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Preclinical Study of Biofunctional Polymer-Coated Upconversion Nanoparticles
摘要： Upconversion nanoparticles (UCNPs) are new-generation photoluminescent nanomaterials gaining considerable recognition in the life sciences due to their unique optical properties that allow high-contrast imaging in cells and tissues. UCNP applications in optical diagnosis, bioassays, therapeutics, photodynamic therapy, drug delivery, and light-controlled release of drugs are promising, demanding a comprehensive systematic study of their pharmacological properties. We report on production of biofunctional UCNP-based nanocomplexes suitable for optical microscopy and imaging of HER2-positive cells and tumors, as well as on the comprehensive evaluation of their pharmacokinetics, pharmacodynamics, and toxicological properties using cells and laboratory animals. The nanocomplexes represent a UCNP core/shell structure of the NaYF4:Yb,Er,Tm/NaYF4 composition coated with an amphiphilic alternating copolymer of maleic anhydride with 1-octadecene (PMAO) and conjugated to the Designed Ankyrin Repeat Protein (DARPin9-29) with high affinity to the HER2 receptor. We demonstrated the specific binding of UCNP-PMAO-DARPin to HER2-positive cancer cells in cultures and xenograft animal models allowing the tumor visualization for at least 24 h. An exhaustive study of the general and specific toxicity of UCNP-PMAO-DARPin including the evaluation of their allergenic, immunotoxic, and reprotoxic properties was carried out. The obtained experimental body of evidence leads to a conclusion that UCNP-PMAO and UCNP-PMAO-DARPin are functional, non-cytotoxic, biocompatible, and safe for imaging applications in cells, small animals, and prospective clinical applications of image-guided surgery.
关键词： nanotoxicology,pharmacodynamics,pharmacokinetics,animal imaging,upconversion nanoparticles,photoluminescent nanomaterials
更新于2025-11-21 11:08:12
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Monitoring unbound warfarin in drug combination therapy by pharmacokinetics and fluorospectrometry
摘要： Objective: Monitoring the unbound drug concentration in blood in combination therapy is necessary, because its concentration determines the efficacy of drug therapy. This study was designed to explore the effect of Dan Hong Injection (DHI) on the unbound warfarin using two approaches including an in vivo pharmacokinetic and in vitro fluorescence studies. Methods: The effect of DHI on the pharmacokinetic properties of the unbound warfarin was investigated by a microdialysis sampling method coupled with LC–MS/MS. The effect of DHI and salvianolic acid B (SaB) on warfarin binding with bovine serum albumin (BSA) was conducted by fluorescence spectrometry. Results: The AUC 0-tn of warfarin with DHI group was higher than that of warfarin alone group. The result showed that DHI could increase the concentration of unbound warfarin in rat blood, which may be due to the competition between warfarin and DHI as well as its components binding to serum albumin. The competition process was demonstrated by fluorescence study. Conclusion: Combination therapy of DHI with warfarin could enhance the release profile of warfarin from serum protein.
关键词： microdialysis,unbound warfarin,pharmacokinetics,fluorospectrometry,Dan Hong Injection
更新于2025-09-23 15:23:52
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Manipulating Pharmacokinetics of Purification-Free <sup>99m</sup> Tc-Labeled Bivalent Probes for In Vivo Imaging of Saturable Targets
摘要： The accumulation of 99mTc-labeled probes targeting saturable systems of the body is hindered by the presence of a large excess of unlabeled ligands needed to ensure high radiochemical yields in short reaction time. To address the issue, we recently reported a novel concept of a metal coordination-mediated synthesis of a bivalent 99mTc-labeled probe from a monovalent ligand using D-penicillamine (Pen) as a chelating molecule and c(RGDfK) as a model targeting device. The Pen-conjugated c(RGDfK) via a hexanoate linkage (Pen-Hx-c(RGDfK)) provided a bivalent [99mTc]Tc-[(Pen-Hx-c(RGDfK))2 that possessed much higher integrin αvβ3 binding affinity than Pen-Hx-c(RGDfK) and visualized murine tumor without purification. However, high radioactivity levels were observed in the abdominal regions, which necessitated improved pharmacokinetic of the probes for practical applications. In this study, a pharmacokinetic (PK) modifier was introduced to manipulate the pharmacokinetics of the 99mTc-Pen2-based bivalent probe. The Hx linkage in Pen-Hx-c(RGDfK) was replaced with acetyl-D-serine-D-serine-glycine (Ac-ssG) or hexanoyl-D-seiner-D-serine-D-serine (Hx-sss) to prepare Pen-Ac-ssG-c(RGDfK) or Pen-Hx-sss-c(RGDfK). Pen-Ac-ssG-c(RGDfK) impaired the complexation ability of Pen-Hx-c(RGDfK), and a monovalent 99mTc-labeled compound was generated at low ligand concentration. However, Pen-Hx-sss-c(RGDfK) provided the objective bivalent 99mTc-labeled probe in high radiochemical yields at the concentration similar to that of Pen-Hx-c(RGDfK). [99mTc]Tc-[Pen-Hx-sss-c(RGDfK)]2 also possessed stability and integrin αvβ3 binding affinity similar to those of [99mTc]Tc-[Pen-Hx-c(RGDfK)]2. As a result, [99mTc]Tc-[Pen-Hx-sss-c(RGDfK)]2 exhibited the tumor and the abdominal radioactivity levels similar to and significantly lower than those of [99mTc]Tc-[Pen-Hx-c(RGDfK)]2. These findings indicate the incorporation of a tripeptide PK modifier to Pen-Hx-c(RGDfK) preserved the complexation ability and improved the pharmacokinetics of the resulting 99mTc-labeled bivalent probe without impairing the targeting ability. Thus, [Pen-Hx-(PK modifier)-(targeting device)] would constitute a basic formulation for preparing the 99mTc-Pen2-based bivalent probes for imaging saturable systems of the body.
