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Advanced Drug Delivery Reviews Sep 2016The RNA interference (RNAi) technique is a new modality for cancer therapy, and several candidates are being tested clinically. In the development of RNAi-based... (Review)
Review
The RNA interference (RNAi) technique is a new modality for cancer therapy, and several candidates are being tested clinically. In the development of RNAi-based therapeutics, imaging methods can provide a visible and quantitative way to investigate the therapeutic effect at anatomical, cellular, and molecular level; to noninvasively trace the distribution; to and study the biological processes in preclinical and clinical stages. Their abilities are important not only for therapeutic optimization and evaluation but also for shortening of the time of drug development to market. Typically, imaging-functionalized RNAi therapeutics delivery that combines nanovehicles and imaging techniques to study and improve their biodistribution and accumulation in tumor site has been progressively integrated into anticancer drug discovery and development processes. This review presents an overview of the current status of translating the RNAi cancer therapeutics in the clinic, a brief description of the biological barriers in drug delivery, and the roles of imaging in aspects of administration route, systemic circulation, and cellular barriers for the clinical translation of RNAi cancer therapeutics, and with partial content for discussing the safety concerns. Finally, we focus on imaging-guided delivery of RNAi therapeutics in preclinical development, including the basic principles of different imaging modalities, and their advantages and limitations for biological imaging. With growing number of RNAi therapeutics entering the clinic, various imaging methods will play an important role in facilitating the translation of RNAi cancer therapeutics from bench to bedside.
Topics: Drug Delivery Systems; Genetic Therapy; Humans; Neoplasms; RNA Interference; RNA, Small Interfering; Tissue Distribution
PubMed: 26805788
DOI: 10.1016/j.addr.2016.01.008 -
Nutrients May 2019Understanding how the gut responds to food has always been limited by the available investigatory techniques. Previous methods involving intubation and aspiration are... (Review)
Review
Understanding how the gut responds to food has always been limited by the available investigatory techniques. Previous methods involving intubation and aspiration are largely limited to liquid-only meals. The aim of this review is to describe how MRI has allowed analysis of the processing of complex multiphase meals. This has demonstrated the role of physical factors such as viscosity, fat and fibre content in controlling gastric secretion and motility. It has also allowed the description of changes induced in small bowel water content and the role of osmotic effects of poorly absorbed carbohydrates such as fructose, sorbitol and mannitol. Intestinal secretions can be shown to be stimulated by a range of fruit and vegetables and the effect of this on colonic water content can also be measured. This has been used to demonstrate the mode of action of commonly used laxatives including bran and psyllium. The wealth of data which can be obtained together with its non-invasive nature and safety makes the technique ideal for the serial evaluation of the impact of different nutrients and drugs in both health and disease.
Topics: Animals; Diet; Eating; Gastrointestinal Absorption; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Intestines; Magnetic Resonance Imaging; Nutritional Status; Nutritive Value; Predictive Value of Tests; Stomach
PubMed: 31126027
DOI: 10.3390/nu11051147 -
Environment International Sep 2021This study describes the development and intercomparison of generic physiologically-based toxicokinetic (PBTK) models for humans comprised of internally consistent...
Development and intercomparison of single and multicompartment physiologically-based toxicokinetic models: Implications for model selection and tiered modeling frameworks.
This study describes the development and intercomparison of generic physiologically-based toxicokinetic (PBTK) models for humans comprised of internally consistent one-compartment (1Co-) and multi-compartment (MCo-) implementations (G-PBTK). The G-PBTK models were parameterized for an adult male (70 kg) using common physiological parameters and in vitro biotransformation rate estimates and subsequently evaluated using independent concentration versus time data (n = 6) and total elimination half-lives (n = 15) for diverse organic chemicals. The model performance is acceptable considering the inherent uncertainty in the biotransformation rate data and the absence of model calibration. The G-PBTK model was then applied using hypothetical neutral organics, acidic ionizable organics and basic ionizable organics (IOCs) to identify combinations of partitioning properties and biotransformation rates leading to substantial discrepancies between 1Co- and MCo-PBTK calculations for whole body concentrations and half-lives. The 1Co- and MCo-PBTK model calculations for key toxicokinetic parameters are broadly consistent unless biotransformation is rapid (e.g., half-life less than five days). When half-lives are relatively short, discrepancies are greatest for the neutral organics and least for the acidic IOCs which follows from the estimated volumes of distribution (e.g., VD = 9.6-15.4 L/kg vs 0.3-1.6 L/kg for the neutral and acidic compounds respectively) and the related approach to internal chemical equilibrium. The model intercomparisons demonstrate that 1Co-PBTK models can be applied with confidence to many exposure scenarios, particularly those focused on chronic or repeat exposures and for prioritization and screening-level decision contexts. However, MCo-PBTK models may be necessary in certain contexts, particularly for intermittent, short-term and highly variable exposures. A key recommendation to guide model selection and the development of tiered PBTK modeling frameworks that emerges from this study is the need to harmonize models with respect to parameterization and process descriptions to the greatest extent possible when proceeding from the application of simpler to more complex modeling tools as part of chemical assessment activities.
