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Abstract Mesenchymal stem cells (MSCs) have demonstrated promising advantages in the therapies of many diseases, while its multi-directional differentiation potential and immunotoxicity are the major concerns hindered their clinical translation. In this study, human umbilical Mesenchymal stem cell (hUC-MSCs) were labeled with a near-infrared fluorescent dye DiR before infused into cynomolgus monkeys, and the amount of hUC-MSCs in the peripheral blood were dynamically estimated from 5 min to 28 days post a single administration at 3 × 106 cells/kg and 2 × 107 cells/kg intravenously. As results, some hUC-MSCs distributed to the whole body within 5 min, while most of the cells accumulate in the lungs along with the systemic blood circulation, and subsequently released into the blood. The toxicity potentials of hUC-MSCs were investigated in another 30 cynomolgus monkeys, and the cells were repeatedly administrated at doses of 3 × 106 cells/kg and 2 × 107 cells/kg for 5 times on a weekly basis, with a recovery period of 1 months. hUC-MSCs showed no obvious toxic effects in cynomolgus monkeys, except xenogeneic immune rejection to human stem cells. Low levels of the hUC-MSC gene were detected in the peripheral blood of a few animals administered 2 × 107 cells/kg at 30 min subsequent to the first and last administration, and there was no significant difference in the copy number of the hUC-MSC gene in the blood samples compared with the first and last administration, indicating that the hUC-MSC was not significantly amplified in vivo, and it its safe in non-human primates. Our study for the first time verified the safety of long-term use of hUC-MSCs in primates. We have pioneered a technology for the real-time detection of hUC-MSCs in peripheral blood and provide dynamicand rapid monitoring of the distribution characteristics of hUC-MSCs in vivo. Here, we provide data supporting the application of such products for clinical treatment and the application of stem cells in major refractory diseases and regenerative medicine.

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have demonstrated promising advantages in the therapies of many diseases, while its multi-directional differentiation potential and immunotoxicity are the major concerns hindered their clinical translation. In this study, human umbilical Mesenchymal stem cell (hUC-MSCs) were labeled with a near-infrared fluorescent dye DiR before infused into cynomolgus monkeys, and the amount of hUC-MSCs in the peripheral blood were dynamically estimated from 5 min to 28 days post a single administration at 3 × 106 cells/kg and 2 × 107 cells/kg intravenously. As results, some hUC-MSCs distributed to the whole body within 5 min, while most of the cells accumulate in the lungs along with the systemic blood circulation, and subsequently released into the blood. The toxicity potentials of hUC-MSCs were investigated in another 30 cynomolgus monkeys, and the cells were repeatedly administrated at doses of 3 × 106 cells/kg and 2 × 107 cells/kg for 5 times on a weekly basis, with a recovery period of 1 months. hUC-MSCs showed no obvious toxic effects in cynomolgus monkeys, except xenogeneic immune rejection to human stem cells. Low levels of the hUC-MSC gene were detected in the peripheral blood of a few animals administered 2 × 107 cells/kg at 30 min subsequent to the first and last administration, and there was no significant difference in the copy number of the hUC-MSC gene in the blood samples compared with the first and last administration, indicating that the hUC-MSC was not significantly amplified in vivo, and it its safe in non-human primates. Our study for the first time verified the safety of long-term use of hUC-MSCs in primates. We have pioneered a technology for the real-time detection of hUC-MSCs in peripheral blood and provide dynamicand rapid monitoring of the distribution characteristics of hUC-MSCs in vivo. Here, we provide data supporting the application of such products for clinical treatment and the application of stem cells in major refractory diseases and regenerative medicine. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain. [ABSTRACT FROM AUTHOR]

This research work is focused on pharmacokinetic and biochemical experiments to assess baicalin-loaded lipid–polymer hybrid nanoparticles (LPHNPs) with colon-targeting specificity. The nanoprecipitation method was used to develop the LPHNPs, and the characterized formulation revealed the 184.3 nm particle size, PDI of 0.177, spherical shape, and zeta potential of −19.8 mV. The baicalin LPHNPs are said to be poorly absorbed in the stomach and small intestine, and in vitro drug release tests have shown that the drug is released mostly in the caecal fluid. Additionally, the LPHNPs showed stability and nonsignificant drug loss at 25 °C for 3 months. The least viable population of baicalin-loaded LPHNPs was detected at a lower IC50 value after 48 h, and no cytotoxicity was observed by blank suspension and blank LPHNPs up to the concentration of 100 µg/mL. Apart from this, the pharmacokinetics study showed that baicalin from LPHNPs is much less absorbed and least available in the blood plasma and maximum available in the colon. Concurrently, organ distribution studies demonstrated that baicalin-loaded LPHNPs were distributed more widely in the colon compared to baicalin suspension. Moreover, baicalin-loaded LPHNPs were found to be superior to a baicalin suspension in reducing elevated liver enzyme levels. In a nutshell, baicalin-loaded LPHNPs show superior efficacy and can be maximally localized into the colon rectal cancer along with systemic availability of the drug. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

Archaeosomes, composed of sulfated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. They have classically been prepared using a thin-film hydration method with an average particle size of 100–200 nm. In this study, we developed methods to generate SLA archaeosomes at different sizes, i.e., 30 nm and 100 nm, via microfluidic mixing technology and evaluated their physicochemical characteristics, as well as adjuvant activity and in vivo biodistribution in mice. Archaeosomes, prepared using thin-film and microfluidic mixing techniques, had similar nanostructures and physicochemical characteristics, with both appearing stable during the course of this study when stored at 4 °C or 37 °C. They also demonstrated similar adjuvant activity when admixed with ovalbumin antigen and used to immunize mice, generating equivalent antigen-specific immune responses. Archaeosomes, labeled with CellVueTM NIR815, had an equivalent biodistribution with both sizes, namely the highest signal at the injection site at 24 h post injection, followed by liver, spleen and inguinal lymph node. The presence of SLA archaeosomes of either size helped to retain OVA antigen (OVA-Cy5.5) longer at the injection site than unadjuvanted OVA. Overall, archaeosomes of two sizes (30 nm and 100 nm) prepared using microfluidic mixing maintained similar physicochemical properties, adjuvant activity and biodistribution of antigen, in comparison to those compared by the conventional thin film hydration method. This suggests that microfluidics based approaches could be applied to generate consistently sized archaeosomes for use as a vaccine adjuvant. [ABSTRACT FROM AUTHOR]

Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined. Results In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not. Conclusion The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.

Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The success of this therapy depends on efficient tumor-antigen presentation to cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the DCs. Therefore, simulation of such a biological system by computational modeling is appealing because it can improve our understanding of the molecular mechanisms underlying CTL induction by DCs and help identify new strategies to improve therapeutic DC vaccination for cancer. Here, we developed a multi-level model accounting for the life cycle of DCs during anti-cancer immunotherapy. Specifically, the model is composed of three parts representing different stages of DC immunotherapy – the spreading and bio-distribution of intravenously injected DCs in human organs, the biochemical reactions regulating the DCs’ maturation and activation, and DC-mediated activation of CTLs. We calibrated the model using quantitative experimental data that account for the activation of key molecular circuits within DCs, the bio-distribution of DCs in the body, and the interaction between DCs and T cells. We showed how such a data-driven model can be exploited in combination with sensitivity analysis and model simulations to identify targets for enhancing anti-cancer DC vaccination. Since other previous works show how modeling improves therapy schedules and DC dosage, we here focused on the molecular optimization of the therapy. In line with this, we simulated the effect in DC vaccination of the concerted modulation of combined intracellular regulatory processes and proposed several possibilities that can enhance DC-mediated immunogenicity. Taken together, we present a comprehensive time-resolved multi-level model for studying DC vaccination in melanoma. Although the model is not intended for personalized patient therapy, it could be used as a tool for identifying molecular targets for optimizing DC-based therapy for cancer, which ultimately should be tested in in vitro and in vivo experiments.

Ting Zhou,1,* Wei Zhang,1,* Dongliang Cheng,1 Xin Tang,2 Jianfang Feng,3 Wei Wu1 1School of Pharmacy, Guilin Medical University, Guilin 541004, People’s Republic of China; 2School of Public Health, Guilin Medical University, Guilin 541004, People’s Republic of China; 3School of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei WuSchool of Pharmacy, Guilin Medical University, 109 North 2nd Huancheng Road, Guilin 541004, People’s Republic of ChinaEmail wuwei@glmc.edu.cnJianfang FengSchool of Pharmacy, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning 530200, People’s Republic of ChinaEmail fengjianfang@vip.163.comPurpose: In this study, NK4-conjugated hydroxycamptothecin liposomes (NK4-HCPT-Lips) were prepared with the aim of improving drug targeting to the liver.Methods: NK4-HCPT-Lips were prepared using the thin-film dispersion method. In vitro antitumor activities were evaluated by MTT assay. HCPT levels in plasma and tissues were determined via high-performance liquid chromatography (HPLC) with camptothecin as the internal standard, and the characteristics, pharmacokinetics, and bio-distribution of NK4-HCPT-Lips were evaluated.Results: The liposomes showed a regular spherical-shaped morphology, and the entrapment efficiency and drug loading capacity reached 82.5 ± 2.4% and 3.01 ± 0.23%, respectively, with a particle size of 155.6 ± 2.6 nm and a zeta potential of − 24.8 ± 3.3 mV. Inhibition effect experiments found that NK4-HCPT-Lips had a good inhibition on the HepG2 cells. Pharmacokinetic studies revealed an increase in the area under the curve and mean residence time as well as a decrease in plasma clearance (p < 0.05) of the NK4-HCPT-Lips compared to those of HCPT liposomes and a commercial HCPT injection. Tissue distribution studies showed that NK4-HCPT-Lips were present at high levels in the liver but were cleared from the kidneys.Conclusion: These results demonstrate that NK4-HCPT-Lips possess excellent liver-targeting attributes, which could enhance the therapeutic effects of drug treatments for hepatic diseases.Keywords: hydroxycamptothecin, NK4, liposomes, pharmacokinetics, bio-distribution

A simple, rapid, sensitive, robust and reproducible and specific high-performance liquid chromatography (HPLC) analysis method for the simultaneous determination of Curcumin (CU) and Paclitaxel (PTX) was developed and validated. After pretreating with citric acid/trisodium citrate (CA) buffer (pH 3.6) as stabilizer and extracting from the biosamples with ethyl acetate/methanol (90/10, v/v), CU and PTX were chromatographed on a Luna C18 column (4.6 mm × 250 mm, 5 µm) at a flow rate of 1 mL·min−1 with acetonitrile (A)/triethylamine phosphate buffer (pH 3.5; 0.012 M) (B) as the mobile phase by variable wavelength and gradient elution method of 0–9.5 (min)/55% A–45% B at 425 nm, 9.51–11.5 (min)/40% A–60% B at 227 nm, 11.51–19.0 (min)/55% A–45% B at 425 nm. The method was validated related to linearity, accuracy, precision and stability. After pretreatment, CU and PTX were stable in biological samples at room temperature for 24 h and at – 20 °C storage for 7 days. Besides, compared to CU or PTX alone, an altered pharmacokinetics in rabbits and bio-distribution behavior in rats by co-administration were observed, and its influence rules and mechanisms still need further study. [ABSTRACT FROM AUTHOR]

Archaeosomes, composed of sulfated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. They have classically been prepared using a thin-film hydration method with an average particle size of 100–200 nm. In this study, we developed methods to generate SLA archaeosomes at different sizes, i.e., 30 nm and 100 nm, via microfluidic mixing technology and evaluated their physicochemical characteristics, as well as adjuvant activity and in vivo biodistribution in mice. Archaeosomes, prepared using thin-film and microfluidic mixing techniques, had similar nanostructures and physicochemical characteristics, with both appearing stable during the course of this study when stored at 4 °C or 37 °C. They also demonstrated similar adjuvant activity when admixed with ovalbumin antigen and used to immunize mice, generating equivalent antigen-specific immune responses. Archaeosomes, labeled with CellVueTM NIR815, had an equivalent biodistribution with both sizes, namely the highest signal at the injection site at 24 h post injection, followed by liver, spleen and inguinal lymph node. The presence of SLA archaeosomes of either size helped to retain OVA antigen (OVA-Cy5.5) longer at the injection site than unadjuvanted OVA. Overall, archaeosomes of two sizes (30 nm and 100 nm) prepared using microfluidic mixing maintained similar physicochemical properties, adjuvant activity and biodistribution of antigen, in comparison to those compared by the conventional thin film hydration method. This suggests that microfluidics based approaches could be applied to generate consistently sized archaeosomes for use as a vaccine adjuvant.