关键词： metal coordination,99mTc,cyclic RGD peptide,bivalent probe,pharmacokinetics
更新于2025-09-23 15:19:57
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PET Imaging of the EPR Effect in Tumor Xenografts Using Small 15 nm Diameter Polyethylene Glycols Labeled with Zirconium-89
摘要： The goal was to develop and characterize a companion diagnostic for the releasable PEG40kDa~SN-38 oncology drug, PLX038, that would identify tumors susceptible to high accumulation of PLX038. PEG conjugates of the zirconium ligand desferroxamine B (DFB) of similar size and charge to PLX038 were prepared that contained one or four DFB as well as one that contained three SN-38 moieties and one DFB. Uptake and associated kinetic parameters of the 89Zr-labeled nanocarriers was determined in tumor and normal tissues in mice using μPET/CT imaging. The data were fit to physiologically-based pharmacokinetic models to simulate the mass-time profiles of distribution of conjugates in the tissues of interest. The time activity curves for normal tissues showed high levels at the earliest time of measurement due to vascularization, followed by a monophasic loss. In tumors, levels were initially lower than in normal tissues but increased to 9 to 14% of injected dose over several days. The efflux half-life in tumors was a very long ~400 h. and tumor levels remained at about 10% ID nine days after injection. Compared to diagnostic liposomes, the PEG nanocarriers have a longer serum half-life, are retained in tumors at higher levels, remain there longer, and afford higher tumor exposure. The small PEG40kDa nanocarriers studied here show properties for passive targeting of tumors that are superior than most nanoparticles and might be effective probes to identify tumors susceptible to a similar size therapeutic nanocarriers such as PLX038.
关键词： nanoparticle,imaging,Enhanced permeability and retention,tumor,pharmacokinetics,theranostics
更新于2025-09-23 15:19:57
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Pharmacokinetic Properties of Fluorescently Labelled Hydroxypropyl-Beta-Cyclodextrin
摘要： 2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is utilized in the formulation of pharmaceutical products and recently orphan designation was granted for the treatment of Niemann–Pick disease, type C. The exact mechanism of HPBCD action and side effects are not completely explained. We used fluorescently labelled hydroxypropyl-beta-cyclodextrin (FITC-HPBCD) to study its pharmacokinetic parameters in mice and compare with native HPBCD data. We found that FITC-HPBCD has fast distribution and elimination, similar to HPBCD. Interestingly animals could be divided into two groups, where the pharmacokinetic parameters followed or did not follow the two-compartment, first-order kinetic model. Tissue distribution studies revealed, that a significant amount of FITC-HPBCD could be detected in kidneys after 60 min treatment, due to its renal excretion. Ex vivo fluorescent imaging showed that fluorescence could be measured in lung, liver, brain and spleen after 30 min of treatment. To model the interaction and cellular distribution of FITC-HPBCD in the wall of blood vessels, we treated human umbilical vein endothelial cells (HUVECs) with FITC-HPBCD and demonstrated for the first time that this compound could be detected in the cytoplasm in small vesicles after 30 min of treatment. FITC-HPBCD has similar pharmacokinetic to HPBCD and can provide new information to the detailed mechanism of action of HPBCD.
