Long circulating nanoparticles of etoposide using PLGA‐MPEG and PLGA‐pluronic block copolymers: characterization,drug‐release,blood‐clearance,and biodistribution studies

The anti‐leukemic drug, etoposide (ETO), has variable oral bioavailability ranging from 24–74% with a short terminal half‐life of 1.5 h i.v. necessitating continuous infusion for 24–34 h for the treatment of leukemia. In the present study, etoposide‐loaded PLGA‐based surface‐modified nanoparticles (NPs) with long circulation were designed as an alternative to continuous i.v. administration. PLGA‐mPEG and PLGA‐PLURONIC copolymers were synthesised and used to prepared ETO‐loaded NPs by high‐pressure homogenization. The mean particle size of ETO‐loaded PLGA‐MPEG nanoparticles was 94.02±3.4 nm, with an Entrapment Efficiency (EE) of 71.2% and zeta potential value of −6.9±1.3 mV. ETO‐loaded PLGA‐pluronic nanoparticles had a mean particle size of 148.0±2.1 nm, an EE of 73.12±2.7%, and zeta potential value of −21.5±1.6 mV. In vitro release of the pure drug was complete within 4 h, but was sustained up to 7 days from PLGA‐mPEG nanoparticles and for 5 days from PLGA‐pluronic nanoparticles. Release was first order and followed non‐Fickian diffusion kinetics in both instances. ETO and ETO‐loaded PLGA nanoparticles labeled with ^99mTc were used in blood clearance studies in rats where the two coated NPs, ^99mTc‐ ETO‐PLGA‐PLU NP and ^99mTc‐ ETO‐PLGA‐mPEG NP, were found to be available in higher concentrations in the circulation as compared to the pure drug. Biodistribution studies in mice showed that ETO‐loaded PLGA‐MPEG NP and PLGA‐PLURONIC NP had reduced uptake by the RES due to their steric barrier properties and were present in the circulation for a longer time. Moreover, the NPs had greater uptake in bone and brain where concentration of the free drug, ETO, was negligible. Drug delivered from these NPs could result in a single i.v. injection that would release the drug for a number of days, which would be potentially beneficial and in better control of leukemia therapy. Drug Dev Res 71: 228–239, 2010. © 2010 Wiley‐Liss, Inc.     

Preparation and in‐vitro/in‐vivo evaluation of surface‐modified poly (lactide‐co‐glycolide) fluorescent nanoparticles

Objective The aim was to develop biodegradable nanoparticles suitable for cellular delivery of chemotherapeutic drugs. Methods Poly (lactide‐co‐glycolide) (PLGA) nanoparticles were prepared using a modified solvent evaporation method. Chitosan and calcium chloride were tested as surface modifiers. Coumarin‐6 was incorporated into some formulations as a fluorescent marker. Key findings The median size of the particles was between 400 nm and 7 μm, and scanning electron microscope pictures showed that the particles were smooth and spherical. The zeta potentials of the particles with and without surface modifier ranged between ‐25.7 mV and ‐7.0 mV, respectively. Fluorescence microscopy and flow cytometry (FACS) analysis showed that smaller surface‐modified particles were efficiently internalised by neoplastic 4T1 cells. Image analysis of frozen tissue sections from Balb/c mice given nanoparticles via the tail vein showed that the particles were distributed preferentially into the lungs, followed by the liver, spleen, kidney and heart. Conclusions Chitosan‐modified PLGA nanoparticles showed significant uptake by neoplastic 4T1 cells, and were distributed to several major organs frequently seen as sites of cancer metastasis in mice.     

