Transferability evaluation of the deep potential model for simulating water-graphene confined system.

Machine learning potentials (MLPs) are poised to combine the accuracy of ab initio predictions with the computational efficiency of classical molecular dynamics (MD) simulation. While great progress has been made over the last two decades in developing MLPs, there is still much to be done to evaluate their model transferability and facilitate their development. In this work, we construct two deep potential (DP) models for liquid water near graphene surfaces, Model S and Model F, with the latter having more training data. A concurrent learning algorithm (DP-GEN) is adopted to explore the configurational space beyond the scope of conventional ab initio MD simulation. By examining the performance of Model S, we find that an accurate prediction of atomic force does not imply an accurate prediction of system energy. The deviation from the relative atomic force alone is insufficient to assess the accuracy of the DP models. Based on the performance of Model F, we propose that the relative magnitude of the model deviation and the corresponding root-mean-square error of the original test dataset, including energy and atomic force, can serve as an indicator for evaluating the accuracy of the model prediction for a given structure, which is particularly applicable for large systems where density functional theory calculations are infeasible. In addition to the prediction accuracy of the model described above, we also briefly discuss simulation stability and its relationship to the former. Both are important aspects in assessing the transferability of the MLP model.

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

Inhibiting Phase Transfer of Protein Nanoparticles by Surface Camouflage-A Versatile and Efficient Protein Encapsulation Strategy.

Engineering a system with a high mass fraction of active ingredients, especially water-soluble proteins, is still an ongoing challenge. In this work, we developed a versatile surface camouflage strategy that can engineer systems with an ultrahigh mass fraction of proteins. By formulating protein molecules into nanoparticles, the demand of molecular modification was transformed into a surface camouflage of protein nanoparticles. Thanks to electrostatic attractions and van der Waals interactions, we camouflaged the surface of protein nanoparticles through the adsorption of carrier materials. The adsorption of carrier materials successfully inhibited the phase transfer of insulin, albumin, ß-lactoglobulin, and ovalbumin nanoparticles. As a result, the obtained microcomposites featured with a record of protein encapsulation efficiencies near 100% and a record of protein mass fraction of 77%. After the encapsulation in microcomposites, the insulin revealed a hypoglycemic effect for at least 14 d with one single injection, while that of insulin solution was only ∼4 h.

Colloidal Jamming by Interfacial Self-Assembled Polymers: A Robust Route for Ultrahigh Efficient Encapsulation.

The control of cargo phase-transfer is of interest for many applications in science and technology. Herein, we report a simple, versatile and robust method to block the phase-transfer of cargo colloids by interfacial self-assembled amphiphilic polymer molecules. After simply increasing the concentration of amphiphilic polymers, the orientation of interfacial polymer molecules changed from flat to upright, forming a thick three-dimensional polymer layer at the oil-water interface. Even under fierce external force, this thick interfacial layer robustly prevented the phase-transfer of cargo colloids, resulting in an ultrahigh encapsulation efficiency (up to 97.1 %) for proteins and peptides. One single injection of high insulin-loaded microcomposites (58.3 wt%) kept the blood glucose level within the normoglycemic state for 10 days in type 1 diabetic rats. The mass of administrated amphiphilic polymers was 1889 times smaller than that of microcomposites prepared with non-amphiphilic ones.

Engineered Multifunctional Albumin-Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin.

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection-based delivery of insulin. Neonatal Fc receptor (FcRn)-mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn-targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH-responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH-sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn-targeted NPs. Overall, these FcRn-targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.

Core/Shell Nanocomposites Produced by Superfast Sequential Microfluidic Nanoprecipitation.