Background: Uncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined. Results: In this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not. Conclusion: The i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects. [ABSTRACT FROM AUTHOR]

Iron oxide and other ferrite nanoparticles have not yet found widespread application in the medical field since the translation process faces several big hurdles. The incomplete knowledge of the interactions between nanoparticles and living organisms is an unfavorable factor. This complex subject should be made simpler by synthesizing magnetic nanoparticles with good physical (relaxivity) and chemical (colloidal stability, anti-fouling) properties and no biological activity (no immune-related effects, minimal internalization, fast clearance). Such an innocent scaffold is the main aim of the present paper. We systematically searched for it within the class of small-to-medium size ferrite nanoparticles coated by small (zwitter)ionic ligands. Once established, it can be functionalized to achieve targeting, drug delivery, etc. and the observed biological effects will be traced back to the functional molecules only, as the nanosized scaffold is innocent. We synthesized nine types of magnetic nanoparticles by systematic variation of core composition, size, coating. We investigated their physico-chemical properties and interaction with serum proteins, phagocytic microglial cells, and a human model of inflammation and studied their biodistribution and clearance in healthy mice. The nanoparticles have good magnetic properties and their surface charge is determined by the preferential adsorption of anions. All nanoparticle types can be considered as immunologically safe, an indispensable pre-requisite for medical applications in humans. All but one type display low internalization by microglial BV2 cells, a process strongly affected by the nanoparticle size. Both small (3 nm) and medium size (11 nm) zwitterionic nanoparticles are in part captured by the mononuclear phagocyte system (liver and spleen) and in part rapidly (≈1 h) excreted through the urinary system of mice. The latter result questions the universality of the accepted size threshold for the renal clearance of nanoparticles (5.5 nm). We suggest that it depends on the nature of the circulating particles. Renal filterability of medium-size magnetic nanoparticles is appealing because they share with small nanoparticles the decreased accumulation-related toxicity while performing better as magnetic diagnostic/therapeutic agents thanks to their larger magnetic moment. In conclusion, many of our nanoparticle types are a bio-compatible innocent scaffold with unexpectedly favorable clearance. [ABSTRACT FROM AUTHOR]

Xiaolin Zhang,1,2,* Jiankang Song,3,* Alexey Klymov,3,* Yang Zhang,3 Leonie de Boer,1 John A Jansen,3 Jeroen JJP van den Beucken,3 Fang Yang,3 Sebastian AJ Zaat,1,* Sander CG Leeuwenburgh3,* 1Department of Medical Microbiology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 2Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands; 3Department of Biomaterials, Radboud University Medical Centre, Nijmegen, the Netherlands *These authors contributed equally to this work Background: Infections such as biomaterial-associated infection and osteomyelitis are often associated with intracellular survival of bacteria (eg, Staphylococcus aureus). Treatment of these infections remains a major challenge due to the low intracellular efficacy of many antibiotics. Therefore, local delivery systems are urgently required to improve the therapeutic efficacy of antibiotics by enabling their intracellular delivery. Purpose: To assess the potential of gelatin nanospheres as carriers for local delivery of vancomycin into macrophages of zebrafish larvae in vivo and into THP-1-derived macrophages in vitro using fluorescence microscopy. Materials and methods: Fluorescently labeled gelatin nanospheres were prepared and injected into transgenic zebrafish larvae with fluorescent macrophages. Both the biodistribution of gelatin nanospheres in zebrafish larvae and the co-localization of vancomycin-loaded gelatin nanospheres with zebrafish macrophages in vivo and uptake by THP-1-derived macrophages in vitro were studied. In addition, the effect of treatment with vancomycin-loaded gelatin nanospheres on survival of S. aureus-infected zebrafish larvae was investigated. Results: Internalization of vancomycin-loaded gelatin nanospheres by macrophages was observed qualitatively both in vivo and in vitro. Systemically delivered vancomycin, on the other hand, was hardly internalized by macrophages without the use of gelatin nanospheres. Treatment with a single dose of vancomycin-loaded gelatin nanospheres delayed the mortality of S. aureus-infected zebrafish larvae, indicating the improved therapeutic efficacy of vancomycin against (intracellular) S. aureus infection in vivo. Conclusion: The present study demonstrates that gelatin nanospheres can be used to facilitate local and intracellular delivery of vancomycin. Keywords: in vivo real-time monitoring, fluorescence microscopy, biodistribution, cell-material interaction, Staphylococcus aureus, intracellular infection

In 2015, liposomal formulation of irinotecan (ONIVYDE) has been approved by FDA and widely applied in the treatment of pancreatic cancer. ONIVYDE is a novel liposome formulation, entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method. Due to toxicity concerns, it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal, namely, free CPT-11and total CPT-11 in plasma. This study focuses on separation of non-liposomal CPT-11, evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome. Free CPT-11 in plasma was separated by solid-phase extraction (SPE). The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma was quantified by ultra-performance liquid chromatography-MS/MS. The calibration curves fitted well and lower limit of quantitation for SN-38, free CPT-11, total CPT-11 and CPT-11 in tissue and were 5 ng/ml, 10 ng/ml, 4.44 ng/ml and 25 ng/ml respectively. The recoveries, precision and accuracy of the method appear satisfactory. Using this method, the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated. [ABSTRACT FROM AUTHOR]

Yan Zhao,1,* Yue Zhang,2,* Gaofeng Qin,1 Jinjun Cheng,1 Wenhao Zeng,2 Shuchen Liu,1 Hui Kong,1 Xueqian Wang,1 Qingguo Wang,1 Huihua Qu3 1School of Basic Medical Sciences, 2School of Chinese Materia Medica, 3Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: The unique features of quantum dots (QDs) make them desirable fluorescent tags for cell and developmental biology applications that require long-term, multitarget, and highly sensitive imaging. In this work, we imaged fluorescent cadmium telluride/zinc sulfide (CdTe/ZnS) QDs in organs, tissues, and cells, and analyzed the mechanism of their lymphatic uptake and cellular distribution. We observed that the fluorescent CdTe/ZnS QDs were internalized by lymph nodes in four cell lines from different tissue sources. We obtained the fluorescence intensity–QD concentrations curve by quantitative analysis. Our results demonstrate that cells containing QDs can complete mitosis normally and that distribution of QDs was uniform across cell types and involved the vesicular transport system, including the endoplasmic reticulum. This capacity for CdTe/ZnS QD targeting provides insights into the applicability and limitations of fluorescent QDs for imaging biological specimens. Keywords: quantum dots, lymph nodes, fluorescence imaging, biodistribution

