ABSTRACT
The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26â PF6 and FY26â Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26â PF6 and FY26â Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26â Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Coordination Complexes/therapeutic use , Liver Neoplasms/drug therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Coordination Complexes/administration & dosage , Coordination Complexes/adverse effects , Coordination Complexes/pharmacokinetics , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Tissue DistributionABSTRACT
P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient's benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Circadian Rhythm , Citalopram/pharmacokinetics , Eating/physiology , Fasting/physiology , Propanolamines/pharmacokinetics , Sex Characteristics , ATP Binding Cassette Transporter, Subfamily B/genetics , Animals , Biological Transport , Colon/metabolism , Crosses, Genetic , Female , Gene Expression Regulation , Ileum/metabolism , Intestinal Mucosa/metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Biological , Propanolamines/analysis , RNA, Messenger/biosynthesisABSTRACT
Current approaches to generate core-shell nanoparticles for biomedical applications are limited by factors such as synthetic scalability and circulatory desorption of cytotoxic surfactants. Developments in controlled radical polymerization, particularly in dispersed states, represent a promising method of overcoming these challenges. In this work, well-defined PEGylated nanoparticles are synthesized using reversible addition fragmentation chain transfer emulsion polymerization to control particle size and surface composition and were further characterized with light scattering, electron microscopy, and size exclusion chromatography. Importantly, the nanoparticles are found to be tolerated both in vitro and in vivo, without the need for any purification after particle synthesis. Pharmacokinetic and biodistribution studies in mice, following intraperitoneal injection of the nanoparticles, reveal a long (>76 h) circulation time and accumulation in the liver.
Subject(s)
Latex , Materials Testing , Nanoparticles/chemistry , Polymerization , Animals , Caco-2 Cells , Emulsions , Humans , Latex/chemistry , Latex/pharmacokinetics , Latex/pharmacology , Male , MiceABSTRACT
Emerging evidence suggests that components of the metabolic syndrome either in isolation or in aggregate may impact the onset or severity of neurodegenerative processes, including those physiologic changes that lead to Alzheimer's Disease (AD). Several animal models that were originally designed to interrogate the metabolic syndrome are readily available. These models can now be used to support studies that may provide new mechanistic links between the metabolic syndrome and neurodegeneration. In addition, animal strains currently being generated and phenotyped through the efforts of an array of NIDDK-supported projects are likely to provide novel and better tools to advance Alzheimer's disease research in the near future.