Although a number of techniques exist for generating structured organic nanocomposites, it is still challenging to fabricate them in a controllable, yet universal and scalable manner. In this work, a microfluidic platform, exploiting superfast (milliseconds) time intervals between sequential nanoprecipitation processes, has been developed for high-throughput production of structured core/shell nanocomposites. The extremely short time interval between the sequential nanoprecipitation processes, facilitated by the multiplexed microfluidic design, allows us to solve the instability issues of nanocomposite cores without using any stabilizers. Beyond high throughput production rate (∼700 g/day on a single device), the generated core/shell nanocomposites harness the inherent ultrahigh drug loading degree and enhanced payload dissolution kinetics of drug nanocrystals and the controlled drug release from polymer-based nanoparticles.

Photoluminescent Hybrids of Cellulose Nanocrystals and Carbon Quantum Dots as Cytocompatible Probes for in Vitro Bioimaging.

We present an approach to construct biocompatible and photoluminescent hybrid materials comprised of carbon quantum dots (CQDs) and TEMPO-oxidized cellulose nanocrystals (TO-CNCs). First, the amino-functionalized carbon quantum dots (NH2-CQDs) were synthesized using a simple microwave method, and the TO-CNCs were prepared by hydrochloric acid (HCl) hydrolysis followed by TEMPO-mediated oxidation. The conjugation of NH2-CQDs and TO-CNCs was conducted via carbodiimide-assisted coupling chemistry. The synthesized TO-CNC@CQD hybrid nanomaterials were characterized using X-ray photoelectron spectroscopy, cryo-transmittance electron microscopy, confocal microscopy, and fluorescence spectroscopy. Finally, the interactions of TO-CNC@CQD hybrids with HeLa and RAW 264.7 macrophage cells were investigated in vitro. Cell viability tests suggest the surface conjugation with NH2-CQDs not only improved the cytocompatibility of TO-CNCs, but also enhanced their cellular association and internalization on both HeLa and RAW 264.7 cells after 4 and 24 h incubation.

Smart Porous Silicon Nanoparticles with Polymeric Coatings for Sequential Combination Therapy.

In spite of the advances in drug delivery, the preparation of smart nanocomposites capable of precisely controlled release of multiple drugs for sequential combination therapy is still challenging. Here, a novel drug delivery nanocomposite was prepared by coating porous silicon (PSi) nanoparticles with poly(beta-amino ester) (PAE) and Pluronic F-127, respectively. Two anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately loaded into the core of PSi and the shell of F127. The nanocomposite displayed enhanced colloidal stability and good cytocompatibility. Moreover, a spatiotemporal drug release was achieved for sequential combination therapy by precisely controlling the release kinetics of the two tested drugs. The release of PTX and DOX occurred in a time-staggered manner; PTX was released much faster and earlier than DOX at pH 7.0. The grafted PAE on the external surface of PSi acted as a pH-responsive nanovalve for the site-specific release of DOX. In vitro cytotoxicity tests demonstrated that the DOX and PTX coloaded nanoparticles exhibited a better synergistic effect than the free drugs in inducing cellular apoptosis. Therefore, the present study demonstrates a promising strategy to enhance the efficiency of combination cancer therapies by precisely controlling the release kinetics of different drugs.

Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery.

We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH-responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi-drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH-response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH-values, and enhances their release at higher pH-values, which can be further used for colon cancer prevention and treatment. Overall, the pH-responsive polymer/PSi-based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy.

In vivo evaluation of porous silicon and porous silicon solid lipid nanocomposites for passive targeting and imaging.

The use of nanoparticle carriers for the sustained release of cytotoxic drugs in cancer therapy can result in fewer adverse effects and can thus be of great benefit for the patient. Recently, a novel nanocomposite, prepared by the encapsulation of THCPSi nanoparticles within solid lipids (SLN), was developed and characterized as a promising drug delivery carrier in vitro. The present study describes the in vivo evaluation of unmodified THCPSi nanoparticles and THCPSi-solid lipid nanocomposites (THCPSi-SLNCs) as potential drug delivery carriers for cancer therapy by using (18)F radiolabeling for the detection of the particle biodistribution in mice. Passive tumor targeting of (18)F-THCPSis and (18)F-THCPSi-SLNCs by the enhanced permeation and retention effect was investigated in a murine breast cancer model. Encapsulation of THCPSi nanoparticles with solid lipids improved their accumulation in tumors at a 7 week time point (tumor-to-liver ratio 0.10 ± 0.08 and 0.24 ± 0.09% for (18)F-THCPSis and (18)F-THCPSi-SLNCs, respectively).

