pass effects, and P-glycoprotein efflux. Here, we loaded the natural polyphenol curcumin (Cc) into natural polysaccharide-cloaked lipidic nanocarriers (Cc@CLNs) to improve the efficacy in small-cell lung cancer (SCLC) associated with oral administration. Compared to other nanoformulations, Cc@CLNs have advantages of simple operation, easy scale-up, low cost, and high safety. Cc@CLNs improve bioavailability by inducing synergistic effects (efficient cell membrane penetration, inherent muco-adhesiveness, resistance to pepsin and trypsin degradation, promoted dissolution, enhanced epithelia/M cellular uptake and inhibition of efflux transporters) and countering the tendency of nanocarriers to aggregate and fuse, which limit lipid-based nanosystems. In this study, we first evaluated the oral bioavailability of Cc@CLNs in rats and their efficacy in H446 tumor-bearing mice. The oral bioavailability increased by 8.94-fold, and the tumor growth inhibition rate doubled compared to that achieved with free Cc. We investigated the action of Cc against SCLC stem cells, and Cc@CLNs greatly enhanced this action. The expression of CD133 and ABCG2 in the Cc@CLNs group decreased by 38.05% and 32.57%, respectively, compared to the respective expression levels in the control.

Difference and alteration in pharmacokinetic and metabolic characteristics of low-solubility natural medicines.

Drug metabolism plays vital roles in the absorption and pharmacological activity of poorly soluble natural medicines. It is important to choose suitable delivery systems to increase the bioavailability and bioactivity of natural medicines with low solubility by regulating their metabolism and pharmacokinetics. This review investigates recent developments about the metabolic and pharmacokinetic behavior of poorly soluble natural medicines and their delivery systems. Delivery systems, dosage, administration route and drug-drug interactions alter the metabolic pathway, and bioavailability of low-solubility natural medicines to different degrees. Influencing factors such as formulation, dosage, and administration route are discussed. The metabolic reactions, metabolic enzymes, metabolites and pharmacokinetic behaviors of low-solubility natural medicines, and their delivery systems are systematically reviewed. There are various metabolic situations in the case of low-solubility natural medicines. CYP3A4 and CYP2C are the most common metabolic enzymes, and hydroxylation is the most common metabolic reaction of low solubility natural medicines. The stereo isomeric configuration can have a large influence on metabolism. This review will be useful for physicians and pharmacists to guide more accurate treatment with low-solubility natural medicines by increasing drug efficacies and protecting patients from toxic side effects.

Metabolic pathways and pharmacokinetics of natural medicines with low permeability.

Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine.

[Pharmacokinetics of Curcumin Ethosomes in Rats in vitro].

OBJECTIVES: To study the oral phamacokinetics of curcumin ethosomes in rats. METHODS: Pharmacokinetics parameters were detected by DAS 2.1.1 software analysis through data of blood concentrations harvested from HPLC after oral administration of curcumin ethosomes in rats. RESULTS: Analyzed by non-compartmental method, the area under concentration-time curve from 0 to last time [AUC(0-72h)] of curcumin ethosomes was 1.6 times larger than that of free curcumin, the peak concentration (C max) of curcumin ethosomes was 1.5 times higher than that of free curcumin, the relative bioavailability of curcumin ethosomes was 152.2%. The 90% confidential interval of AUC(0-72 h)was 102.2%-128.5%, which was not in standard interval of bioequialence. Analyzed by compartmental method, the AUC(0-72 h)of curcumin ethosomes was 1.4 times larger than that of free curcumin and the relative bioavailability of curcumin ethosomes was 128.2%. CONCLUSION: The curcumin ethosomes can enhance bioavailability, which has a bioinequivalence with free curcumin.

Functional nanoemulsion-hybrid lipid nanocarriers enhance the bioavailability and anti-cancer activity of lipophilic diferuloylmethane.

The purpose of this study was to assess the enhanced physicochemical characteristics, in vitro release behavior, anti-lung cancer activity, gastrointestinal absorption, in vivo bioavailability and bioequivalence of functional nanoemulsion-hybrid lipid nanocarriers containing diferuloylmethane (DNHLNs). The DNHLNs were first fabricated by loading water-in-oil nanoemulsions into hybrid lipid nanosystems using nanoemulsion-thin film-sonication dispersion technologies. The in situ absorption and in vitro and in vivo kinetic features of DNHLNs were measured using an in situ unidirectional perfusion method, a dynamic dialysis method and a plasma concentration-time profile-based method, respectively. The cytotoxic effects of DNHLNs in lung adenocarcinoma A549 cells were examined using MTT colorimetric analysis. The absorptive constants and permeabilities of DNHLNs in four gastrointestinal sections increased by 1.43-3.23 times and by 3.10-7.76 times that of diferuloylmethane (DIF), respectively. The relative bioavailability of DNHLNs to free DIF was 855.02%. DNHLNs inhibited cancer cell growth in a time- and dose-dependent manner. DNHLNs markedly improved the absorption and bioavailability of DIF after oral administration. DNHLNs had stronger inhibitory effects on the viability of A549 cells than that of free DIF. DNHLNs might be potentially promising nanocarriers for DIF delivery via the oral route to address unmet clinical needs.

