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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., (© 2024. The Author(s).)

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 × 10 6 cells/kg and 2 × 10 7 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 × 10 6  cells/kg and 2 × 10 7 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 × 10 7 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., (© 2024. The Author(s).)

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 [ 11 C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [ 11 C]BIIB104. The study found that [ 11 C]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 [ 11 C]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.

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.)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 IC 50 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.

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.)

Background and Purpose: 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 pharmacologyandpharmacokinetics of GMP-grade UC-MSCs products on carbon tetrachloride (CCl4)-induced ACLF mouse model and the concomitant therapeutic dose for intravenous administration., Methods: 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 correlationshipbetween 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)., Results: The biological characteristics of UC-MSCs products were in conformity with the International Society of Cell Therapy (ISCT) criteriaand 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., Conclusion: Collectively, our data indicated the feasibility of UC-MSC-based cytotherapy for ACLF model administration. Our findings have provided new references for pharmacologyandpharmacokinetics assessments, which will provide overwhelming evidence for pre-clinical study in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 CellVue TM 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.

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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: NS and JD are named as inventors on a patent on caIKK-RNA-electroporated DCs (WO/2012/055551), which is held by the Friedrich-Alexander-Universität Erlangen-Nürnberg., (Copyright © 2022 Lai, Keller, Santos, Schaft, Dörrie and Vera.)

Naringenin, a lipophilic flavanone of citrus fruits, was encapsulated for enhanced bioavailability using biodegradable polymers of polylactic acid/polyvinyl alcohol (PLA/PVA) as well as zein/pectin as P/P-Nar-NPs and Z/P-Nar-NPs, respectively. The formulation variables were optimized using response surface methodology to achieve smaller particle size with higher surface charge and encapsulation efficiencies. The optimized formulations were physically characterized by SEM, FTIR, TGA and XRD techniques. Compared to Z/P-Nar-NPs, the P/P-Nar-NPs had better encapsulation efficiency and sustained release of naringenin under simulated gastrointestinal conditions. Furthermore, the oral administration of single dose of free and nanoforms of naringenin in rats (90 mg/kg b.wt) showed higher efficacy of PLA/PVA in improving the relative bioavailability of naringenin (4.7-fold) as compared to the zein/pectin polymer (1.9-fold). Overall, the present study provides insights into the formulation performance of the encapsulated bioactive compound under different polymeric matrices., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

Sirolimus is a hydrophobic macrolide compound that has been used for long-term immunosuppressive therapy, prevention of restenosis, and treatment of lymphangioleiomyomatosis. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of sirolimus in both porcine whole blood and lung tissue. Blood and lung tissue homogenates were deproteinized with acetonitrile and injected into the LC-MS/MS system for analysis using the positive electrospray ionization mode. The drug was separated on a C18 reversed phase column with a gradient mobile phase (ammonium formate buffer (5 mM) with 0.1% formic acid and acetonitrile) at 0.2 mL/min. The selected reaction monitoring transitions of m / z 931.5 → 864.4 and m/z 809.5 → 756.5 were applied for sirolimus and ascomycin (the internal standard, IS), respectively. The method was selective and linear over a concentration range of 0.5-50 ng/mL. The method was validated for sensitivity, accuracy, precision, extraction recovery, matrix effect, and stability in porcine whole blood and lung tissue homogenates, and all values were within acceptable ranges. The method was applied to a pharmacokinetic study to quantitate sirolimus levels in porcine blood and its distribution in lung tissue following the application of stents in the porcine coronary arteries. It enabled the quantification of sirolimus concentration until 2 and 14 days in blood and in lung tissue, respectively. This method would be appropriate for both routine porcine pharmacokinetic and bio-distribution studies of sirolimus formulations.

