Half-life Of Drug Research Articles

Optimizing Chronotherapy in Psychiatric Care: The Impact of Circadian Rhythms on Medication Timing and Efficacy

In many medical settings, medications are typically administered in the morning or evening, aligning with patients’ daily routines. This practice does not stem from chronotherapy, which involves scheduling drug administration to enhance its effectiveness, but rather from the way clinical operations are structured. The timing of drug administration can significantly affect a medication’s effectiveness and side effects, with the impact varying by up to ten times based on circadian rhythms. Disorders such as major depression, bipolar disorder, and schizophrenia are linked to disruptions in these rhythms. Recent studies have found that circadian dysfunctions, including genetic and neurohumoral changes, underlie many psychiatric conditions. Issues such as an altered glucocorticoid rhythm due to impaired HPA axis function, disturbed melatonin balance, and sleep disturbances have been noted in psychotic disorders. Furthermore, mood disorders have been associated with changes in the expression of circadian rhythm genes such as Clock, Bmal1, and Per. Considering that the absorption, biodistribution, effects on target organs, half-life, metabolism, and elimination of drugs are all influenced by the body’s circadian rhythms, this narrative review explores the optimal timing of medication administration to maximize efficacy and minimize side effects in the treatment of psychiatric disorders. By closely monitoring circadian variations in cortisol, melatonin, and key clock genes, as well as by deepening our understanding of the metabolisms and pharmacokinetics of antipsychotic medications, we propose a chronotherapy approach for psychiatric patients that could significantly enhance patient care.

Non-invasive, continuous oral delivery of solid levodopa-carbidopa for management of Parkinson's disease.

When short plasma half-life drugs act only briefly, they require frequent or continuous administration. We report the engineering of a non-invasive oral drug delivery system for long-term, continuous administration of these drugs. Their non-invasive, long-term, continuous administration at daily doses exceeding 100 mg has, for many years, been considered an insurmountable challenge. We show that over 1200 mg/day of 4:1 levodopa-carbidopa (LD-CD) can be non-invasively and continuously extruded when formulated as a semisolid paste, loaded with 63%w/w of the solid drugs. The drug delivery system comprises a reusable orthodontic retainer with a co-molded pocket into which the patient inserts after each meal a new 1 mL propellant-driven, prefilled, disposable, drug delivery extruder. The paste is delivered to the lingual side of the teeth where it is mixed with saliva and swallowed. As reported elsewhere, a 15-day, 16 patient open label clinical trial of the drug delivery system continuously extruding LD-CD paste significantly reduces the variability of the plasma LD concentration and alleviates symptoms of advanced Parkinson's disease (PD) as compared to LD-CD tablets.

Intestinal transport of organic food compounds and drugs: a scoping review on the alterations observed in chronic kidney disease

Background and aimsAround 850 million people worldwide are affected by chronic kidney disease (CKD). Patients with CKD often develop malnutrition and sarcopenia and changes in the pharmacokinetics of drugs. A reduced kidney function partially explains the prolonged half-life of certain drugs due to decreased renal clearance, which leads to an increased risk of adverse effects. While the intestine plays a fundamental role in this context, a systematic review of the effects of CKD on intestinal transport is lacking. We aimed to systematically summarize all the available evidence on intestinal transport of organic food components (carbohydrates/sugar, proteins/amino acids, fats, vitamins) and drugs (including drug transporters) in chronic kidney disease. MethodsWe conducted a systematic search of all the articles published until the 1st of April 2024, on five databases i.e. Embase, PubMed, Web of Science Core Collection, Cochrane Library, and Scopus. This systematic review was registered on the Open Science Framework (OSF) (osf.io/5e6wb) and was carried out according to the PRISMA 2020 guidelines. ResultsFrom 9205 articles identified, 68 met the inclusion criteria. Absorption of organic food compounds seems to be altered, in general, and reduced for vitamins. The expression of intestinal efflux drug transporters may be altered in CKD. ConclusionsDespite alterations in intestinal transport is suggested to be altered in CKD, the lack of recent studies, the paucity of human data and the heterogeneity of the methodologies used underscore the need for more research on the effect of CKD and uremia on intestinal transport.