Nanocapsule assemblies as effective enzyme delivery systems against hyperuricemia.

The uricase nanocapsule assemblies (UNAs) were developed as effective delivery systems against hyperuricemia following parenteral enzyme therapy. UNAs were characterized in terms of micromorphology, size, catalytic activity, stability, and enzymatic kinetics. The pharmacokinetics/pharmacodynamics in rats after intravenous or subcutaneous injection was investigated. Immunogenicity, hemolysis and stimulation were determined. UNA was composed of many nanocapsules, and thus had higher loading efficiencies and stabilities than a single nanocapsule. The uricase molecules entrapped inside nanocapsules were separated from the circulating bloodstream to retain catalytic activities for a longer time than free uricase. UNAs increased the bioavailability and uric acid-lowering efficacy of uricase, while the immunogenicity and hemolysis rate of uricase were decreased. The superior properties of UNAs might be ascribed to the favorable conformational changes of uricase. Nanocapsule assemblies appeared to be able to deliver uricase effectively. This study also highlighted the importance of suitable systems for therapeutic enzyme delivery.

Catanionic lipid nanosystems improve pharmacokinetics and anti-lung cancer activity of curcumin.

Novel catanionic lipid nanosystems (CLNs) incorporating curcumin (CCM) were developed, and improvements in pharmacokinetics and enhanced anti-lung cancer activity were observed. CCM was present in a lipid matrix surrounded by cationic, anionic and zwitterionic surfactants, forming the core-shell nanosystems. Compared with free CCM, the CCM-CLNs had much higher oral and intravenous bioavailabilities due to enhanced absorption and reduced clearance. The CCM-CLNs exhibited greater cytotoxicity in Lewis lung cancer (LLC) cells, which might have been due to increased antiproliferative, proapoptotic and anti-invasive activities and induction of cell cycle arrest. The CCM-CLNs increased the antitumor efficacy of CCM and decreased the tumor growth rate in tumor-bearing mice. This is the first report of induction of apoptosis in LLC cells by CCM through the PI3K/Akt/FoxO1/Bim signaling pathway. Catanionic lipid nanocarriers show promise for the therapeutic delivery of insoluble anti-tumor drugs.

Evodiamine and Its Role in Chronic Diseases.

Evodiamine (EVO) is a major alkaloid compound extracted from the dry unripened fruit Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae). EVO has a variety of pharmacological activities, such as anti-obesity, anti-allergenic, analgesic, anti-tumor, anti-ulcerogenic, and neuroprotective activities. EVO has varying efficacies in animal models and humans. Here, the physicochemical properties of EVO are presented, and the EVO's functions and mechanisms of action in various chronic diseases are reviewed. EVO is worth exploring in more depth in the future for its potential use in various chronic diseases.

[Pharmacokinetics and Bioequiavailability of Asparaginase in Asparaginase Nanospheres].

OBJECTIVE: To determine the pharmacokinetics and bioequivalence of self-assembled hyaluronic acid-graft-poly (ethylene glycol)/hydroxypropyl-beta-cyclodextrin hollow nanospheres loaded with asparaginase (AHHPs) in SD rats. METHODS: AHHPs were prepared and observed under transmission electron microscopy. Its size, Zeta potential and entrapment efficiency were detected. Asparaginase (AAS) activities were measured after intravenous injection of AHHPs or free AAS in rats. The pharmacokinetic parameters were calculated using software DAS 2.1.1 for bioequivalence assessment. RESULTS: The self-prepared AHHPs had an average particle size of (367.43 ± 2.72) nm, Zeta potential of (-15. 70 ± 1.25) mV, and average entrapment efficiency of (66.03 ± 3.81)%. The intravenous injection of AHHPs and free AAS produced an area under concentration-time Curve (AUC)(0-48 h) of (162.06 ± 4.01) U/mL · h and (46.38 ± 1.98) U/mL · h, AUC(0-∞) of (203.74 ± 12.91) U/mL · h and (51.44 ± 3.01) U/mL · h, mean residence time (MRT) (0-72h) of (4.35 ± 0.06) h and (1.76 ± 0.06) h, MRT(0-∞) of (7.53 ± 1.05) h and (2.44 ± 0.29) h, peak concentration (Cmax) of (30.37 ± 0.43) U/mL and (26.06 ± 0.88) U/mL, and time to peak concentration (Tmax) of (0.75 ± 0.00) h and (0.08 ± 0.00) h, respectively. Compared with free AAS, the AUC(0-48 h), AUC(0-∞), MRT(0-72 h), MRT(0-∞),Cmax and Tmax of AHHPs increased by 3.5, 4.0, 2.5, 3.1, 1.2 and 9.4 times, respectively. The 90% confidential intervals of AUC(0-48 h), AUC(0.∞) and Cmax of the tested formulation were 72.6%-74.0%, 72.3%-73.7%, 94.7%-96.3%, respectively. CONCLUSION: AHHPs can improve the bioavailability of AAS, extending its biological half-life in rats. AHHPs and free AAS are not bioequivalent.