Formulation and characterization of hydrophilic drug diclofenac sodium-loaded solid lipid nanoparticles based on phospholipid complexes technology.

To successfully prepare the diclofenac sodium (DS)-loaded solid lipid nanoparticles (SLNs), phospholipid complexes (PCs) technology was applied here to improve the liposolubility of DS. Solid lipid nanoparticles (SLNs) loaded with phospholipid complexes (PCs) were prepared by the modified emulsion/solvent evaporation method. DS could be solubilized effectively in the organic solvents with the existence of phospholipid and apparent partition coefficient of DS in PCs increased significantly. X-ray diffraction analysis suggested that DS in PCs was either molecularly dispersed or in an amorphous form. However, no significant difference was observed between the Fourier transform infrared spectroscopy (FT-IR) spectra of physical mixture and that of PCs. Particles with small sizes, narrow polydispersity indexes and high entrapment efficiencies could be obtained with the addition of PCs. Furthermore, according to the transmission electron microscopy, a core-shell structure was likely to be formed. The presence of PCs caused the change of zeta potential and retarded the drug release of SLNs, which indicated that phospholipid formed multilayers around the solid lipid core of SLNs. Both FT-IR and differential scanning calorimetry analysis also illustrated that some weak interactions between DS and lipid materials might take place during the preparation of SLNs. In conclusion, the model hydrophilic drug-DS can be formulated into the SLNs with the help of PCs.

Advancements in nanoscale delivery systems: optimizing intermolecular interactions for superior drug encapsulation and precision release.

Nanoscale preparations, such as nanoparticles, micelles, and liposomes, are increasingly recognized in pharmaceutical technology for their high capability in tailoring the pharmacokinetics of the encapsulated drug within the body. These preparations have great potential in extending drug half-life, reducing dosing frequency, mitigating drug side effects, and enhancing drug efficacy. Consequently, nanoscale preparations offer promising prospects for the treatment of metabolic disorders, malignant tumors, and various chronic diseases. Nevertheless, the complete clinical potential of nanoscale preparations remains untapped due to the challenges associated with low drug loading degrees and insufficient control over drug release. In this review, we comprehensively summarize the vital role of intermolecular interactions in enhancing encapsulation and controlling drug release within nanoscale delivery systems. Our analysis critically evaluates the characteristics of common intermolecular interactions and elucidates the techniques employed to assess them. Moreover, we highlight the significant potential of intermolecular interactions in clinical translation, particularly in the screening and optimization of preparation prescriptions. By attaining a deeper understanding of intermolecular interaction properties and mechanisms, we can adopt a more rational approach to designing drug carriers, leading to substantial advancements in the application and clinical transformation of nanoscale preparations. Moving forward, continued research in this field offers exciting prospects for unlocking the full clinical potential of nanoscale preparations and revolutionizing the field of drug delivery.

Nanoparticle surface decoration mediated efficient protein and peptide co-encapsulation with precise ratiometric control for self-regulated drug release.