Macrophage membrane-mediated targeted curcumin biomimetic nanoparticles delivery for diagnosis and treatment of spinal cord injury by suppressing neuroinflammation and ferroptosis

Spinal cord injury (SCI) is a severe and debilitating central nervous system disorder characterized by permanent motor and sensory deficits, with limited effective treatment options available. Recent advancements have been made in the functionalization of biomimetic surfaces of nanoparticles through the incorporation of synthetic bionic and naturally derived cell membranes. One emerging strategy involves integrating biomimetic features into therapeutic agents to achieve low immunogenicity, high targeting specificity, and prolonged drug half-life. In this study, we detail the preparation of nanoparticles via the self-assembly of the amphiphilic diblock copolymer PEG-b-PHPMA with curcumin and PCPDTBT in water, followed by macrophage cell membrane coating using an extrusion method, resulting in the formation of stable curcumin-loaded nanoparticles coated with cell membrane (MM@Cur). Our experimental results demonstrate that MM@Cur treatment specifically targets the SCI site, effectively mitigates ferroptosis and central inflammation in a mouse model featuring spinal cord contusion, and enhances the recovery of the motor function of hind limbs post-SCI. Therefore, our findings highlight MM@Cur as a highly targeted biomimetic nanoparticle possessing potent anti-ferroptosis and anti-inflammatory properties, offering a promising therapeutic approach for the restoration of hind limb function post-spinal cord injury

Development of Predictive Statistical Model for Gaining Valuable Insights in Pharmaceutical Product Recalls.

The rapid progress in artificial intelligence (AI) has revolutionized problem-solving across various domains. The global challenge of pharmaceutical product recalls imposes the development of effective tools to control and reduce shortage of pharmaceutical products and help avoid such recalls. This study employs AI, specifically machine learning (MI), to analyze critical factors influencing formulation, manufacturing, and formulation complexity which could offer promising avenue for optimizing drug development processes. Utilizing FDAZilla and SafeRX tools, an open database model was constructed, and predictive statistical models were developed using Multivariate Analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) Approach. The study focuses on key descriptors such as delivery route, dosage form, dose, BCS classification, solid-state and physicochemical properties, release type, half-life, and manufacturing complexity. Through statistical analysis, a data simplification process identifies critical descriptors, assigning risk numbers and computing a cumulative risk number to assess product complexity and recall likelihood. Partial Least Square Regression and the LASSO approach established quantitative relationships between key descriptors and cumulative risk numbers. Results have identified key descriptors; BCS Class I, dose number, release profile, and drug half-life influencing product recall risk. The LASSO model further confirms these identified descriptors with 71% accuracy. In conclusion, the study presents a holistic AI and machine learning approach for evaluating and forecasting pharmaceutical product recalls, underscoring the importance of descriptors, formulation complexity, and manufacturing processes in mitigating risks associated with product quality.

Engineered IgG Fc-conjugation prolongs the half-life of florfenicol and alleviates pneumonia in mice

Small molecule drugs often exhibit short half-lives, requiring frequent administrations to maintain therapeutic concentrations over an extended period. To address this issue, the fragment crystallizable (Fc) region of IgG, known to prolong the half-life of antibodies via its interaction with the Fc neonatal receptor, was harnessed as a carrier protein to extend the half-life of a small molecule drug, florfenicol. Florfenicol, was chemically coupled to a recombinant Fc protein expressed using the eukaryotic expression system in HEK293 cells. The Fc-florfenicol conjugate exhibited a substantially prolonged half-life of from 3.8 to 9.1 hours compared to unconjugated florfenicol and demonstrated excellent therapeutic properties in treating pneumonia in a mouse model. Our results, combined with the literature analysis on Fc-small molecule conjugates, show that Fc can substantially enhance the drug’s half-life and suggest the potential for its use as a carrier in novel delivery systems.