Recent advances in molecular recognition based on nanoengineered platforms.

Nanoparticles and nanoengineered platforms have great potential for technologies involving biomoleuclar detection or cell-related biosensing, and have provided effective chemical interfaces for molecular recognition. Typically, chemists work on the modification of synthetic polymers or macromolecules, which they link to the nanoparticles by covalent or noncovalent approaches. The motivation for chemical modification is to enhance the selectivity and sensitivity, and to improve the biocompatibility for the in vivo applications. In this Account, we present recent advances in the development and application of chemical interfaces for molecular recognition for nanoparticles and nanoengineered platforms, in particular single-walled carbon nanotubes (SWNTs). We discuss emerging approaches for recognizing small molecules, glycosylated proteins, and serum biomarkers. For example, we compare and discuss detection methods for ATP, NO, H2O2, and monosaccharides for recent nanomaterials. Fluorometric detection appears to have great potential for quantifying concentration gradients and determining their location in living cells. For macromolecular detection, new methods for glycoprofiling using such interfaces appear promising, and benefit specifically from the potential elimination of cumbersome labeling and liberation steps during conventional analysis of glycans, augmenting the currently used mass spectrometry (MS), capillary electrophoresis (CE), and liquid chromatography (LC) methods. In particular, we demonstrated the great potential of fluorescent SWNTs for glycan-lectin interactions sensing. In this case, SWNTs are noncovalently functionalized to introduce a chelated nickel group. This group provides a docking site for the His-tagged lectin and acts as the signal modulator. As the nickel proximity to the SWNT surface changes, the fluorescent signal is increased or attenuated. When a free glycan or glycosylated probe interacts with the lectin, the signal increases and they are able to obtain loading curves similar to surface plasmon resonance measurements. They demonstrate the sensitivity and specificity of this platform with two higher-affined glycan-lectin pairs: fucose (Fuc) to PA-IIL and N-acetylglucosamine (GlcNAc) to GafD. Lastly, we discuss how developments in protein biomarker detection in general are benefiting specifically from label-free molecular recognition. Electrical field effect transistors, chemi-resistive and fluorometric nanosensors based on various nanomaterials have demonstrated substantial progress in recent years in addressing this challenging problem. In this Account, we compare the balance between sensitivity, selectivity, and nonspecific adsorption for various applications. In particular, our group has utilized SWNTs as fluorescence sensors for label-free protein-protein interaction measurements. In this assay, we have encapsulated each nanotube in a biocompatible polymer, chitosan, which has been further modified to conjugate nitrilotriacetic acid (NTA) groups. After Ni(2+) chelation, NTA Ni(2+) complexes bind to his-tagged proteins, resulting in a local environment change of the SWNT array, leading to optical fluorescence modulation with detection limit down to 100 nM. We have further engineered the platform to monitor single protein binding events, with an even lower detection limit down to 10 pM.

2D equation-of-state model for corona phase molecular recognition on single-walled carbon nanotube and graphene surfaces.

Corona phase molecular recognition (CoPhMoRe) has been recently introduced as a means of generating synthetic molecular recognition sites on nanoparticle surfaces. A synthetic heteropolymer is adsorbed and confined to the surface of a nanoparticle, forming a corona phase capable of highly selective molecular recognition due to the conformational imposition of the particle surface on the polymer. In this work, we develop a computationally predictive model for analytes adsorbing onto one type of polymer corona phase composed of hydrophobic anchors on hydrophilic loops around a single-walled carbon nanotube (SWCNT) surface using a 2D equation of state that takes into consideration the analyte-polymer, analyte-nanoparticle, and polymer-nanoparticle interactions using parameters determined independently from molecular simulation. The SWCNT curvature is found to contribute weakly to the overall interaction energy, exhibiting no correlation for three of the corona phases considered, and differences of less than 5% and 20% over a larger curvature range for two other corona phases, respectively. Overall, the resulting model for this anchor-loop CoPhMoRe is able to correctly predict 83% of an experimental 374 analyte-polymer library, generating experimental fluorescence responses within 20% error of the experimental values. The modeling framework presented here represents an important step forward in the design of suitable polymers to target specific analytes.