Molecular Pharmaceutics最新文献_第8页

Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with In Situ Stimulated Raman Scattering Microscopy. 利用原位受激拉曼散射显微镜揭示无定形固体分散体的动态相行为。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-19 DOI: 10.1021/acs.molpharmaceut.4c01032

Teemu Tomberg, Ilona Hämäläinen, Clare J Strachan, Bert van Veen

{"title":"Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with In Situ Stimulated Raman Scattering Microscopy.","authors":"Teemu Tomberg, Ilona Hämäläinen, Clare J Strachan, Bert van Veen","doi":"10.1021/acs.molpharmaceut.4c01032","DOIUrl":"10.1021/acs.molpharmaceut.4c01032","url":null,"abstract":"This study reports the application of in situ stimulated Raman scattering (SRS) microscopy for real-time chemically specific imaging of dynamic phase phenomena in amorphous solid dispersions (ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate) films with different drug loadings (0-100% w/w) as model systems, we employed SRS microscopy with fast spectral focusing to analyze ASD behavior upon contact with a dissolution medium. Multivariate unmixing of the SRS spectra allowed changes in the distributions of the drug, polymer, and water to be (semi)quantitatively imaged in real time, both in the film and the adjacent dissolution medium. The SRS analyses were further augmented with complementary correlative sum frequency generation and confocal reflection for additional crystallinity and phase sensitivity. In the ASDs with drug loadings of 20, 40, and 60% w/w, the water penetration front within the film, followed by both surface-directed and bulk phase separation in the film, was apparent but differed quantitatively. Additionally, drug-loading and phase-dependent polymer and drug release behavior was imaged, and liquid-liquid phase separation was observed for the 20% drug loading ASD. Overall, SRS microscopy with fast spectral focusing provides quantitative insights into water-induced ASD phase phenomena, with chemical, solid-state, temporal, and spatial resolution. These insights are important for optimal ASD formulation development.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6444-6457"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of Multi-Pharmacokinetics Property in Multi-Species: Bayesian Neural Network Stacking Model with Uncertainty. 预测多物种的多重药代动力学特性：具有不确定性的贝叶斯神经网络堆积模型。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-07 DOI: 10.1021/acs.molpharmaceut.4c00406

Yuanyuan Zhang, Zhiyin Xie, Fu Xiao, Jie Yu, Zhehuan Fan, Shihui Sun, Jiangshan Shi, Zunyun Fu, Xutong Li, Dingyan Wang, Mingyue Zheng, Xiaomin Luo

{"title":"Prediction of Multi-Pharmacokinetics Property in Multi-Species: Bayesian Neural Network Stacking Model with Uncertainty.","authors":"Yuanyuan Zhang, Zhiyin Xie, Fu Xiao, Jie Yu, Zhehuan Fan, Shihui Sun, Jiangshan Shi, Zunyun Fu, Xutong Li, Dingyan Wang, Mingyue Zheng, Xiaomin Luo","doi":"10.1021/acs.molpharmaceut.4c00406","DOIUrl":"10.1021/acs.molpharmaceut.4c00406","url":null,"abstract":"Pharmacokinetic (PK) properties of a drug are vital attributes influencing its therapeutic effectiveness, playing an important role in the drug development process. Focusing on the difficult task of predicting PK parameters, we compiled an extensive data set comprising parameters across multiple species. Building upon this groundwork, we introduced the PKStack ensemble model to predict PK parameters across diverse species. PKStack integrates a variety of base models and includes uncertainty in its predictions. We also manually collected PK data from animals as an external test set. We predicted a total of 45 tasks for nine PK parameters in five species, and in general, the prediction accuracy was better for intravenous injections, including parameters such as human Vd (R2 = 0.72, RMSE = 0.31), human CL (R2 = 0.52, RMSE = 0.32), and others. In addition to predictive accuracy, we also considered the interpretability of the results and the definition of the model's application domain. Based on the findings, our model has great potential for practical applications in drug discovery.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6177-6192"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DeepCt: Predicting Pharmacokinetic Concentration-Time Curves and Compartmental Models from Chemical Structure Using Deep Learning. DeepCt：利用深度学习从化学结构预测药代动力学浓度-时间曲线和区室模型。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-06 DOI: 10.1021/acs.molpharmaceut.4c00562