关键词： endocytosis,pharmacokinetics,fluorescence,hydroxypropyl-beta-cyclodextrin,HUVECs
更新于2025-09-16 10:30:52
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Intraocular pharmacokinetics of antia??vascular endothelial growth factor agents by intraoperative subretinal versus intravitreal injection in silicone oila??filled eyes of proliferative diabetic retinopathy: a randomized controlled pilot study
摘要： Purpose: Intraoperative subretinal anti-vascular endothelial growth factor (VEGF) injections have been used clinically in some case, but the pharmacokinetic characteristics have not yet been determined. In this pilot study, we investigate the pharmacokinetic parameters of anti-VEGF agents by intraoperative subretinal or intravitreal injection in silicone oil (SiO)-filled eyes of patients with proliferative diabetic retinopathy (PDR). Methods: Randomized controlled trial including 13 patients (16 eyes) with PDR underwent pars plana vitrectomy (PPV) with SiO tamponade and randomly received a subretinal (8 eyes) or intravitreal (8 eyes) conbercept injection (0.5 mg/0.05 ml) intraoperatively. Aqueous humour (AH) was obtained on the 1st, 3rd, 7th, 10th, 14th, 21st and 28th day after the injection. Drug concentrations in the AH were determined by enzyme-linked immunosorbent assay (ELISA). The last best-corrected visual acuity (BCVA) was examined 6 months postoperatively. Results: The clearance rate of anti-VEGF agents by subretinal injection was reduced in vitrectomized eyes with SiO tamponade (p < 0.05). With the same drug dose, subretinal injection (5.49 (cid:1) 6.11 lg/ml) resulted in higher drug concentrations in the AH when compared with intravitreal injection (0.42 (cid:1) 0.46 lg/ml, p = 0.001) 4 weeks after the treatment. The mean residence time last (MRT0-t) by subretinal injection (11.57 (cid:1) 0.83 days) was significantly longer than the mean MRT0-t by intravitreal injection (7.10 (cid:1) 1.00 days, p < 0.001). A self-paired analysis showed that subretinal injection led to the BCVA improvement by +28.59 letters 6 months postoperatively (p = 0.028) while the BCVA did not improve significantly by intravitreal injection (p = 0.715). Conclusions: The drug maintenance phase was prolonged by intraoperative subretinal injection in SiO-filled eyes of PDR. The results suggest that subretinal injection might be a valuable treatment option for the management of PDR.
关键词： proliferative diabetic retinopathy,pharmacokinetics,subretinal injection,anti-VEGF agents,pars plana vitrectomy
更新于2025-09-16 10:30:52
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Gold nanoroda??loaded (PLGA-PEG) nanocapsules as near-infrared controlled release model of anticancer therapeutics
摘要： Despite of high in vitro anticancer efficacy of many chemotherapeutics, their in vivo use is limited due to lack of biocompatibility and tumor targeting. Near-infrared (NIR) photothermally induced phase transition of PLGA-PEG regime was utilized for developing highly efficient photoresponsive drug delivery systems. Co-encapsulation of plasmonic gold nanorods (GNRs), as NIR-trigger, with the novel and highly efficient anticancer drug N′-(2-Methoxybenzylidene)-3-methyl-1-phenyl-H-Thieno[2,3-c]Pyrazole-5-Carbohyd-razide (MTPC) produced NIR-responsive biodegradable polymeric (PLGA-b-PEG) nanocapsules. This remotely controllable drug release significantly enhanced both biodistribution and pharmacokinetics of the hydrophobic drug. Intravenous (IV) injection of the prepared nanocapsules (MTPC/GNRs@PLGA-PEG) to tumor-bearing mice followed by extracorporeal exposure of the tumor to NIR light resulted in highly selective drug accumulation at the tumor sites. In vivo biodistribution and pharmacokinetics utilizing iodine-131 drug-radiolabelling technique revealed a maximum target to non-target ratio (T/NT) of 5.8, 4 h post-injection with maximum drug level in the tumor (6.3 ± 0.6% of the injected dose).