Development of machine learning-based quantitative structure–activity relationship models for predicting plasma half-lives of drugs in six common food animal species

Abstract Plasma half-life is a crucial pharmacokinetic parameter for estimating extralabel withdrawal intervals of drugs to ensure the safety of food products derived from animals. This study focuses on developing a quantitative structure–activity relationship (QSAR) model incorporating multiple machine learning and artificial intelligence algorithms, and aims to predict the plasma half-lives of drugs in 6 food animals, including cattle, chickens, goats, sheep, swine, and turkeys. By integrating 4 machine learning algorithms with 5 molecular descriptor types, 20 QSAR models were developed using data from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database. The deep neural network (DNN) algorithm demonstrated the best prediction ability of plasma half-lives. The DNN model with all descriptors achieved superior performance with a high coefficient of determination (R2) of 0.82 ± 0.19 in 5-fold cross-validation on the training sets and an R2 of 0.67 on the independent test set, indicating accurate predictions and good generalizability. The final model was converted to a user-friendly web dashboard to facilitate its wide application by the scientific community. This machine learning-based QSAR model serves as a valuable tool for predicting drug plasma half-lives and extralabel withdrawal intervals in 6 common food animals based on physicochemical properties. It also provides a foundation to develop more advanced models to predict the tissue half-life of drugs in food animals.

A Comparative Clinical Pharmacology Analysis of FDA-Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology.

Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose. Elucidating the clinical relevance of these expected benefits requires an integrated assessment of pharmacokinetics (PK), efficacy, safety, and DDI data. In this review, we compared the clinical pharmacology attributes of FDA-approved oncology TCIs within the last 10 years against their reversible inhibitor (RI) counterparts. Our findings indicated that (i) PK half-lives of TCIs were typically shorter and (ii) at their respective recommended clinical doses per drug label, the molar unbound steady state areas under the concentration-time curve (AUCss) of TCIs were lower than those of RIs, but with longer clinically observed durations of response. However, (iii) there was no conclusive evidence supporting improved clinical safety profiles for TCIs, and (iv) DDI perpetrator profiles appeared to be similar between TCIs and RIs. The overall clinical pharmacology comparison of TCI vs. RI surveyed in this paper suggested that at least two of the four forecasted clinical benefits were achieved by TCIs.

NIR-II AIE Luminogen-Based Erythrocyte-Like Nanoparticles with Granuloma-Targeting and Self-Oxygenation Characteristics for Combined Phototherapy of Tuberculosis.

Tuberculosis, a fatal infectious disease caused by Mycobacterium tuberculosis (M.tb), is difficult to treat with antibiotics due to drug resistance and short drug half-life. Phototherapy represents a promising alternative to antibiotics in combating M.tb. Exploring an intelligent material allowing effective tuberculosis treatment is definitely appealing, yet a significantly challenging task. Herein, an all-in-one biomimetic therapeutic nanoparticle featured by aggregation-induced second near-infrared emission, granuloma-targeting, and self-oxygenation is constructed, which can serve for prominent fluorescence imaging-navigated combined phototherapy toward tuberculosis. After camouflaging the biomimetic erythrocyte membrane, the nanoparticles show significantly prolonged blood circulation and increased selective accumulation in tuberculosis granuloma. Upon laser irradiation, the loading photosensitizer of aggregation-induced emission photosensitizer elevates the production of reactive oxygen species (ROS), causing M.tb damage and death. The delivery of oxygen to relieve the hypoxic granuloma microenvironment supports ROS generation during photodynamic therapy. Meanwhile, the photothermal agent, Prussian blue nanoparticles, plays the role of good photothermal killing effect on M.tb. Moreover, the growth and proliferation of granuloma and M.tb colonies are effectively inhibited in the nanoparticle-treated tuberculous granuloma model mice, suggesting the combined therapeutic effects of enhancing photodynamic therapy and photothermal therapy.

Drug delivery under cover of erythrocytes extends drug half-life: A thrombolytic targeting therapy utilizing microenvironment-responsive artificial polysaccharide microvesicles