Maximilian Beckers, Dimitar Yonchev, Sandrine Desrayaud, Grégori Gerebtzoff, Raquel Rodríguez-Pérez

{"title":"DeepCt: Predicting Pharmacokinetic Concentration-Time Curves and Compartmental Models from Chemical Structure Using Deep Learning.","authors":"Maximilian Beckers, Dimitar Yonchev, Sandrine Desrayaud, Grégori Gerebtzoff, Raquel Rodríguez-Pérez","doi":"10.1021/acs.molpharmaceut.4c00562","DOIUrl":"10.1021/acs.molpharmaceut.4c00562","url":null,"abstract":"After initial triaging using in vitro absorption, distribution, metabolism, and excretion (ADME) assays, pharmacokinetic (PK) studies are the first application of promising drug candidates in living mammals. Preclinical PK studies characterize the evolution of the compound's concentration over time, typically in rodents' blood or plasma. From this concentration-time (C-t) profiles, PK parameters such as total exposure or maximum concentration can be subsequently derived. An early estimation of compounds' PK offers the promise of reducing animal studies and cycle times by selecting and designing molecules with increased chances of success at the PK stage. Even though C-t curves are the major readout from a PK study, most machine learning-based prediction efforts have focused on the derived PK parameters instead of C-t profiles, likely due to the lack of approaches to model the underlying ADME mechanisms. Herein, a novel deep learning approach termed DeepCt is proposed for the prediction of C-t curves from the compound structure. Our methodology is based on the prediction of an underlying mechanistic compartmental PK model, which enables further simulations, and predictions of single- and multiple-dose C-t profiles.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6220-6233"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From Preformulative Design to in Vivo Tests: A Complex Path of Requisites and Studies for Nanoparticle Ocular Application. Part 2: In Vitro, Ex Vivo, and In Vivo Studies. 从预制设计到体内试验：纳米粒子眼部应用的要求和研究的复杂路径。第 2 部分：体外、体内和体内研究。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-08 DOI: 10.1021/acs.molpharmaceut.4c00725

Cinzia Cimino, Lorena Bonilla Vidal, Federica Conti, Elena Sánchez López, Claudio Bucolo, Maria Luisa García, Teresa Musumeci, Rosario Pignatello, Claudia Carbone

{"title":"From Preformulative Design to in Vivo Tests: A Complex Path of Requisites and Studies for Nanoparticle Ocular Application. Part 2: In Vitro, Ex Vivo, and In Vivo Studies.","authors":"Cinzia Cimino, Lorena Bonilla Vidal, Federica Conti, Elena Sánchez López, Claudio Bucolo, Maria Luisa García, Teresa Musumeci, Rosario Pignatello, Claudia Carbone","doi":"10.1021/acs.molpharmaceut.4c00725","DOIUrl":"10.1021/acs.molpharmaceut.4c00725","url":null,"abstract":"The incidence of ocular pathologies is constantly increasing, as is the interest of the researchers in developing new strategies to ameliorate the treatment of these conditions. Nowadays, drug delivery systems are considered among the most relevant approaches due to their applicability in the treatment of a great variety of inner and outer eye pathologies through painless topical administrations. The design of such nanocarriers requires a deep study of many aspects related to the administration route but also a consideration of the authorities and pharmacopeial requirements, in order to achieve a clinical outcome. On such bases, the scope of this review is to describe the path of the analyses that could be performed on nanoparticles, along with the assessment of their applicability for ophthalmic treatments. Preformulation studies, physicochemical and technological characterization, and preliminary noncellular in vitro studies have been described in part 1 of this review. Herein, first the in vitro cellular assays are described; subsequently, nonocular organotypic tests and ex vivo studies are reported, as to present the various analyses to which the formulations can be subjected before in vivo studies, described in the last part. In each step, the models that could be used are presented and compared, highlighting the pros and cons. Moreover, their reliability and eventual acceptance by regulatory agencies are discussed. Hence, this review provides an overview of the most relevant assays applicable for nanocarriers intended for ophthalmic administration to guide researchers in the experimental decision process.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6062-6099"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-30 DOI: 10.1021/acs.molpharmaceut.4c00974