关键词： Pharmacokinetics,Biocompatible polymers,Radiolabelling,NIR-responsive nanocapsules,Biodistribution
更新于2025-09-16 10:30:52
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In vivo evaluation of safety, biodistribution and pharmacokinetics of laser-synthesized gold nanoparticles
摘要： Capable of generating plasmonic and other effects, gold nanostructures can offer a variety of diagnostic and therapy functionalities for biomedical applications, but conventional chemically-synthesized Au nanomaterials cannot always match stringent requirements for toxicity levels and surface conditioning. Laser-synthesized Au nanoparticles (Aunp) present a viable alternative to chemical counterparts and can offer exceptional purity (no trace of contaminants) and unusual surface chemistry making possible direct conjugation with biocompatible polymers (dextran, polyethylene glycol). this work presents the first pharmacokinetics, biodistribution and safety study of laser-ablated dextran-coated Aunp (Aunpd) under intravenous administration in small animal model. our data show that Aunpd are rapidly eliminated from the blood circulation and accumulated preferentially in liver and spleen, without inducing liver or kidney toxicity, as confirmed by the plasmatic ALAT and ASAT activities, and creatininemia values. Despite certain residual accumulation in tissues, we did not detect any sign of histological damage or inflammation in tissues, while IL-6 level confirmed the absence of any chronic inflammation. The safety of AuNPd was confirmed by healthy behavior of animals and the absence of acute and chronic toxicities in liver, spleen and kidneys. our results demonstrate that laser-synthesized Aunp are safe for biological systems, which promises their successful biomedical applications.
关键词： gold nanoparticles,biodistribution,pharmacokinetics,toxicity,laser ablation
更新于2025-09-11 14:15:04
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7.5: Research on Quantum Dots and Phosphor Blend Backlight Module
摘要： DP‐VPA is a phospholipid prodrug of valproic acid (VPA) that is developed as a potential treatment for epilepsy. To characterize the pharmacokinetics and excretion of DP‐VPA, four reliable ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) methods were validated for quantitation of DP‐VPA and its metabolite, VPA, in human plasma, urine, and feces. Protein precipitation and solid‐phase extraction (SPE) were used for extraction of C16, C18 homologs of DP‐VPA and VPA, respectively, from plasma. Urine and fecal homogenate involving the three analytes were efficiently prepared by methanol precipitation. The determinations of C16 DP‐VPA, C18 DP‐VPA, and VPA were performed using the positive multiple reaction monitoring (MRM) mode and the negative single ion monitoring (SIM) mode, respectively. The analytes were separated using gradient elution on C8 or phenyl column. Satisfactory results pertaining to selectivity, linearity, matrix effect, accuracy and precision, recovery, stability, dilution integrity, carryover, and incurred sample analysis (ISR) were obtained. The calibration ranges in human plasma were as follows: 0.00200–1.00 μg/mL for C16 DP‐VPA, 0.0100–5.00 μg/mL for C18 DP‐VPA, and 0.0500–20.0 μg/mL for VPA. The linear ranges in urine and fecal homogenate were 0.00500–2.00 μg/mL and 0.00200–0.800 μg/mL for C16 DP‐VPA, 0.00500–2.00 μg/mL and 0.0100–4.00 μg/mL for C18 DP‐VPA, and 0.200–80.0 μg/mL for VPA, respectively. The intra‐ and inter‐batch coefficients of variation in three matrices ranged from 1.7% to 12.4% while the accuracy values ranged from 85.4% to 111.7%. The developed methods were successfully applied to determine pharmacokinetics of DP‐VPA tablet after a single oral dose of 1200 mg in 12 healthy Chinese subjects under fed condition.
关键词： UPLC–MS/MS,pharmacokinetics,excretion,epilepsy,DP‐VPA
更新于2025-09-11 14:15:04
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<i>In vitro</i> and <i>in vivo</i> phasor analysis of stoichiometry and pharmacokinetics using short lifetime near-infrared dyes and time-gated imaging
摘要： We introduce a simple new approach for time-resolved multiplexed analysis of complex systems using near-infrared (NIR) dyes, applicable to in vitro and in vivo studies. We show that fast and precise in vitro quantification of NIR fluorophores? short (sub-nanosecond) lifetime and stoichiometry can be done using phasor analysis, a computationally efficient and user-friendly representation of complex fluorescence intensity decays obtained with pulsed laser excitation and time-gated camera imaging. We apply this approach to the study of binding equilibria by F?rster resonant energy transfer using two different model systems: primary/secondary antibody binding in vitro and ligand/receptor binding in cell cultures. We then extend it to dynamic imaging of the pharmacokinetics of transferrin engagement with the transferrin receptor in live mice, elucidating the kinetics of differential transferrin accumulation in specific organs, straightforwardly differentiating specific from non-specific binding. Our method, implemented in a freely-available software, has the advantage of time-resolved NIR imaging, including better tissue penetration and background-free imaging, but simplifies and considerably speeds up data processing and interpretation, while remaining quantitative. These advances make this method attractive and of broad applicability for in vitro and in vivo molecular imaging, and could be extended to applications as diverse as image guided-surgery or optical tomography.
关键词： Lifetime,Fluorescence,FRET,Mouse,Phasor,in vivo,binding equilibrium,transferrin,pharmacokinetics,Near-infrared
更新于2025-09-09 09:28:46