The development of thrombolytic drug carriers capable of thrombus-targeting, prolonged circulation time, intelligent responsive release, and the ability to inhibit thrombotic recurrences remains a promising but significant challenge. To tackle this, an artificial polysaccharide microvesicle drug delivery system (uPA-CS/HS@RGD-ODE) was constructed. It is composed of cationic chitosan and anionic heparin assembled in a layer by layer structure, followed by surface modification using RGD peptide and 2-(N-oxide-N,N-diethylamino) ethylmethacrylate (ODE) before encapsulation of urokinase-type plasminogen activator (uPA). The effect of chitosan on the basic performances of uPA-CS/HS@RGD-ODE was estimated. The in vitro results suggest the uPA carrier, CS/HS@RGD-ODE, displayed outstanding targeting specific to activated platelets (61 %) and microenvironment-responsiveness at pH 6.5, facilitating thrombus-targeting and a controlled drug release, respectively. Most importantly, in vivo experiment suggests ODE from uPA-CS/HS@RGD-ODE substantially extends the half-life of uPA (120 min), as uPA-CS/HS@RGD-ODE can adhere onto erythrocytes and deliver uPA under cover of erythrocytes enabling a prolonged circulation time in the bloodstream. Further tail vein and abdominal aorta thrombosis models confirmed uPA-CS/HS@RGD-ODE exhibited superior targeting and thrombolysis capabilities compared to systemic administration of free uPA. To the knowledge of authors, this may be the first study to develop new drug carriers for delivery of thrombolytic drugs under the cover of erythrocytes for extended drug half-lives.

A comparative investigation of release kinetics of paclitaxel from natural protein and macromolecular nanocarriers in nanoscale drug delivery systems

Understanding the release behaviour of nanodrugs is a crucial step to better assess and control therapeutic outcomes and unfavourable side effects. Herein, we report a systematic study comparing the release kinetics and thermodynamics of paclitaxel (PTX) from supramolecularly assembled sub-micron particles based on natural macromolecules such as zein, whey, casein, bovine serum albumin (BSA) and conventional stabilizers such as pluronic F-127 (poloxamer 407), and β-cyclodextrin (β-CD) to gain insights into the role of carrier chemistry. For this purpose, nanomedicines with statistically indifferent sizes —in the range of 191.0 ± 0.8 nm (BSA) to 243.3 ± 11.6 nm (zein) were prepared (p > 0.05). The zeta potential values ranged from −3.2 ± 1.1 mV (pluronic F-127) to −17.2 ± 1.8 mV (whey) in phosphate buffered saline. The type of nanocarrier significantly influenced the long-term steady-state plateau of the release, resulting in a cumulative release of 70.3 ± 2.0 % of PTX from casein (the highest) and 46.8 ± 4.7 % of PTX from zein (the lowest). Time-resolved release data were analysed with various kinetical models, encompassing zero-order, first-order, Higuchi, Peppas-Sahlin, and Korsmeyer-Peppas kinetics. The analysis revealed that the Korsmeyer-Peppas model best captured the data. For these nanomedicines, the half-life of the encapsulated drugs was found to be 106.4 ± 31.3 h (zein), 4.7 ± 1.2 h (whey), 10.7 ± 1.8 h (pluronic F-127), 6.4 ± 0.9 h (casein), 10.8 ± 3.2 h (β-CD), and 4.0 ± 1.0 h (BSA). TEM characterization revealed differences in the macromolecular arrangement of the active ingredient within these nanocarriers, in addition to the structural differences among the various encapsulating agents. These differences manifested as variations in the internal nanostructures, leading to the creation of distinct microenvironments that could either facilitate or impede the movement of PTX molecules through the encapsulant matrices. In clinical settings, such fine details of nanocarrier design are important: by choosing the most appropriate nanocarrier (or their mixtures), clinicians can fine-tune drug administration to obtain the intended therapeutic window while mitigating the risk of potential negative reactions.

Innovations in Skin Cancer Nanotechnology: A Comprehensive Review.

Skin cancer is the most common type of cancer among white people, according to the World Health Organisation. The incidence of melanoma and non-melanoma skin cancers has increased to epidemic levels, making them the most widespread type of skin cancer. Melanoma is a very aggressive form of cancer, characterized by limited treatment choices due to multidrug resistance and an extremely low probability of patient survival. This article explores the various impediments and limitations associated with conventionally available treatments. Chemotherapy, radiation, immunotherapy, and targeted therapy are among the conventional treatments for melanoma; however, each of these approaches has several adverse reactions. Recently, there has been a focus on biological and pharmacological research on developing alternative, site-specific therapy approaches. Nanotechnology offers several benefits in this regard, with the potential to enhance the longevity of melanoma patients while minimizing adverse effects. Nanoparticles serve as effective drug carrier systems due to their capacity to improve the solubility of medications with low water solubility, modify pharmacokinetics, prolong drug half-life by reducing immunogenicity, boost bioavailability, and decrease drug metabolism. This article highlights recent advancements in utilizing several nanotechnological techniques, including solid lipid nanoparticles, nanostructured lipid carriers, liposomes, transferosomes, ethosomes, and nanoemulsion polymeric mixed micelles.