Nobuki Kazuta, Kazuma Nakashima, Yuta Tarumizu, Takumi Sato, Yoshifumi Maya, Hiroyuki Watanabe, Masahiro Ono

{"title":"Novel Radiotheranostic Ligands Targeting Prostate-Specific Membrane Antigen Based on Dual Linker Approach.","authors":"Nobuki Kazuta, Kazuma Nakashima, Yuta Tarumizu, Takumi Sato, Yoshifumi Maya, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acs.molpharmaceut.4c00974","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00974","url":null,"abstract":"Radiotheranostics using prostate-specific membrane antigen (PSMA)-targeting radioligands offers precision medicine by performing radionuclide therapy based on results of diagnosis. Albumin binder (ALB) binds to albumin reversibly and contributes to effective radiotheranostics by enhancing tumor accumulation of PSMA-targeting radioligands. We newly developed two ALB-containing PSMA-targeting radioligands including dual functional linkers, a hydrophilic linker, d-glutamic acid, and a hydrophobic linker, 4-(aminomethyl)benzoic acid, with the opposite arrangement (PNT-DA6 and PNT-DA7). A biodistribution study of [111In]In-PNT-DA6 indicated that the introduction and arrangement of dual functional linkers contributed to improved pharmacokinetics. A single photon emission computed tomography study of [111In]In-PNT-DA6 produced a clear PSMA-expressing tumor image. Moreover, [225Ac]Ac-PNT-DA6 showed the inhibition of tumor growth in targeted radionuclide therapy in PSMA-expressing tumor-bearing mice. These results indicated that [111In]In-PNT-DA6 and [225Ac]Ac-PNT-DA6 exhibited useful characteristics as PSMA-targeting radiotheranostic ligands.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of Self-Association and Solution Behavior of Monoclonal Antibodies Using the QCM-D Metric of Loosely Interacting Layer.

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-29 DOI: 10.1021/acs.molpharmaceut.4c00656

Yusra Rahman, Siddhanth Hejmady, Reza Nejadnik

{"title":"Prediction of Self-Association and Solution Behavior of Monoclonal Antibodies Using the QCM-D Metric of Loosely Interacting Layer.","authors":"Yusra Rahman, Siddhanth Hejmady, Reza Nejadnik","doi":"10.1021/acs.molpharmaceut.4c00656","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00656","url":null,"abstract":"Despite the increasing availability and success of monoclonal antibodies (mAb), early identification of candidate molecules with desirable developability attributes remains challenging due to self-association and poor solution behavior. Measuring these phenomena experimentally using the available methods is complicated in mAbs development. Quartz crystal microbalance with dissipation monitoring (QCM-D) detects a loosely interacting layer on top of the irreversibly adsorbed layer of molecules, providing information about the mAbs interaction. This work aimed to explore whether the characteristics of this layer can be used as a reliable self-association metric. QCM-D experiments showed a large frequency shift (Δf) associated with loosely interacting layers for omalizumab but a small or absent layer for tocilizumab. Accordingly, the viscosity of omalizumab increased exponentially at high concentrations compared to tocilizumab. Testing eight mAbs with different self-association behaviors revealed a strong rank order correlation between the mostly used metric of self-association, i.e., diffusion interaction parameter (kD-DLS), and Δf, indicating Δf's potential for predicting mAb solution behavior. The study also highlighted the robustness of the metric to impurities and temperature variations compared to the sensitive kD-DLS. Overall, we demonstrate that the loosely interacting layer provides valuable information about mAb self-association, predicting the colloidal stability and solution behavior in therapeutic development.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Machine Learning Models for Predicting Monoclonal Antibody Biophysical Properties from Molecular Dynamics Simulations and Deep Learning-Based Surface Descriptors. 从分子动力学模拟和基于深度学习的表面描述符预测单克隆抗体生物物理特性的机器学习模型。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-28 DOI: 10.1021/acs.molpharmaceut.4c00804