Topics: Adult; Humans; Male; Models, Biological; Organic Chemicals; Toxicokinetics
PubMed: 33892222
DOI: 10.1016/j.envint.2021.106557 -
International Journal of Molecular... Nov 2020The rise of antibiotic resistance and the growing number of biofilm-related infections make bacterial infections a serious threat for global human health. Nanomedicine... (Review)
Review
The rise of antibiotic resistance and the growing number of biofilm-related infections make bacterial infections a serious threat for global human health. Nanomedicine has entered into this scenario by bringing new alternatives to design and develop effective antimicrobial nanoweapons to fight against bacterial infection. Among them, mesoporous silica nanoparticles (MSNs) exhibit unique characteristics that make them ideal nanocarriers to load, protect and transport antimicrobial cargoes to the target bacteria and/or biofilm, and release them in response to certain stimuli. The combination of infection-targeting and stimuli-responsive drug delivery capabilities aims to increase the specificity and efficacy of antimicrobial treatment and prevent undesirable side effects, becoming a ground-breaking alternative to conventional antibiotic treatments. This review focuses on the scientific advances developed to date in MSNs for infection-targeted stimuli-responsive antimicrobials delivery. The targeting strategies for specific recognition of bacteria are detailed. Moreover, the possibility of incorporating anti-biofilm agents with MSNs aimed at promoting biofilm penetrability is overviewed. Finally, a comprehensive description of the different scientific approaches for the design and development of smart MSNs able to release the antimicrobial payloads at the infection site in response to internal or external stimuli is provided.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Biofilms; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Humans; Nanoparticles; Silicon Dioxide
PubMed: 33203098
DOI: 10.3390/ijms21228605 -
Langmuir : the ACS Journal of Surfaces... Aug 2019Microbubble-assisted ultrasound has emerged as a promising method for the delivery of low-molecular-weight chemotherapeutic molecules, nucleic acids, therapeutic... (Review)
Review
Microbubble-assisted ultrasound has emerged as a promising method for the delivery of low-molecular-weight chemotherapeutic molecules, nucleic acids, therapeutic peptides, and antibodies in vitro and in vivo. Its clinical applications are under investigation for local delivery drug in oncology and neurology. However, the biophysical mechanisms supporting the acoustically mediated membrane permeabilization are not fully established. This review describes the present state of the investigations concerning the acoustically mediated stimuli (i.e., mechanical, chemical, and thermal stimuli) as well as the molecular and cellular actors (i.e., membrane pores and endocytosis) involved in the reversible membrane permeabilization process. The different hypotheses, which were proposed to give a biophysical description of the membrane permeabilization, are critically discussed.
Topics: Animals; Cell Membrane; Cell Membrane Permeability; Endocytosis; Microbubbles; Pharmacokinetics; Reactive Oxygen Species; Ultrasonic Waves; Ultrasonics
PubMed: 30525655
DOI: 10.1021/acs.langmuir.8b03538 -
Journal of Proteomics Nov 2011Mass spectrometric imaging (MSI) is a powerful analytical technique that provides two- and three-dimensional spatial maps of multiple compounds in a single experiment.... (Review)
Review
Mass spectrometric imaging (MSI) is a powerful analytical technique that provides two- and three-dimensional spatial maps of multiple compounds in a single experiment. This technique has been routinely applied to protein, peptide, and lipid molecules with much less research reporting small molecule distributions, especially pharmaceutical drugs. This review's main focus is to provide readers with an up-to-date description of the substrates and compounds that have been analyzed for drug and metabolite composition using MSI technology. Additionally, ionization techniques, sample preparation, and instrumentation developments are discussed.
Topics: Animals; Diagnostic Imaging; Humans; Mass Spectrometry; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 21515430
DOI: 10.1016/j.jprot.2011.03.032 -
Molecules (Basel, Switzerland) Aug 2018Scorpionate ligands have played a crucial role in the development of technetium chemistry and, recently, they have also fueled important advancements in the discovery of... (Review)
Review
Scorpionate ligands have played a crucial role in the development of technetium chemistry and, recently, they have also fueled important advancements in the discovery of novel diagnostic imaging agents based on the γ-emitting radionuclide technetium-99m. The purpose of this short review is to provide an illustration of the most general and relevant results in this field, however without being concerned with the details of the analytical features of the various compounds. Thus, emphasis will be given to the description of the general features of technetium complexes with scorpionate ligands including coordination modes, structural properties and an elementary bonding description. Similarly, the most relevant examples of technetium-99m radiopharmaceuticals derived from scorpionate ligands and their potential interest for nuclear imaging will be summarized.