The purpose of this research was to develop cubosomal mucoadhesive in situ nasal gel to enhance the donepezil HCl delivery to the brain. Glycerol mono-oleate (GMO) and surfactant poloxamer 407 were used to prepare cubosomes. The developed formulations were characterized for particle size (PS), poly dispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), transmission electron microscopy (TEM), in vitro drug release and in vivo bio-distribution study in blood and brain tissue. Central composite design was used for the optimization purpose and the selected formulation (containing GMO 2 g and poloxamer 1.5%) was prepared in presence of gellan gum and konjac gum as gelling agent and mucoadhesive agent respectively. The optimal cubosomal dispersion and optimal cubosomal mucoadhesive in situ nasal gel were subjected to in vivo bio-distribution studies in rat model. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the drug solution. Thus, the formulated cubosomal mucoadhesive in situ gel could be considered as a promising carrier for brain targeting of CNS acting drugs through the transnasal route. [ABSTRACT FROM AUTHOR]

• Bio-based synthesis of Nano-Ceria was performed in Linum usitatissimum L. seeds extract as capping and stabilizing agent. • Smaller particles were produced in lower calcination temperatures. • Nano-Ceria has not shown toxic effect on cell viability. • Nano-Ceria could remarkably decrease ROS produced by cell metabolism. • Bio-distribution of radiolabeled Nano-Ceria showed the highest accumulation in kidneys. Bio-based synthesis of Nano-Ceria (NC) was performed in Linum usitatissimum L. (Lu) seeds extract as capping agent. Obtained gel was calcined at 400, 500, and 600 °C to investigate the effect of temperature on the size and morphology of the particles. All samples had spherical morphology which their crystallite size was decreased in higher temperature. Products were characterized by TGA/DTA, UV–vis, FESEM, FTIR and XRD. The band gap of the prepared samples was calculated through Tauc plot in the range of 3.2–3.4 eV. The results of MTT assay confirmed that NC has been shown no significant toxicity on A549 cell line. 2′,7′–dichlorofluorescin diacetate (DCFDA) was used to determine antioxidant properties of NC on A549 cell and the results showed that all concentrations of NC could reduce reactive oxygen species (ROS). NC was labeled with technetium (99mTc) for in vivo bio-distribution study in Wistar rat. Radiolabeled NC was stable in different environments of PBS buffer and human serum with radiochemical purity of more than 95% according to the instant thin layer chromatography (ITLC) method. DLS analysis showed radiolabeled particles had small size and pleasant colloidal stability. Bio-distribution of radiolabeled NC illustrated the highest accumulation in kidneys (1 h: 5.94 ± 0.77%ID/g, 4 h: 10.95 ± 5.99%ID/g, 24 h 7.94 ± 0.36%ID/g). Moreover, low uptake of 99mTc-NC in stomach confirmed the in vivo stability of 99mTc-NC. Accordingly, NC could be a worthy candidate for biological purposes and in vivo studies. [ABSTRACT FROM AUTHOR]

Accelerated blood clearance (ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells (KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl- α- D -mannopyranoside (APM) lipid derivative DSPE-PEG 2000 -APM (DPM), and 4-aminophenyl- β- L -fucopyranoside (APF) lipid derivative DSPE-PEG 2000 -APF (DPF) were conjugated and modified on alendronate sodium (AD) liposomes to specifically target and deplete KCs. The dualligand modified PEGylated liposomes (MFPL) showed stronger ability to damage KCs in vitro and in vivo , which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes (PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What's more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role in the ABC phenomenon. [ABSTRACT FROM AUTHOR]

Abstract Aims The in vivo targeted diagnostic applications of biosynthetic Cerium oxide nanoparticles (CeO 2 -NPs), prepared by applying chitosan as a stabilizer, was explored by evaluating the cytotoxicity through MTT assay on WEHI 164 cell line, the Hemolytic activity of CeO 2 -NPs and biodistribution in rats. Main methods The CeO 2 -NPs were characterized through the use of TGA/DTG, PXRD, FESEM, FTIR, and UV–Vis spectroscopy. The biodistribution of CeO 2 -NPs were determined by directly labeled nanoparticles with Technetium-99 m (99mTc) radioisotope (99mTc-CeO 2 -NPs). The labeling efficiency and stability of 99mTc-CeO 2 -NPs were also measured with Instant Thin Layer Chromatography (ITLC) method. The saturation study was investigated by 1 mCi of 99mTc-CeO 2 -NPs using different concentrations of WEHI 164 cells after 4 h of incubation. In vivo biodistribution study was performed by intravenous injection of 600 μCi/200 μL 99mTc-CeO 2 -NPs through rat's tail. Key findings CeO 2 -NPs seemed to have a low cytotoxic effect on WEHI 164 cell line and did not result in hemolysis. The biodistribution of CeO 2 -NPs has shown that a huge amount of 99mTc-CeO 2 -NPs was amassed in the living human organs, including liver, lung, spleen, stomach, and thyroid which shows the in vivo stability of the labeled conjugate. Herein, we have developed a facile, economical, and greener synthetic procedure applying Chitosan template. This green approach is comparable to conventional methods that utilize hazardous materials which are would be a suitable alternative to circumvent synthetic issues related to these materials. Significance The bio-applications of nano-sized CeO 2 -NPs were explored to find new horizon to use nanotechnology as the diagnostic tool. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Aluminum (Al) is present on earth surface has different chemical forms. It is a toxic metal and it may cause different disorders such as osteomalacia, microcytic anemia, Alzheimer and Parkinson's disease. Thus, it is very important to understand the effects of Al on different organs. In order to examine its accumulation, rats (male Wistar) were exposed to 5 mg/kg/day AlCl3 through gavage method for 30 days. At the end of the process, heart, brain, kidney and skin were removed and dried under sunlight. The samples were analyzed on a sequential Wavelength Dispersive X-ray Fluorescence (WDXRF) spectrometer. The results indicate that Al accumulates significantly in the brain. These results can be associated with neurotoxin effects. Although this study focused on the accumulation of Al, the concentration changes of detected elements from Beryllium (Be) to Uranium (U) accumulations were analyzed. The current study has proved that the WDXRF method is a quick, inexpensive and effective method in toxicological studies. [ABSTRACT FROM AUTHOR]

This study establishes and validates a series of three dimentional (3D) DNA origami frameworks (DOFs) carrying imaging probes to evaluate their pharmacokinetics and real-time bio-distribution in mice. Three typical DOFs with distinguished structural properties are subjected to mice intravenous injection to systematically investigate their in vivo behaviors. Tracing the radioisotope zirconium-89 ( 89 Zr) trapped at the inner space of the frameworks, positron emission tomography (PET) imaging is employed to record the real-time bio-distribution of the structures and acquire their pharmacokinetic parameters in the major metabolic organs. The 3D DOFs show different behavior compared to previous structures, with lower kidney accumulation and higher liver retention. Modifications to the structures, such as exposed ssDNA or polyethylene glycol (PEG) moieties, impact their behavior, but are structure-dependent. The 43 nm icosahedra framework among the DOFs perform the best in liver targeting, with the ssDNA extensions enhancing this tendency. The modification of triantennary N-acetylgalactosamine (GalNAc), further improves its uptake in liver cells, especially in hepatocytes over other cell types, discovered by flow cytometry analysis., (© 2023 Wiley-VCH GmbH.)