I-En Wu, Lateefat Kalejaye, Pin-Kuang Lai

{"title":"Machine Learning Models for Predicting Monoclonal Antibody Biophysical Properties from Molecular Dynamics Simulations and Deep Learning-Based Surface Descriptors.","authors":"I-En Wu, Lateefat Kalejaye, Pin-Kuang Lai","doi":"10.1021/acs.molpharmaceut.4c00804","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00804","url":null,"abstract":"Monoclonal antibodies (mAbs) have found extensive applications and development in treating various diseases. From the pharmaceutical industry's perspective, the journey from the design and development of mAbs to clinical testing and large-scale production is a highly time-consuming and resource-intensive process. During the research and development phase, assessing and optimizing the developability of mAbs is of paramount importance to ensure their success as candidates for therapeutic drugs. The critical factors influencing mAb development are their biophysical properties, such as aggregation propensity, solubility, and viscosity. This study utilized a data set comprising 12 biophysical properties of 137 antibodies from a previous study (Proc Natl Acad Sci USA. 114(5):944-949, 2017). We employed full-length antibody molecular dynamics simulations and machine learning techniques to predict experimental data for these 12 biophysical properties. Additionally, we utilized a newly developed deep learning model called DeepSP, which directly predicts the dynamical and structural properties of spatial aggregation propensity and spatial charge map in different antibody regions from sequences. Our research findings indicate that the machine learning models we developed outperform previous methods in predicting most biophysical properties. Furthermore, the DeepSP model yields similar predictive results compared to molecular dynamic simulations while significantly reducing computational time. The code and parameters are freely available at https://github.com/Lailabcode/AbDev. Also, the webapp, AbDev, for 12 biophysical properties prediction has been developed and provided at https://devpred.onrender.com/AbDev.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From Sequence to System: Enhancing IVT mRNA Vaccine Effectiveness through Cutting-Edge Technologies. 从序列到系统：通过尖端技术提高 IVT mRNA 疫苗的有效性。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-27 DOI: 10.1021/acs.molpharmaceut.4c00863

Lifeng Xu, Chao Li, Rui Liao, Qin Xiao, Xiaoran Wang, Zhuo Zhao, Weijun Zhang, Xiaoyan Ding, Yuxue Cao, Larry Cai, Joseph Rosenecker, Shan Guan, Jie Tang

{"title":"From Sequence to System: Enhancing IVT mRNA Vaccine Effectiveness through Cutting-Edge Technologies.","authors":"Lifeng Xu, Chao Li, Rui Liao, Qin Xiao, Xiaoran Wang, Zhuo Zhao, Weijun Zhang, Xiaoyan Ding, Yuxue Cao, Larry Cai, Joseph Rosenecker, Shan Guan, Jie Tang","doi":"10.1021/acs.molpharmaceut.4c00863","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00863","url":null,"abstract":"The COVID-19 pandemic has spotlighted the potential of in vitro transcribed (IVT) mRNA vaccines with their demonstrated efficacy, safety, cost-effectiveness, and rapid manufacturing. Numerous IVT mRNA vaccines are now under clinical trials for a range of targets, including infectious diseases, cancers, and genetic disorders. Despite their promise, IVT mRNA vaccines face hurdles such as limited expression levels, nonspecific targeting beyond the liver, rapid degradation, and unintended immune activation. Overcoming these challenges is crucial to harnessing the full therapeutic potential of IVT mRNA vaccines for global health advancement. This review provides a comprehensive overview of the latest research progress and optimization strategies for IVT mRNA molecules and delivery systems, including the application of artificial intelligence (AI) models and deep learning techniques for IVT mRNA structure optimization and mRNA delivery formulation design. We also discuss recent development of the delivery platforms, such as lipid nanoparticles (LNPs), polymers, and exosomes, which aim to address challenges related to IVT mRNA protection, cellular uptake, and targeted delivery. Lastly, we offer insights into future directions for improving IVT mRNA vaccines, with the hope to spur further progress in IVT mRNA vaccine research and development.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shape and Size Dependence of Pharmacokinetics, Biodistribution, and Toxicity of Gold Nanoparticles. 金纳米粒子的药代动力学、生物分布和毒性与形状和尺寸有关。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-26 DOI: 10.1021/acs.molpharmaceut.4c00832