Preparation of carboxy‐PEG‐PLA nanoparticles loaded with camptothecin and their body distribution in solid tumor–bearing mice

Carboxy‐polyethylene glycol‐poly(DL‐lactic acid) block copolymer was synthesized by reductive amination of carboxy‐polyethylene glycol‐amine and aldehyde‐ended poly(DL‐lactic acid). The obtained product, PA‐PEG‐CB, composed of pure carboxy‐polyethylene glycol‐poly(DL‐lactic acid) block copolymer and poly(DL‐lactic acid), was used to prepare nanoparticles loaded with camptothecin (CPT), designated CPT‐NP. CPT‐NP with 500–600 nm and approximately 1% (w/w) drug content were obtained by emulsification/evaporation, while nanoparticles with a drug content of only less than 0.1% (w/w) were prepared by dialysis. CPT‐NP produced by emulsification/evaporation were used for in vitro and in vivo studies. CPT‐NP released CPT gradually in phosphate‐buffered saline, pH 7.4, at 37°C over 48 h. Biodistribution profiles were compared between CPT‐NP and CPT solution after i.v. injection into mice bearing sarcoma 180 solid tumor. CPT‐NP retained CPT approximately 10 times more in plasma during the initial 8 h than CPT solution. The tumor level of CPT was more than 10 times higher with CPT‐NP for the observation period (24 h), though the CPT concentration in the liver and spleen was much higher with CPT‐NP. CPT‐NP may be useful for tumor localization of CPT. Drug Dev Res 70: 512–519, 2009. © 2009 Wiley‐Liss, Inc.     

Synthesis and biological evaluation of a series of 99mTc‐labeled diphosphonates as novel radiotracers with improved bone imaging

Three radiolabeled diphosphonates, ^99mTc‐labeled 1‐hydroxy‐3‐(2‐propyl‐1H‐imidazol‐1‐yl)propane‐1,1‐diyldiphosphonic acid (PIPrDP), 1‐hydroxy‐4‐(2‐propyl‐1H‐imidazol‐1‐yl)butane‐1,1‐diyldiphosphonic acid (PIBDP), and 1‐hydroxy‐5‐(2‐propyl‐1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid (PIPeDP), have been designed and synthesized with good chemical yields and high radiochemical purity. Their in vitro and in vivo biological properties were investigated and compared. All radiotracers evaluated in mice showed substantial retention in bone (8.42 ± 0.53, 9.08 ± 0.65, and 10.3 ± 0.61 ID%/g, respectively) at 1 h post‐injection and had rapid clearance in blood (1.9484, 1.3666, and 0.7704 ID%/g/min, respectively). ^99mTc‐PIBDP has the highest uptake ratio of bone‐to‐soft tissue at 1 h post‐injection among the three radiotracers. The results indicate that ^99mTc‐PIBDP is the most promising bone imaging agent. Copyright © 2012 John Wiley & Sons, Ltd.     

Brain‐targeted distribution and high retention of silver by chronic intranasal instillation of silver nanoparticles and ions in Sprague–Dawley rats

The wide applications of silver nanoparticles (AgNPs) have been concerned regarding their unintentional toxicities. Different exposure modes may cause distinct accumulation, retention and elimination profiles, which are closely related with their toxicities. Unlike silver accumulation profiles through other regular administration modes, the biodistribution, accumulation and elimination of AgNPs by intranasal instillation are not fully understood. This study conducted intranasal instillation of polyvinylpyrrolidone‐coated AgNPs in neonatal Sprague–Dawley rats at doses of 1 and 0.1 mg kg^?1 day^?1 for 4 and 12 weeks, respectively. The 4‐week recovery was also designed after the 12‐week exposure. Silver concentrations in the main tissues or organs were periodically monitored. Parallel exposures using silver ion were performed for the comparative studies. No physiological alterations were observed in AgNP exposures. In comparison, 1 mg kg^?1 day^?1 silver ions decreased body weight gain and caused mortality of 18.2%, showing ionic silver had a relatively higher toxicity than AgNPs. A relatively higher silver accumulation was observed in silver ion groups than AgNP groups. The silver ion release could not fully explain silver accumulation in AgNP exposures, showing silver distribution caused by particulate silver occurred in vivo. The highest silver concentration was in the liver at week 4, while it shifted to the brain after a 12‐week exposure. Dose‐related silver accumulation occurred for both AgNP and silver ion groups. The time course revealed a uniquely high concentration and retention of brain silver, implying chronic intranasal instillation caused brain‐targeted silver accumulation. These findings provided substantial evidence on the potential neuronal threat from the intranasal administration of AgNPs or silver colloid‐based products. Copyright © 2015 John Wiley & Sons, Ltd.     