Accuratly controlling drug release from a smart "self-regulated" drug delivery system is still an ongoing challenge. Herein, we developed a surface decoration strategy to achieve an efficient drug encapsulation with precise ratiometric control. Thanks to the surface decoration with cationic carrier materials by electrostatic attraction, the surface properties of different protein and peptide nanoparticles were uniformed to those adsorbed carrier materials. These carrier materials endowed protein and peptide nanoparticles with good dispersity in the oil phase and significantly inhibited the drug transfer from oil to water. With uniform surface properties, we realized the co-encapsulation of multiple types of proteins and peptides with precise ratiometric control. The encapsulation efficiency was higher than 87.8% for insulin. After solidification, the adsorbed materials on the surface of nanoparticles formed a solid protection layer, which prolonged the mean residence time of insulin from 3.3 ± 0.1 h (for insulin solution) to 47.5 ± 1.3 h. In type 1 diabetes, the spermine-modified acetalated dextran microparticle co-loaded with insulin, glucose oxidase and catalase maintained the blood glucose level within the normal range for 7 days.

Controlled Interfacial Polymer Self-Assembly Coordinates Ultrahigh Drug Loading and Zero-Order Release in Particles Prepared under Continuous Flow.

Microparticles are successfully engineered through controlled interfacial self-assembly of polymers to harmonize ultrahigh drug loading with zero-order release of protein payloads. To address their poor miscibility with carrier materials, protein molecules are transformed into nanoparticles, whose surfaces are covered with polymer molecules. This polymer layer hinders the transfer of cargo nanoparticles from oil to water, achieving superior encapsulation efficiency (up to 99.9%). To control payload release, the polymer density at the oil-water interface is enhanced, forming a compact shell for microparticles. The resultant microparticles can harvest up to 49.9% mass fraction of proteins with zero-order release kinetics in vivo, enabling an efficient glycemic control in type 1 diabetes. Moreover, the precise control of engineering process offered through continuous flow results in high batch-to-batch reproducibility and, ultimately, excellent scale-up feasibility.

Ab Initio Molecular Dynamics Simulation of Water Transport through Short Carbon Nanotubes.

Water transport through short single-walled (6, 6) carbon nanotubes (CNTs) was investigated with ab initio molecular dynamics (AIMD) simulation at different temperatures. The water molecules under extreme confinement present a one-dimensional jagged pattern owing to hydrogen bonding, with the near-perfect alignment of the dipole orientations. CNTs ending with dangling bonds can promote water dissociation near the entrance and the occurrence of dipole flipping along the water wire at high temperatures, accompanied by the formation of D defects and L defects in the hydrogen-bond network. In contrast, dissociation of water molecules rarely takes place if the dangling bonds at the ends of the CNTs are terminated with H atoms. Angular jumps of water molecules are commonplace inside the narrow CNTs, implying a low-energy barrier for hydrogen-bond exchange among water molecules in narrow CNTs. The simulation results demonstrate the high activity of dangling bonds at the ends of short CNTs, accompanying passivation processes and their profound impact on water structure and transport, which is important for diverse technological applications.

Prediction of drug capturing by lipid emulsions in vivo for the treatment of a drug overdose.

Despite the successful treatment of drug intoxications, little information is available to quantitively predict the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules. We defined two new parameters, drug accommodation capacity and drug capture kinetics, to characterize the drug capture capability of lipid emulsions. By precisely characterizing their drug capture capability, the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules was quantitively described. This quantitative description enabled an accurate prediction of the reducing extent on the half-life and area under drug concentration-time curve, which was verified by the successful treatment of overdosed propafenone. Moreover, the capture effect prediction using drug capture capability was more accurate than that of directly using logP. Overall, the developed capture capability accurately described the effect of lipid emulsions on drug pharmacokinetic features, which can guide the clinical application of lipid emulsions for the treatment of drug overdose.

Neutrophil Cyto-Pharmaceuticals Suppressing Tumor Metastasis via Inhibiting Hypoxia-Inducible Factor-1α in Circulating Breast Cancer Cells.