Huaping Wu, Lin Tang, Huanhuan Dong, Maoxin Zhi, Liqiong Guo, Xuechuan Hong, Mingzhe Liu, Yuling Xiao, Xiaodong Zeng

{"title":"Shape and Size Dependence of Pharmacokinetics, Biodistribution, and Toxicity of Gold Nanoparticles.","authors":"Huaping Wu, Lin Tang, Huanhuan Dong, Maoxin Zhi, Liqiong Guo, Xuechuan Hong, Mingzhe Liu, Yuling Xiao, Xiaodong Zeng","doi":"10.1021/acs.molpharmaceut.4c00832","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00832","url":null,"abstract":"Gold nanoparticles (AuNPs) are extensively utilized in biomolecular sensing, photothermal therapy, drug delivery, and various imaging techniques like photoacoustic and fluorescent imaging. Despite their diverse applications, inconsistent findings from previous toxicity studies underscore the critical need for standardized methodologies. This study introduces ten distinct types of AuNPs─cubes, stars, rods, dumbbells, and bipyramids at sizes of 50 and 100 nm, to systematically assess their toxicity under controlled conditions both in vitro and in vivo. Our findings reveal a clear correlation between cytotoxicity and the morphology, size, incubation duration, and concentration of AuNPs. Anisotropically shaped nanoparticles, such as nanorods, nanodumbbells, and nanobipyramids, tend to exhibit higher cytotoxicity compared to more spherical forms like nanocubes and nanostars. Interestingly, while in vivo plasma biochemistry parameters show minimal variation, biodistribution, histopathological alterations, and pharmacokinetics are notably influenced by the shape and size of AuNPs. In most instances, smaller and anisotropic AuNPs that remain in the bloodstream for extended periods are observed. This research offers significant insights into the design of AuNPs with specific morphologies and sizes, particularly for their application in drug delivery systems via intravenous injection. These outcomes emphasize the nuanced toxicity profiles of AuNPs, necessitating tailored approaches in preclinical and clinical research.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation. 包裹 BDNF 基因的 Penetratin 和甘露糖功能化大麻二酚脂质纳米颗粒可减轻淀粉样蛋白诱导的炎症。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-11-26 DOI: 10.1021/acs.molpharmaceut.4c00811

Bivek Chaulagain, Jagdish Singh

{"title":"Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation.","authors":"Bivek Chaulagain, Jagdish Singh","doi":"10.1021/acs.molpharmaceut.4c00811","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00811","url":null,"abstract":"Inflammation is emerging as a critical player in the disease progression of Alzheimer's disease (AD) by its interaction with amyloid beta plaques in a feed-forward loop. There is also a decline in the nourishment and enriching neurotrophic factor, brain-derived neurotrophic factor (BDNF), in the brain. Therefore, supplementing the brain with BDNF by gene delivery and delivering the anti-inflammatory agent, cannabidiol (CBD) in this case, to mitigate inflammation-induced disease cascade offers an attractive treatment strategy. To achieve the brain localization of CBD and pBDNF, lipid nanoparticles (LNPs) functionalized with mannose and penetratin were utilized. CBD and pBDNF were successfully encapsulated in the LNPs (more than 80%) with a size less than 180 nm, polydispersity index less than 0.25, and zeta potential of 23 mV. CBD was released from the formulation over a period of a week. The dual-functionalized LNPs demonstrated higher cellular uptake of CBD and expressed a significantly higher amount of BDNF (p-value <0.05) after transfection than their nonmodified counterparts in four brain cell lines, i.e., brain endothelial cells (b.END3), immortalized microglia cells (IMGs), primary astrocytes, and primary neurons. Similarly, the permeation of CBD through the dual-modified LNPs across the in vitro coculture blood-brain barrier model was significantly higher (p-value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta1-42 oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α (p < 0.05) and IL-1β (p < 0.05) in IMG cells. In summary, the penetratin and mannose-functionalized LNPs encapsulating CBD and pBDNF could serve as a promising therapy in AD, requiring further validation in animal models.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0