This study aimed to evaluate the suitability of pterostilbene for anti-inflammatory application. The in vitro anti-inflammatory activities of pterostilbene were assessed using resveratrol, piceatannol and resveratrol trimethyl ether as comparators while its pharmacokinetics was examined in rats. All tested compounds displayed concentration-dependent anti-proliferative effect in E11 human rheumatoid arthritic synovial fibroblasts. They also suppressed LPS-induced NF-κB p65 nuclear translocation, down-regulated the secretions of IL-6, IL-18, VEGF, nitric oxide, MMP-2 and MMP-9 in E11 cells and attenuated E11-driven migration of THP-1 and U937 monocytes. Similarly, they inhibited LPS-induced pro-inflammatory cytokines in THP-1 cells. Interestingly, pterostilbene usually displayed in vitro anti-inflammatory potencies stronger than resveratrol. In vivo studies revealed that pterostilbene was extensively distributed to major drug target organs like liver, kidney, heart, lung as well as brain and repeated oral dosing did not significantly alter its pharmacokinetics. In conclusion, pterostilbene appears to be a promising candidate for further development.

In this study, magnetic multimodal nanoparticles with potential applications in magnetic- and nuclear-medicine imaging, magnetic resonance imaging, hyperthermia, and theranostic (therapeutic and diagnostic), applications were prepared by coating iron oxide nanoparticles with silica (core-shell), functionalizing with aminopropyltriethoxy silane and coupling with diethylenetriamine pentaacetic acid ligand (DTPA). Radiolabeling of core-shell-DTPA particles with 68Ga radiometal was carried out through chelation of 68Ga(III) ions by DTPA and was used for positron emission tomography. The biodistribution of the 68Ga-radiolabeled magnetic nanoparticles compared to free 68Ga(III) was checked in normal Balb/c mice up to 2 h. [ABSTRACT FROM AUTHOR]

To ensure the safe use of nanoparticles (NPs) in modern society, it is necessary and urgent to assess the potential toxicity of NPs. Cardiovascular system is required for the systemic distribution of NPs entering circulation. Therefore, the adverse cardiovascular effects of NPs have gained extensive research interests. Metal based NPs, such as TiO2, ZnO and Ag NPs, are among the most popular NPs found in commercially available products. They may also have potential applications in biomedicine, which could increase their contact with cardiovascular systems. This review aimed at providing an overview about the adverse cardiovascular effects of TiO2, ZnO and Ag NPs. We discussed about the bio-distribution of NPs following different exposure routes. We also discussed about the cardiovascular toxicity of TiO2, ZnO and Ag NPs as assessed by in vivo and in vitro models. The possible mechanisms and contribution of physicochemical properties of metal based NPs were also discussed. [ABSTRACT FROM AUTHOR]

This study reports the bio-distribution and clearance of Abutilon indicum silver and gold nanoparticles (AIAgNPs and AIAuNPs) in Wistar rats. Rats in different groups were orally administered with 5 and 10 mg/Kg BW of AIAgNPs and AIAuNPs (size 1–25 nm) for 28 days and few were maintained until 58 days of washout period. Serum biochemical parameters were not changed significantly at both doses of AIAuNPs and at lower concentration of AIAgNPs. But, with 10 mg/Kg BW of AIAgNPs rats showed elevated levels of AST, ALP and ALT on day 29, however, these levels were restored to normal after washout period. Liver oxidative stress markers were not altered with the treatment of AIAgNPs and AIAuNPs. ICP-OES analysis indicated bio-distribution of Ag and Au more in liver, kidney and spleen on day 29 and was found cleared on day 59. Histological analysis of nine vital organs indicated normal tissue architecture at both doses of AIAuNPs and lower dose of AIAgNPs. While the rats treated with higher dose of AIAgNPs showed mild liver sinusoid cell swelling on day 29, which also was recovered on day 59. Findings of this preclinical study indicate biocompatible nature of biogenic nanoparticles supporting their future biomedical applications. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the reproducibility of a rat model to assess the preclinical similarity in safety profiles and tissue accumulation of iron products. Accordingly, the effect of several doses of intravenously administered Venofer® and of Ferrlecit® on blood parameters, and on kidney and particularly liver toxicity were examined in non-anemic Sprague Dawley rats. The different analysis showed neither a clear treatment nor a dose effect after multiple injections. The parameters measured in this rat strain showed some iron induced adverse effects, but these could not be correlated to treatment specific differences. The findings presented in this paper indicate the difficulty to define a useful preclinical model to evaluate iron-based nano-colloidal preparations. [ABSTRACT FROM AUTHOR]

ICD-85 is a combination of three poly-peptides, ranging from 10,000 to 30,000 Dalton, derived from the venoms of an Iranian brown snake (Agkistrodon halys) and a yellow scorpion (Hemiscorpius lepturus). Labeling of this ICD-85 was successfully achieved with 99mTc, through direct method using SnF2 as reducing agent. Labeled ICD-85 was injected into mice to determine the excretion pathway. The results show that the maximum labeling yield (>75%) was obtained by using 30 μg of ICD-85 in phosphate buffer (60 μl, pH 7.1) at room temperature. Bio-distribution studies with radiolabeled ICD-85 shows moderate clearance of the complex from blood. The improvement of the immunotherapeutic treatment of cancer requires a better knowledge of the biological actions of the ICD-85 since tissue distribution studies are very important for clinical purpose. [ABSTRACT FROM AUTHOR]