Macrophage Membrane-Encapsulated Dopamine-Modified Poly Cyclodextrin Multifunctional Biomimetic Nanoparticles for Atherosclerosis Therapy.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. β-Cyclodextrin (β-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. β-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

Characterization and humanization of VNARs targeting human serum albumin from the whitespotted bamboo shark (Chiloscyllium plagiosum)

The Shark-derived immunoglobulin new antigen receptors (IgNARs) have gained increasing attention for their high solubility, exceptional thermal stability, and intricate sequence variation. In this study, we immunized whitespotted bamboo shark (Chiloscyllium plagiosum) to create phage display library of variable domains of IgNAR (VNARs) for screening against Human Serum Albumin (HSA), a versatile vehicle in circulation due to its long in vivo half-life. We identified two HSA-binding VNAR clones, 2G5 and 2G6, and enhanced their expression in E. coli with the FKPA chaperone. 2G6 exhibited a strong binding affinity of 13 nM with HSA and an EC50 of 1 nM. In vivo study with a murine model further provided initial validation of 2G6's ability to prolong circulation time by binding to HSA. Additionally, we employed computational molecular docking to predict the binding affinities of both 2G6 and its humanized derivative, H2G6, to HSA. Our analysis unveiled that the complementarity-determining regions (CDR1 and CDR3) are pivotal in the antigen recognition process. Therefore, our study has advanced the understanding of the potential applications of VNARs in biomedical research aimed at extending drug half-life, holding promise for future therapeutic and diagnostic progressions.

In Vivo Ocular Pharmacokinetics and Toxicity of Siponimod in Albino Rabbits.

Siponimod is a promising agent for the inhibition of ocular neovascularization in diabetic retinopathy and age-related macular degeneration. Siponimod's development for ophthalmological application is hindered by the limited information available on the drug's solubility, stability, ocular pharmacokinetics (PK), and toxicity in vivo. In this study, we investigated the aqueous stability of siponimod under stress conditions (up to 60 °C) and its degradation behavior in solution. Additionally, siponimod's ocular PK and toxicity were investigated using intravitreal injection of two different doses (either 1300 or 6500 ng) in an albino rabbit model. Siponimod concentration was quantified in the extracted vitreous, and the PK parameters were calculated. The drug half-life after administration of the low and high doses was 2.8 and 3.9 h, respectively. The data obtained in vivo was used to test the ability of published in silico models to predict siponimod's PK accurately. Two models that correlated siponimod's molecular descriptors with its elimination from the vitreous closely predicted the half-life. Furthermore, 24 h and 7 days after intravitreal injections, the retinas showed no signs of toxicity. This study provides important information necessary for the formulation and development of siponimod for ophthalmologic applications. The short half-life of siponimod necessitates the development of a sustained drug delivery system to maintain therapeutic concentrations over an extended period, while the lack of short-term ocular toxicity observed in the retinas of siponimod-treated rabbits supports possible clinical use.

Enhanced Pharmacokinetics of Celastrol via Long-Circulating Liposomal Delivery for Intravenous Administration.

Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Tripterygium wilfordii Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability. In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA. Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats. The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of -31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t1/2) to 11.71 hr, mean residence time (MRT(0-∞)) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution. In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.

Targeted Delivery of Macrophage Membrane Biomimetic Liposomes Through Intranasal Administration for Treatment of Ischemic Stroke.

Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.

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.

Predicting Elimination of Small-Molecule Drug Half-Life in Pharmacokinetics Using Ensemble and Consensus Machine Learning Methods.