Topics: Animals; Blood-Brain Barrier; Cell Membrane Permeability; Contrast Media; Coordination Complexes; Humans; Ligands; Molecular Structure; Radiopharmaceuticals; Technetium; Tissue Distribution
PubMed: 30111708
DOI: 10.3390/molecules23082039 -
Methodist DeBakey Cardiovascular Journal 2014The emergence of personalized medicine mandates a complete understating of DNA sequence variation that modulates drug response. Initial forays have been made in the... (Review)
Review
The emergence of personalized medicine mandates a complete understating of DNA sequence variation that modulates drug response. Initial forays have been made in the cardiac arena, yet much remains to be elucidated in the pharmacogenetics of cardiac drugs. Most progress has been made in describing DNA sequence variation related to the anticoagulant warfarin and the antiplatelet drug clopidogrel. This includes a description of DNA sequence variation that underlies pharmacokinetic and pharmacodynamic variability, the impact of such variation on predicting hard outcomes, and the ability of genotype-guided prescription to facilitate rapid titration to a therapeutic range while avoiding unnecessary high plasma levels. Nuanced prescription will require a complete inventory of DNA sequence variants that underlie drug-related side effects.
Topics: Animals; Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Gene Expression Regulation; Genotype; Humans; Pharmacogenetics; Phenotype; Precision Medicine; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 24932357
DOI: 10.14797/mdcj-10-1-13 -
International Journal of Pharmaceutics Jun 2022Subcutaneous injection is a commonly used route of drug administration for both small molecules and biologics. To facilitate the development of new subcutaneously... (Review)
Review
Subcutaneous injection is a commonly used route of drug administration for both small molecules and biologics. To facilitate the development of new subcutaneously administered drugs, methods for prediction of drug absorption from the injection site are essential. For this purpose, in silico models have increasingly been used. This report summarize the current state of in silico models for description and prediction of subcutaneous drug absorption. Original articles on physiologically based models describing subcutaneous administration published from 2010 and onward were reviewed. Eighteen physiologically based models were identified: eleven for small molecules and seven for biologics. Most models described the PK of one drug and for one species. In models for small molecules, the subcutaneous administration site was most often described as a depot compartment with first-order absorption into the plasma or blood. Most models for biologics divided administration and organ compartments into vascular and interstitial subcompartments. Mass transfer to these compartments was frequently described with convection and diffusion, according to the one- or two-pore theory. Tremendous improvement in the quantitative aspects of subcutaneous administration and subsequent absorption of physiologically based models has occurred the last decade. However, improvements related to data translation and generalization of these models were identified.
Topics: Biological Products; Biopharmaceutics; Computer Simulation; Models, Biological; Pharmaceutical Preparations; Subcutaneous Absorption
PubMed: 35533921
DOI: 10.1016/j.ijpharm.2022.121808 -
Computers in Biology and Medicine Sep 2022Clinical trials are essential in medical science and are currently the most robust strategy for evaluating the effectiveness of a treatment. However, some of these... (Review)
Review
BACKGROUND
Clinical trials are essential in medical science and are currently the most robust strategy for evaluating the effectiveness of a treatment. However, some of these studies are less reliable than others due to flaws in their design. Assessing the robustness of a clinical trial can be a very complex and time-consuming task, with factors such as randomization, masking and the description of withdrawals needing to be considered.
METHOD
We built a program based on artificial intelligence (AI) approaches, designed to assess the robustness of a clinical trial by estimating its Jadad's score. The program is composed of five Recursive Neural Networks (RNN), each of them trained to spot one specific item constituting the Jadad's scale. After training, the algorithm was tested on two different validation sets (one from the original database: 35% of this database was used for validation and 65% for training; one composed of 10 articles, out of the original database, for which the Jadad's score has been computed by each contributor of this study).
RESULT
After training, the algorithm achieved a mean accuracy of 96,2% (ranging from 93% to 98%) and a mean area under the curve (AUC) of 96% (ranging from 95% to 97%) on the first validation dataset. These results indicate good feature detection capacity for each of the five RNN. On the second validation dataset the algorithm extracted 100% of the item to retrieve for 70% of the articles and between 66% and 75% for 30% of the articles. Overall 85% of the items present in the second validation dataset were correctly extracted. None of the extracted items was misclassified.
CONCLUSION
We developed a program that can automatically estimate the Jadad's score of a clinical trial with a good accuracy. Automating the assessment of this metric could be very useful in a systematic review of the literature and will probably save clinicians time.
Topics: Algorithms; Area Under Curve; Artificial Intelligence; Databases, Factual; Neural Networks, Computer
PubMed: 35947929
DOI: 10.1016/j.compbiomed.2022.105851