Preparation of [11C]formaldehyde using a silver‐containing ceramic catalyst

A ceramic material, prepared from kaolin doped with silver ions in various concentrations, was evaluated as a catalyst for the conversion of [¹¹C] methanol into [¹¹C]formaldehyde in a gas flow system. Employment of [¹¹C] methanol with a minimized water content, 300 mg of catalyst (20% of silver) at 500°C and a carrier gas flow rate of 40 mL/min resulted in a radiochemical decay‐corrected [¹¹C]formaldehyde yield of 67% relative to [¹¹C]methanol. Wet [¹¹C]methanol under the same conditions gave 54% of [¹¹C] formaldehyde. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and pharmacological evaluation of 99mTc‐labeled imidazolyl‐containing diphosphonic acid as a novel bone imaging agent

In order to develop a superior bone imaging agent, a new radiotracer ^99mTc‐1‐hydroxy‐5‐(2‐butyl‐1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid (BIPeDP) was designed and prepared with good radiochemical yield and stability. The biodistribution in mice shows that ^99mTc‐BIPeDP has high specificity in the skeleton with the maximum uptake of 17.30 ± 0.14 injected dose per gram at 60 min. Kinetics of blood clearance shows that the distribution half‐life (T_1/2α) and elimination half‐life (T_1/2β) of ^99mTc‐BIPeDP are 3.7 and 49.7 min, respectively. An excellent image can be obtained at 1‐h post‐injection with the single photon emission computed tomography bone scanning, which is clearer and quicker than ^99mTc‐zoledronic acid, ^99mTc‐1‐hydroxy‐5‐(1H‐imidazol‐1‐yl)pentane‐1,1‐diyldiphosphonic acid, and ^99mTc‐methylenediphosphonic acid All results indicate that ^99mTc‐BIPeDP holds great potential as a novel promising bone imaging agent. Copyright © 2013 John Wiley & Sons, Ltd.     

Preparation and biological evaluation of 99mTcN‐4‐(cyclohexylpiperazin‐1‐yl)‐dithioformate as a potential sigma receptor imaging agent

The goal of this study is to develop a novel ^99mTc‐labeled σ receptor imaging agent. Potassium 4‐(cyclohexylpiperazin‐1‐yl)‐dithioformate, 2 , and the corresponding rhenium complex, ReN‐2 , were synthesized and characterized. ReN‐2 possessed moderate affinity toward σ₁ (K_i = 1.94 ± 0.60 µmol/L) and σ₂ (K_i = 2.83 ± 1.39 µmol/L) receptors. The radiolabeled complex ^99m TcN‐2 was prepared in high yield (> 95%) through the [^99mTcN] precursor and characterized by HPLC. ^99m TcN‐2 was found to be a lipophilic and neutral complex with good stability. The biodistribution in tumor‐bearing mice showed that ^99m TcN‐2 had good tumor uptake (2.12 ± 0.01 %ID/g at 2 h p.i.) and moderate brain uptake (0.27 ± 0.05 %ID/g at 2 h p.i.). After blocking with haloperidol, the uptakes by tumor and brain were lower than control. The results indicated that the complex has specific binding to the σ receptors in vivo. Further structural modifications of this complex are needed to obtain ^99mTc‐based σ receptor imaging agents with high affinity and subtype selectivity. Copyright © 2007 John Wiley & Sons, Ltd.     