Half-life is a significant pharmacokinetic parameter included in the excretion phase of absorption, distribution, metabolism, and excretion. It is one of the key factors for the successful marketing of drug candidates. Therefore, predicting half-life is of great significance in drug design. In this study, we employed eXtreme Gradient Boosting (XGboost), randomForest (RF), gradient boosting machine (GBM), and supporting vector machine (SVM) to build quantitative structure-activity relationship (QSAR) models on 3512 compounds and evaluated model performance by using root-mean-square error (RMSE), R2, and mean absolute error (MAE) metrics and interpreted features by SHapley Additive exPlanation (SHAP). Furthermore, we developed consensus models through integrating four individual models and validated their performance using a Y-randomization test and applicability domain analysis. Finally, matched molecular pair analysis was used to extract the transformation rules. Our results revealed that XGboost outperformed other individual models (RMSE = 0.176, R2 = 0.845, MAE = 0.141). The consensus model integrating all four models continued to enhance prediction performance (RMSE = 0.172, R2 = 0.856, MAE = 0.138). We evaluated the reliability, robustness, and generalization ability via Y-randomization test and applicability domain analysis. Meanwhile, we utilized SHAP to interpret features and employed matched molecular pair analysis to extract chemical transformation rules that provide suggestions for optimizing drug structure. In conclusion, we believe that the consensus model developed in this study serve as a reliable tool to evaluate half-life in drug discovery, and the chemical transformation rules concluded in this study could provide valuable suggestions in drug discovery.

Abstract 7397: Application of state transition theory for predicting responses of acute myeloid leukemia to chemotherapy

Abstract Acute Myeloid Leukemia (AML) is aggressive cancer that initiates in the bone marrow (BM) and circulates in the peripheral blood (PB). The AML initiation and progressions are complex disease evolution associated with gene mutations and chromosomal abnormalities that change expression profiles of downstream genes characterizing functional networks of leukemic cells. We previously reported the application of the state-transition theory to characterize AML disease progression by modeling transcriptome changes during AML progression as a dynamic system that undergoes state-transition in an AML state-space characterized by an AML potential. Here, we investigate the impact of treatment on transcriptome state-transition and examine the hypothesis that treatment dynamically alters the AML potential. We use the Cbfb-MYH11 (CM) knock-in AML mouse model and a ”5+3” chemotherapy regimen to model the impact of current standard of care for newly diagnosed AML. CM leukemic mice were treated with a combination of cytarabine (Ara-C; 50mg/kg/day; 5 days) and Daunorubicin (DNR; 1.5mg/kg/day; 3 days) after detection of overt leukemia, defined by > 20% leukemia blast (cKit+) detected by flow cytometry in the PB. Time-series samples of peripheral blood mononuclear cell (PBMC) (n=174) were collected weekly before, during, and following “5+3” chemotherapy and subjected to RNA sequencing. All samples were mapped to the AML state-space constructed based on time-sequential RNA-seq collected over the course of CM AML development. Based on the state-transition model, all 10 treated AML mice achieved partial response to chemotherapy with a mean time to relapse (return to leukemia state) of 5 weeks confirming the anti-leukemia effects of treatment by the blast percentages (ckit%). We used the state-transition treatment model to study the dynamics of chemotherapy on the AML potential using state-space trajectories before, during, and after “5+3” chemotherapy. Dynamic changes of concentrations of Ara-C and DNR in the CM mouse model during ”5+3” chemotherapy were modeled by drug doses, half-life, and Heaviside step function. The drug effects were introduced to the AML potential as anti-leukemic treatment forces. Several treatment protocols were examined to find combinations of drug doses and timing that showed the longest survival rates. The model predicted that sequential doses reducing 50% of the original “5+3” chemotherapy dose would produce the longest survival rate. The model suggests that controlling the state-space trajectories in the healthy state with reduced doses will provide the most effective outcomes from “5+3” chemotherapy. Citation Format: Lisa Uechi, Yu-Hsuan Fu, David E. Frankhouser, Lianjun Zhang, Ying-Chieh Chen, Denis O'Meally, Sergio Branciamore, Jihyun Irizarry, Bin Zhang, Guido Marcucci, Ya-Huei Kuo, Russell C. Rockne. Application of state transition theory for predicting responses of acute myeloid leukemia to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7397.