As the use of nanoparticles (NPs) is increasing, the potential toxicity and behavior of NPs in living systems need to be better understood. Our goal was to evaluate the developmental toxicity and bio-distribution of two different sizes of fluorescently-labeled SiO2 NPs, 25 and 115 nm, with neutral surface charge or with different surface functionalization, rendering them positively or negatively charged, in order to predict the effect of NPs in humans. We performed a zebrafish embryo toxicity test (ZFET) by exposing the embryos to SiO2 NPs starting from six hours post fertilization (hpf). Survival rate, hatching time, and gross morphological changes were assessed at 12, 24, 36, 48, 60, and 72 hpf. We evaluated the effect of NPs on angiogenesis by counting the number of sub-intestinal vessels between the second and seventh intersegmental vessels and gene expression analysis of vascular endothelial growth factor (VEGF) and VEGF receptors at 72 hpf. SiO2 NPs did not show any adverse effects on survival rate, hatching time, gross morphology, or physiological angiogenesis. We found that SiO2 NPs were trapped by the chorion up until to the hatching stage. After chemical removal of the chorion (dechorionation), positively surface-charged SiO2 NPs (25 nm) significantly reduced the survival rate of the fish compared to the control group. These results indicate that zebrafish chorion acts as a physical barrier against SiO2 NPs, and removing the chorions in ZFET might be necessary for evaluation of toxicity of NPs.

Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio-distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution studies of cyanine5.5-N-Hydroxysuccinimide (Cy5.5) labeled CTP were undertaken in wild-type mice. Cardiac targeting peptide was labeled with Technetium 99m (99mTc) using the chelator hydrazino-nicotinamide (HYNIC), and imaging performed using micro-single photon emission computerized tomography/computerized tomography (SPECT/CT). Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMCs) were incubated with dual-labeled CTP, and imaged using confocal microscopy. TriCEPs technology was utilized to study the mechanism of transduction. Bio-distribution studies showed peak uptake of CTP at 15 min. 99mTc-HYNIC-CTP showed heart-specific uptake. Robust transduction of beating human iPSC-derived CMCs was seen. TriCEPs experiments revealed five candidate binding partners for CTP, with Kcnh5 being felt to be the most likely candidate as it showed a trend towards being competed out by siRNA knockdown. Transduction efficiency was enhanced by increasing extracellular potassium concentration, and with Quinidine, a Kcnh5 inhibitor, that blocks the channel in an open position. We demonstrate that CTP transduces the normal heart as early as 15 min. 99mTc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99mTc Sestamibi. Cardiac targeting peptide’s transduction ability is not species limited and has human applicability. Cardiac targeting peptide appears to utilize Kcnh5 to gain cell entry, a phenomenon that is affected by pre-treatment with Quinidine and changes in potassium levels.

During the last three decades, dendrimers, nano-sized highly-branched fractal-like symmetrical macromolecules, have been intensively studied as promising candidates for application as drug-delivery carriers. Among other important characteristics arising from their unique and highly-controlled architecture, size and surface properties, the possibility of hosting guest molecules in internal voids represents a key advantage underlying the potential of dendrimers as non-covalent drug-encapsulating agents. The impressive amount of accumulating experimental results to date allows researchers to identify the most important and promising theoretical and practical aspects of the use of dendrimers for this purpose. This review covers the main factors, phenomena, and mechanisms involved in this drug-vectorization approach, including mechanisms of non-covalent dendrimer-drug association, dendrimer-dendrimer interactions, as well as biological properties relevant to the host dendrimers. A discussion is then provided to illustrate some successful existing formulation strategies as well as to propose some new possible ones to optimize further development of the field. [ABSTRACT FROM AUTHOR]

In the present study, acute and sub-acute toxicity of pectin-mediated gold nanoparticles (p-GNPs) in Sprague-Dawley rats following OECD guidelines is investigated. Toxicity profile has been assessed from the clinical sign parameters, histopathological examination, clinical biochemistry and antioxidant studies. Bio-distribution of p-GNPs in vivo was evaluated using ICP-MS analysis. Statistical analyses were performed to understand the influence of p-GNPs in in vivo system. Synthesized p-GNPs were found to be highly stable at alkaline pH. Acute and sub-acute toxicity studies suggest that there is no significant toxicity developed in any of the experimental animals. Clinical parameters, clinical chemistry and antioxidant status of the rats were normal and showed no variations when compared with the control group. Results of histopathological examination revealed that negligible changes in the morphology of all vital organs studied. The present study ensures the safety of p-GNPs at sub-acute level to emerge as a promising candidate for biomedical applications following further toxicological evaluation. [ABSTRACT FROM AUTHOR]

Introduction The 11 C/ 18 F–choline is a PET/CT radiopharmaceutical useful in detecting tumors with high lipogenesis. 11 C/ 18 F–choline uptake can occur in physiological conditions or tumors. The knowledge of its bio-distribution is essential to recognize physiologic variants or diagnostic pitfalls. Moreover, few information are available on the bio-distribution of this tracer in female patients. Our aim was to discuss some documented 18 F–choline PET/CT pitfalls in prostate cancer patients. Our secondary aim was to describe the 18 F–choline bio-distribution in the female body. Methods We collected diagnostic pitfalls in three PET centers examining 1000 prostate cancer by 18 F–choline PET/CT. All pitfalls were ensured by follow-up, imaging and/or histology. We also performed whole body 18 F–choline PET/CT in 5 female patients. Results 169/1000 (16.9%) patients showed pitfalls not owing to prostate cancer. These findings were due to inflammation, benign tumors while, in 1% of examined patients, a concomitant neoplasm was found. In the female body, the breast showed low physiological uptake. Conclusions The accurate knowledge of 18 F–choline PET/CT bio-distribution and diagnostic pitfalls is essential. Correlative imaging and histological exam are often necessary to depict pitfalls. In women, the uptake in the breast is due to the physiological gradient of 18 F–choline uptake in the exocrine glands. Advances in knowledge Our results confirm the possibility of 18 F–choline uptake in several diseases other than prostate cancer. However, our experience was acquired on a large population and shows that a conspicuous amount of 18 F–choline diagnostic pitfalls are easily recognizable and attributable to inflammation. A new advance in knowledge is the minimal difference in terms of physiological tracer bio-distribution between male and female patients. Implications for patient care The knowledge of the physiological bio-distribution and of the potential pitfalls linked of a tracer could help physicians to choose the best diagnostic and therapeutic approaches for a better patient quality of life. [ABSTRACT FROM AUTHOR]