Preparation and in vivo biological investigation of 99mTc‐HEIDP as a novel radioligand for bone scanning

A novel diphosphonic acid, 1‐hydroxy‐2‐(1‐ethyl‐imidazol‐2‐yl) ethane‐1,1‐diphosphonic acid (HEIDP), was prepared and labeled with ^99mTc in a high labeling yield under optimized labeling conditions. The biodistribution in mice shows that ^99mTc‐HEIDP has high specificity and efficacy in bone and joint uptake with 5.73 and 9.93%ID/g at 5 min, which increases continuously to a maximum of 7.62 and 18.0%ID/g at 30 min, respectively. Kinetics of blood clearance showed that distribution half‐life (T_1/2α) and elimination half‐life (T_1/2β) of ^99mTc‐HEIDP were 9.91 and 81.1 min, respectively. The total clearance rate was 1.94%ID/g?min^‐1. A plain and clear bone image was obtained at 1 h by using single photon emission computed tomography. All results indicate that ^99mTc‐HEIDP holds potential as a superior tracer agent for bone scanning. Copyright © 2012 John Wiley & Sons, Ltd.     

Plasma pharmacokinetics and tissue distribution of [6]‐gingerol in rats

[6]‐Gingerol is one of the pungent components in ginger which has been found to possess various pharmacological effects. However, there is insufficient information on the properties of [6]‐gingerol based on controlled pharmacokinetic studies. The aim of this study was to clarify distribution profiles of [6]‐gingerol in blood and biological tissues of experimental rats. Rats were administered a 240 mg/kg dose of Gs (a ginger extract, containing 53% [6]‐gingerol) by oral ingestion. Plasma samples were collected at 2.5, 5, 7.5, 10, 15, 20, 30, 45 min, and 1, 1.5, 2, 3, 4 h after dosing (eight samples per time point), and brain, heart, lung, spleen, liver, kidney, stomach and small intestine tissues were collected at 5, 15, 30 min and 1, 2, 4 h after dosing (five animals per time point). Samples were prepared by a liquid‐liquid extraction procedure and the extracts were assayed by HPLC‐UV. After per oral application, [6]‐gingerol was absorbed rapidly into the plasma, and the maximal concentration (4.23 µg/ml) was reached after 10 min post dosing. [6]‐Gingerol plasma concentrations declined with time in a biexponential pattern. The elimination half‐time at the terminal phase was 1.77 h and the apparent total body clearance was 40.8 l/h. When administered orally, [6]‐gingerol was well distributed to the tissues examined, with the highest concentrations found in the gastrointestinal tract. Maximal concentrations of [6]‐gingerol were reached in most tissues at 0.5 h post‐dosing. The concentrations of [6]‐gingerol in tissues all were higher than in plasma with corresponding tissue to plasma ratios greater than 1 after 0.25 h post‐dose, showing high tissue partitioning and extensive distribution. Copyright © 2008 John Wiley & Sons, Ltd.     

Pharmacokinetics and bio‐distribution of novel super paramagnetic iron oxide nanoparticles (SPIONs) in the anaesthetized pig

Manufactured nanomaterials have a variety of medical applications, including diagnosis and targeted treatment of cancer. A series of experiments were conducted to determine the pharmacokinetic, biodistribution and biocompatibility of two novel magnetic nanoparticles (MNPs) in the anaesthetized pig. Dimercaptosuccinic acid (DMSA) coated superparamagnetic iron oxide nanoparticles (MF66‐labelled 12 nm, core nominal diameter and OD15 15 nm); at 0.5, or 2.0 mg/kg) were injected intravenously. Particles induced a dose‐dependent decrease in blood pressure following administration which recovered to control levels several minutes after injection. Blood samples were collected for a 5‐h period and stored for determination of particle concentration using particle electron paramagnetic resonance (pEPR). Organs were harvested post‐mortem for magnetic resonance imaging (MRI at 1.5 T field strength) and histology. OD15 (2.0 mg/kg) MNP had a plasma half‐life of approximately 15 min. Both doses of the MF66 (0.5 and 2.0 mg/kg) MNP were below detection limits. MNP accumulation was observed primarily in the liver and spleen with MRI scans which was confirmed by histology. MRI also showed that both MNPs were present in the lungs. The results show that further modifications may be required to improve the biocompatibility of these particles for use as diagnostic and therapeutic agents.     