Circulating tumor cells (CTCs) are reported as the precursor of tumor metastases, implying that stifling CTCs would be beneficial for metastasis prevention. However, challenges remain for the application of therapies that aim at CTCs due to lack of effective CTC-targeting strategy and sensitive therapeutic agents. Herein, a general CTC-intervention strategy based on neutrophil cyto-pharmaceuticals is proposed for suppressing CTC colonization and metastasis formation. Breast cancer 4T1 cells are infused as the mimic CTCs, and 4T1 cells trapped are first elucidated in neutrophil extracellular traps (NETs) expressing high levels of hypoxia-inducible factor-1α (HIF-1α) due to NET formation and thus promoting tumor cell colonization through enhanced migration, invasion and stemness. After verifying HIF-1α as a potential target for metastasis prevention, living neutrophil cyto-pharmaceuticals (CytPNEs) loaded with HIF-1α inhibitor are fabricated to therapeutically inhibit HIF-1α. It is demonstrated that CytPNEs can specially convey the HIF-1α inhibitor to 4T1 cells according to the inflammatory chemotaxis of neutrophils and down-regulate HIF-1α, thereby inhibiting metastasis and prolonging the median survival of mice bearing breast cancer lung metastasis. The research offers a new perspective for understanding the mechanism of CTC colonization, and puts forward the strategy of targeted intervention of CTCs as a meaningful treatment for tumor metastasis.

High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury.

Drug delivery systems with high content of drug can minimize excipients administration, reduce side effects, improve therapeutic efficacy and/or promote patient compliance. However, engineering such systems is extremely challenging, as their loading capacity is inherently limited by the compatibility between drug molecules and carrier materials. To mitigate the drug-carrier compatibility limitation towards therapeutics encapsulation, we developed a sequential solidification strategy. In this strategy, the precisely controlled diffusion of solvents from droplets ensures the fast in-droplet precipitation of drug molecules prior to the solidification of polymer materials. After polymer solidification, a mass of drug nanoparticles is embedded in the polymer matrix, forming a nano-in-micro structured microsphere. All the obtained microspheres exhibit long-term storage stability, controlled release of drug molecules, and most importantly, high mass fraction of therapeutics (21.8-63.1 wt%). Benefiting from their high drug loading degree, the nano-in-micro structured acetalated dextran microspheres deliver a high dose of methylprednisolone (400 µg) within the limited administration volume (10 µL) by one single intrathecal injection. The amount of acetalated dextran used was 1/433 of that of low drug-loaded microspheres. Moreover, the controlled release of methylprednisolone from high drug-loaded microspheres contributes to improved therapeutic efficacy and reduced side effects than low drug-loaded microspheres and free drug in spinal cord injury therapy.

A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide.

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion-solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA-SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA-SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops.

Polydopamine-Decorated Microcomposites Promote Functional Recovery of an Injured Spinal Cord by Inhibiting Neuroinflammation.

Neuroinflammation following spinal cord injury usually aggravates spinal cord damage. Many inflammatory cytokines are key players in neuroinflammation. Owing largely to the multiplicity of cytokine targets and the complexity of cytokine interactions, it is insufficient to suppress spinal cord damage progression by regulating only one or a few cytokines. Herein, we propose a two-pronged strategy to simultaneously capture the released cytokines and inhibit the synthesis of new ones in a broad-spectrum manner. To achieve this strategy, we designed a core/shell-structured microcomposite, which was composed of a methylprednisolone-incorporated polymer inner core and a biocompatible polydopamine outer shell. Thanks to the inherent adhesive nature of polydopamine, the obtained microcomposite (MP-PLGA@PDA) efficiently neutralized the excessive cytokines in a broad-spectrum manner within 1 day after spinal cord injury. Meanwhile, the controlled release of immunosuppressive methylprednisolone reduced the secretion of new inflammatory cytokines. Benefiting from its efficient and broad-spectrum capability in reducing the level of cytokines, this core/shell-structured microcomposite suppressed the recruitment of macrophages and protected the injured spinal cord, leading to an improved recovery of motor function. Overall, the designed microcomposite successfully achieved the two-pronged strategy in cytokine neutralization, providing an alternative approach to inhibit neuroinflammation in the injured spinal cord.