Lymphatic drug delivery (LDD) is an attractive option for the prevention and treatment of cancer metastasis. This study aims to develop TPGS decorated nanostructure lipid carrier gefitinib loaded (TPGS-NLC-GEF). Biocompatibility and cytotoxicity were studied using erythrocytes and A549 cell lines. Furthermore, cellular uptake of the prepared TPGS-NLC was studied using 5-carboxyfluorescein (5-CF). Pharmacokinetic, biodistribution, and chylomicron-block flow studies were performed using male Wister Albino rats to investigate the influence of TPGS-NLC on plasma concentration-time profile, organ deposition, and LDD of GEF. The present results indicated that the prepared TPGS-NLC and TPGS-NLC-GEF formulation had a particle size range of 268 and 288 nm with a negative zeta-potential value of − 29.3 and − 26.5 mV, respectively. The in-vitro release showed burst drug release followed by sustained release. In addition, the biosafety in the term of the hemocompatibility study showed that the prepared formulation was safe at the therapeutic level. Additionally, an in-vitro cytotoxicity study showed that the TPGS-NLC was able to enhance the activity of GEF against the A549 cell line. The cellular uptake study showed the ability of TPGS-NLC to enhance 5-CF internalization by 12.6-fold compared to the 5-CF solution. Furthermore, the in-vivo study showed that TPGS-NLC was able to enhance GEF bioavailability (1.5-fold) through lymphatic system which was confirmed via the indirect chylomicron-block flow method. The tissue distribution study showed the ability of lipid nanoparticles to enhance lung drug deposition by 5.8-fold compared to a GEF suspension. This study concluded that GEF-NLC-GEF is an encouraging approach for the treatment of metastatic lung cancer through lymphatic delivery, enhanced bioavailability, and reduced systemic toxicity. [Display omitted] • TPGS decorated NLC loaded GEF were prepared and pharmaceutically characterized. • The biosafety, cytotoxicity, bioavailability, organ deposition, and LDD were studied. • TPGS-NLC-GEF have nanosize, negative ZP, sustained release, and biocompatible. • TPGS-NLC enhances cytotoxicity, bioavailability, LDD, and lung deposition of GEF. • GEF-NLC-GEF is promising approach for the treatment of metastatic lung cancer. [ABSTRACT FROM AUTHOR]

Radio immunotherapy is one of the most important and effective therapies for B-cell non Hoddgkin’s lymphoma treatment. Today, anti CD-20 antibodies labeled with beta emitter radionuclides are used in radio immunotherapy. Various radionuclides for labeling anti CD-20 antibodies have been studied and developed for the treatment and diagnosis of malignancies. This paper describes the preparation, bio-distribution and absorbed dose rate of 111In, 90Y, 177Lu, and 153Sm labeled anti CD-20 antibodies (rituximab) in human organs, after injection to rats. The macro cyclic bifunctional chelating agent, N-succinimidyl-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA-NHS) for conjugation to antibody, was used to prepare DOTA-rituximab. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. Radio-labeling was performed at 40 °C for 24 hours. After the quality control studies, the final radioactive solution was injected intravenously into rats through their tail vein. The tissue uptakes of each injection were measured. Then we calculated S values for 177Lu and 153Sm by using specific absorbed fractions and data used in the manner of radio-labeled analysis and dosimetry for humans. The absorbed dose rate of each organ was calculated in the specific time by medical internal radiation dose method with linear approximation in the activity measurements.

• UC-MSCs products were completely in conformity with the ISCT criteria and adapted to adhere to GMP requirements. • UC-MSCs products display a good safety and effectiveness in treatment of NOD-SCID model with ACLF. Especially, high dose group supplied an optimal formulation upon CCl 4 -induced ACLF models. • The BLI-based system was sufficient for monitoring the dynamic metabolism of UC-MSCs in vivo, as well as infused UC-MSCs in NOD-SCID model with ACLF displayed preferable homing and delayed attenuation in the damaged liver tissue. Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) are advanced therapy medicinal products (ATMPs) and thus act as an alternative to liver transplantation for acute-on-chronic liver failure (ACLF). Therewith, we are aiming to evaluate the pharmacology and pharmacokinetics of GMP-grade UC-MSCs products on carbon tetrachloride (CCl4)-induced ACLF mouse model and the concomitant therapeutic dose for intravenous administration. For the purpose, the GMP-grade UC-MSCs products were transplanted intravenously into the aforementioned CCl4-induced ACLF NOD-SCID mouse model, and the therapeutic effect was evaluated with the aid of serological, biochemical and histological assessments. Meanwhile, the correlationship between the treatment groups and other characteristics were determined by conducting principal component analysis (PCA). To further verify the spatio-temporal pharmacokinetics of UC-MSCs products on ACLF treatment, we took advantage of the bioluminescence imaging (BLI) technology with the dual-color fluorescence reporter construct (pLV-Fluc-eGFP). The biological characteristics of UC-MSCs products were in conformity with the International Society of Cell Therapy (ISCT) criteria and the GMP requirements. ACLF mice with high dose of UC-MSCs treatment revealed significantly alleviated pathological manifestations with a dramatically improved survival rate, the alleviation of liver injury with reduced hepatic enzyme, inflammatory infiltration and inflammatory cytokines. Notably, UC-MSCs in ACLF mice displayed preferable homing and delayed attenuation in the damaged liver tissue. Collectively, our data indicated the feasibility of UC-MSC-based cytotherapy for ACLF model administration. Our findings have provided new references for pharmacology and pharmacokinetics assessments, which will provide overwhelming evidence for pre-clinical study in vivo. [ABSTRACT FROM AUTHOR]

• High-performance tracking of BEVs in living systems has been realized with an AIEgen. • The probe can illuminate BEVs and shows remarkable merits over traditional methods. • The spatial and temporal distributions of BEVs within host can be clearly visualized. The nano-sized, membrane-enclosed bacterial extracellular vesicles (BEVs) released by bacteria are now regarded as important mediators involved in various physiological and pathological processes of human. To elucidate their roles in bacteria-to-host communication, methods for visualizing and tracking of these nano-vesicles are crucial, but ideal means are lacking currently. In this work, we report the development of a bioprobe, DPASP, for BEV bioimaging with superior performance. DPASP can target BEVs with boosted fluorescence due to its aggregation-induced emission (AIE) attribute, which allows BEV labeling with a high signal-to-background ratio. For BEV imaging, DPASP outperforms the commercial dyes in terms of labeling efficiency, retention time, photostability, and biocompatibility. The applications of DPASP in studying the spatial and temporal distributions of E. coli -derived BEVs within living cells and mice were also demonstrated. The approach developed here provides a valuable tool to better understand the roles of BEVs in health and diseases. [ABSTRACT FROM AUTHOR]