Comparative biodistribution studies of technetium‐99 m radiolabeled amphiphilic nanoparticles using three different reducing agents during the labeling procedure

Considering the confusing biodistribution data through the literature and few reported alerts as well as our preliminary biodistribution results, we decided to evaluate the interaction and interference of the commonly present ^99mTc (technetium‐99m)‐stannic oxide colloid during the direct stannous chloride ^99mTc‐labeling procedure and to assess its influence on the biodistribution pattern of amphiphilic poly(lactic‐co‐glycolic acid) nanoparticles. In order to confirm our thesis, beside stannous chloride, we employed two different reducing agents that don't form colloidal particles. The use of sodium borohydride was previously reported in the literature, whereas sodium dithionite was adapted for the first time in the ^99mTc direct labeling procedure for nanoparticles. The results in our paper clearly differentiate among samples with and without colloidal impurities originating from the labeling procedure with a logical follow up of the radiochemical, physicochemical evaluation, and biodistribution studies clarifying previously reported data on stannic oxide colloidal interference. ^99mTc‐nanoparticle complex labeled with sodium dithionite as reducing agent illustrated appropriate labeling efficacy, stability, and potential for further use in biodistribution studies thus providing solution for the problem of low‐complex stability when sodium borohydride is used and colloidal stannic oxide interference for stannous chloride procedure. Copyright © 2013 John Wiley & Sons, Ltd.     

Evaluation of percutaneous absorption of the repellent diethyltoluamide and the sunscreen ethylhexyl p‐methoxycinnamate‐loaded solid lipid nanoparticles: an in‐vitro study

Objectives Diethyltoluamide and ethylhexyl p‐methoxycinnamate (OMC) are two active ingredients in insect repellent and sunscreen products, respectively. The concurrent application of these two substances often increases their systemic absorption, compromising the safety and efficiency of the cosmetic product. In this study, diethyltoluamide and OMC were incorporated into solid lipid nanoparticles, a colloidal drug delivery system, to reduce percutaneous absorption and avoid toxic effects and also maintain the efficacy of the two active compounds on the skin surface for a long duration. Methods Solid lipid nanoparticles were prepared based on an ultrasonication technique and characterized by differential scanning calorimetry (DSC) analyses. In‐vitro studies determined the percutaneous absorption of diethyltoluamide and OMC. Key findings DSC data carried out on unloaded and diethyltoluamide‐ and/or OMC‐loaded solid lipid nanoparticles highlighted that diethyltoluamide and OMC modified the temperature and the enthalpy change associated to the calorimetric peak of solid lipid nanoparticles. The concurrent presence of the two compounds in the solid lipid nanoparticles caused a synergic effect, indicating that the lipid matrix of nanoparticles guaranteed a high encapsulation of both diethyltoluamide and OMC. Results from the in‐vitro study demonstrated that the particles were able to reduce the skin permeation of the two cosmetic ingredients in comparison with an oil‐in‐water emulsion. Conclusions This study has provided supplementary evidence as to the potential of lipid nanoparticles as carriers for topical administration of cosmetic active compounds.     