Nanomedicines have been used over time because of their significant impact on human health care for the prevention, early detection, diagnosis, treatment, and follow-up of a wide range of illnesses. Nanomedicines must be adequately characterized in order to develop well-defined nanomedicines with therapeutic value. The surface charge of nanomedicines plays an important role to determine how they interact with biological components where the zeta potential is a useful tool for describing the chemical composition of particle surfaces, such as functional groups, adsorption/desorption, and so on. The main goal of this review is to present an overview of the impact of nanomedicines' surface charges on absorption, distribution, metabolism, and in vivo drug release, for example negatively charged nanoparticles diffuse well through mucus for mucosal drug delivery, whereas positively charged nanoparticles are preferred for transvascular transport, tumor penetration, and cellular absorption. In this review, we also highlight how to improve nanomedicines' therapeutic potential by altering their surface characteristics with the help of various polymers. Future research should be focused on enhancing the therapeutic efficiency of nanomedicines by changing their surface properties, as well as conducting in-depth mechanistic studies by changing the surface properties of nanomedicines for the efficient treatment of diseases with low or no nanomedicine toxicity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Due to lack of specification and solubility of drug molecules, patients have to take high doses of the drug to achieve the desired therapeutic effects for the treatment of diseases. To solve these problems, there are various drug carriers present in the pharmaceuticals, which can used to deliver therapeutic agents to the target site in the body. Mesoporous silica materials become known as a promising candidate that can overcome above problems and produce effects in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles (MSNs) are widely used as a delivery reagent because silica possesses favorable chemical properties, thermal stability, and biocompatibility. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release of the target site. The properties of mesoporous, including pore size, high drug loading, and porosity as well as the surface properties, can be altered depending on additives used to prepare MSNs. Active surface enables functionalization to changed surface properties and link therapeutic molecules. They are used as widely in the field of diagnosis, target drug delivery, bio-sensing, cellular uptake, etc., in the bio-medical field. This review aims to present the state of knowledge of silica containing mesoporous nanoparticles and specific application in various biomedical fields. [ABSTRACT FROM AUTHOR]

Introduction Endothelial progenitor cells (EPCs) has been reported to have the potential for advancing revascularization of ischemic tissue. However, the heterogeneous nature of these cells calls for specification of the angiogenic potential of each subtype. The purpose of this study was to gain additional insight on the homing capacity of the EPC subtype, endothelial outgrowth cells (EOCs) in tumours using a well-established tumour model. Methods 111 Indium ( 111 In) – and 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labelled EOCs derived from human umbilical cord blood were injected into mice with a C3H mammary carcinoma foot tumour. The subsequent capture of the EOCs was traced by estimation of activity in individual organs, autoradiography and fluorescence microscopy. Results 111 In activity was found in tumour and other organs. However, varying parts of the activity originated from free 111 In lost from EOCs. Autoradiography demonstrated accumulation of 111 In activity in the tumour rim. Microscopy proved that a least part of this radioactivity originated from the presence of human derived EOCs and that those EOCs were not located in the endothelial lining of vessels, in the tumour. Conclusion The results demonstrated the presence of xenotransplanted EOCs in the rim of a C3H mammary carcinoma. They were, however, not located in the endothelial lining of the vessels, thus indicating that their effect in vasculogenesis might be mediated via paracrine mechanisms rather than differentiating into endothelial cells (ECs) in tumour vessels. [ABSTRACT FROM AUTHOR]

Liposome in delivering radionuclide for cancer therapy has been expansively studied; however, liposome itself can be deliberately entrapped and destroyed by the reticuloendothelial system, causing an insufficiency of the drug delivery, which in turn would restrict the effectiveness of the drug. In this study, mice with subcutaneous implantation of C26 murine colon cancer received an experimental treatment regimen in which mice took delivery of PEGylated liposomal doxorubicin (LipoDox) first, after a three-day interval, of Rhenium-188 encapsulated into PEGylated liposome ( 188 Re-Liposome) subsequently and by which suppressed the functioning of reticuloendothelial system for the short term. The data showed that based upon the biodistribution assay and the evaluation of the therapeutic efficacy, 188 Re-Liposome was more sufficiently delivered to tumor sites in mice with this treatment regimen than mice without the regimen, and that cancer mortalities in mice with the treatment regimen were much lower than the mortalities in mice without the regimen. Taken together, a new strategy proposed in this study significantly improved both the 188 Re-Liposome delivery and the effectiveness of 188 Re-Liposome, suggesting that the strategy can be an ideal treatment for cancer. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes significant mortality, long term disability and psychological symptoms. Gene therapy is a promising approach for treatment of different pathological conditions. Here we tested chitosan and polyethyleneimine (PEI)-coated magnetic micelles (CP-mag micelles or CPMMs), a potential MRI contrast agent, to deliver a reporter DNA to the brain after mild TBI (mTBI). CPMM-tomato plasmid (ptd) conjugate expressing a red-fluorescent protein (RFP) was administered intranasally immediately after mTBI or sham surgery in male SD rats. Evans blue extravasation following mTBI suggested CPMM-ptd entry into the brain via the compromised blood-brain barrier. Magnetofection increased the concentration of CPMMs in the brain. RFP expression was observed in the brain (cortex and hippocampus), lung and liver 48 h after mTBI. CPMM did not evoke any inflammatory response by themselves and were excreted from the body. These results indicate the possibility of using intranasally administered CPMM as a theranostic vehicle for mTBI. From the Clinical Editor In this study, chitosan and PEI-coated magnetic micelles (CPMM) were demonstrated as potentially useful vehicles in traumatic brain injury in a rodent model. Magnetofection increased the concentration of CPMMs in the brain and, after intranasal delivery, CPMM did not evoke any inflammatory response and were excreted from the body. [ABSTRACT FROM AUTHOR]

Highlights: [•] LC/MS/MS is established for biodistribution and pharmacokinetics of Nobliside A. [•] Biodistribution and pharmacokinetics of Nobliside A and its liposome are compared. [•] Nobliside A and its liposome eliminate slowly in rat after intravenous injection. [•] Similar behavior of Nobliside A and its liposome appears in whole blood of rat. [•] Nobliside A liposome shows much higher AUC in liver and spleen than its solution. [ABSTRACT FROM AUTHOR]