Comparison of distribution and toxicity of different types of zinc‐based nanoparticles

Zinc‐based nanoparticles (Zn‐NPs), mainly zinc oxide (ZnO) NPs, have promising application in a wide area, but their potential harmful effects on environment and human health have been continuously raised together with their high dissolution rate. In this study, we coated the surface of ZnO NPs with phosphate (ZnP NPs) and sulfide (ZnS NPs) which have very low solubility in water, administered orally (0.5 and 1 mg/kg) to mice for 28 days, and then compared their biodistribution and toxicity. As expected, ZnO NPs were rapidly ionized in an artificial gastric fluid. On the other hand, ZnO NPs were more particlized in an artificial intestinal fluid than ZnP and ZnS NPs. After repeated dosing, all three types of Zn‐NPs the most distributed in the spleen and thymus and altered the level of redox reaction‐related metal ions in the tissues. We also found that three types of Zn‐NPs clearly disturb tissue ion homeostasis and influence immune regulation function. However, there were no remarkable difference in distribution and toxicity following repeated exposure of three types of Zn‐NPs, although Na+ and K+ level in the spleen and thymus were notably higher in mice exposed to ZnO NPs compared to ZnP and ZnS NPs. Taken together, we suggest that all three types of Zn‐NPs may influence human health by disrupting homeostasis of trace elements and ions in the tissues. In addition, the surface transformation of ZnO NPs with phosphate and sulfide may not attenuate toxicity due to the higher particlization rate of ZnO NPs in the intestine, at least in part. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1363–1374, 2017.     

Radiosynthesis of 3‐(3‐[18F]fluoropropoxy)‐4‐(benzyloxy)‐N‐[(1‐dimethylaminocyclopentyl)methyl]‐5‐methoxybenzamide,a potential PET radiotracer for the glycine transporter GlyT‐2

The recently described selective and potent GlyT2 antagonist, 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide (IC₅₀=16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT‐2 transporter, 3‐(3‐[¹⁸F]fluoropropoxy)‐4‐(benzyloxy)‐N‐((1‐dimethylaminocyclopentyl) methyl)‐5‐methoxybenzamide ([¹⁸F] 3 ), a novel analog of 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one‐pot, two‐step method. The NCA radiofluorination of 1,3‐propanediol di‐p‐tosylate in the presence of K₂CO₃ and Kryptofix‐222 in acetonitrile gave 81% 3‐[¹⁸F]fluoropropyl tosylate, which was subsequently coupled with 4‐benzyloxy‐3‐hydroxy‐5‐methoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB‐C8 column, 80/20/0.1 MeOH/H₂O/Et₃N, 3.0 ml/min) gave [¹⁸F] 3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0–16.2% at EOS, and the specific activity was 1462±342 GBq/µmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis,preclinical, and pharmacokinetic evaluation of a new zoledronate derivative as a promising antiosteoporotic candidate using radiolabeling technique

A novel zoledronic acid (ZL) derivative, 3‐(2‐ethyl‐4‐methyi‐1H‐imidazole‐1‐yl)‐1‐hydroxy‐1‐phosphonopropyl phosphonic acid (EMIHPBP), was synthesized, characterized, and successfully radiolabeled with ^99mTc. The in vivo biodistribution of ^99mTc‐EMIHPBP was investigated and compared with the previously reported zoledronate derivatives aiming to formulate a novel zoledronate derivative with a high‐potential uptake to bone as a promising antiosteoporotic candidate. To further evaluate the bone uptake efficiency, the pharmacokinetics of ^99mTc‐EMIHPBP was investigated and showed that maximum concentration in bone (C_max) was 31.60 ± 0.15%ID/gram after 60 minutes (t_max). Cumulative residence of ^99mTc‐EMIHPBP in the bone [AUC _(0−∞) (%ID∙min/gram bone)] was 3685.23, mean residence time was 384.354 minutes, and the calculated bone bioavailability was 15.831%. Finally, the time needed for half of the ^99mTc‐EMIHPBP formulation to be eliminated from bone (t_1/2) was 263.914 minutes. Excellent bone uptake can be obtained 1‐hour postinjection with high bone/blood ratio of 23.76 detected with gamma counter. The biodistribution and kinetic studies could recommend EMIHPBP as a promising antiosteoporotic candidate with high selectivity to the skeletal system and rapid clearance from soft tissues.