Hypothesis: 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., Experiments: 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., Findings: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA) is an inflammatory chronic disease characterized by inflammation, pain, swelling and disability, and radiosynovectomy is one of the disease treatment lines. In this study, the possibility of providing rhenium-186/rhenium-188 chitosan radiopharmaceuticals, optimization of conditions for their production and bio-distribution are reported., Objective: In order to build perrhenic acid for labeling, natural rhenium was exposed to radiation. Radionuclidic and radiochemical purities of (186/188Re)-NaReO4 were examined by gamma spectroscopy and paper chromatography methods, respectively., Methods: Labeling of chitosan with rhenium was done in different acidic situations. The radiochemical purity 186/188Re-chitosan was applied by radio thin layer chromatography (RTLC). Lastly, the bio-distribution of the radiolabeled chitosan was studied in various organs after intra articular injection of the complex to lab rats. Gamma spectrometry confirmed the high rhenium radionuclidic purity. Chromatography results showed that perrhenic acid was produced with purity greater than 97% and rhenium chitosan labeling was done over 98% in pH = 3. Dissection results showed a high bio-distribution of 186/188Re-chitosan after injection into the joint with no leakage to surrounding organs., Conclusion: According to the results, there is a possibility of labeling rhenium with chitosan in very high radiochemical purity. Regarding the high retention of these radiopharmaceuticals in joints with no leakage to surrounding organs, 186/188Re-chitosan can be applied as new radiosynovectomy drugs for rheumatoid arthritis treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Novel artificial tissues with potential usefulness in local-based therapies have been generated by tissue engineering using magnetic-responsive nanoparticles (MNPs). In this study, we performed a comprehensive in vivo characterization of bioengineered magnetic fibrin-agarose tissue-like biomaterials. First, in vitro analyses were performed and the cytocompatibility of MNPs was demonstrated. Then, bioartificial tissues were generated and subcutaneously implanted in Wistar rats and their biodistribution, biocompatibility and functionality were analysed at the morphological, histological, haematological and biochemical levels as compared to injected MNPs. Magnetic Resonance Image (MRI), histology and magnetometry confirmed the presence of MNPs restricted to the grafting area after 12 weeks. Histologically, we found a local initial inflammatory response that decreased with time. Structural, ultrastructural, haematological and biochemical analyses of vital organs showed absence of damage or failure. This study demonstrated that the novel magnetic tissue-like biomaterials with improved biomechanical properties fulfil the biosafety and biocompatibility requirements for future clinical use and support the use of these biomaterials as an alternative delivery route for magnetic nanoparticles., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, poly (mPEGMA-co-MAA) (PA) based on monomers of mPEGMA and MAA were synthesized, and different amino-β-Cyclodextrins with various alkyl chains were conjugated to PA through carbodiimide-mediated coupling reactions. The obtained poly (mPEGMA-co-MAA-g-amino-β-CD) (PA-g-amino-β-CD) was characterized by FTIR, NMR and TGA. The fluorescence technique was used to investigate the micellization of PA-g-amino-β-CDs. The results indicated that these polymers could self-assemble into nano-micelles in water, and PA-g-HDA-β-CD possessed the lowest CMC value due to its long alkyl chains. In addition, the PA-g-HDA-β-CD micelles were in spherical shapes with the diameter of 78.5 ± 0.6 nm.The release of the model drug from PA-g-HDA-β-CD micelles was increased as the pH reduced from 7.4-5.5 at 37 °C. Cytotoxicity and cellular uptake experiments were performed in HepG2, which showed that the cargo-free PA-g-HDA-β-CD micelles did not have obvious cytotoxicity and were mainly distributed in the cytoplasm of HepG2 cells by endocytosis. Moreover, the study about in vivo distribution of the experimental rats indicated that the accumulation of PA-g-HDA-β-CD micelles mainly happened in the liver. Therefore, the novel amino-β-CD containing polymers exhibit good potential applications in drug delivery system., (Copyright © 2020 Elsevier B.V. All rights reserved.)

As the application of flow cytometry to a quantitative pharmacokinetic study with adoptive T cell therapy is new, we aimed to investigate the quantitativity of flow cytometry-based analysis for the pharmacokinetic assessment of circulating human T cells in a preclinical study. We evaluated the selectivity, linearity, accuracy, precision, and sensitivity of flow cytometry-based analysis for human CD8 + T cells in immunodeficient mouse blood. The CD3/8/45-positive cell population was successfully distinguished from the negative population. Linear regression analysis for the calibration curve showed good linearity and recovery was approximately 100%. Acceptable inter- and intra-day precision and accuracy were observed and the lower limit of quantification (30 cells/50 μL) was validated with acceptable precision and accuracy. Blood concentrations of human CD8 + T cells in immunodeficient mice were then evaluated after administration using this method and the time-concentration profile of human T cells in mice was successfully assessed. The present study is the first to clarify the quantitativity of flow cytometry-based analysis for circulating human T cells in animals. The concept of the present study would be applicable to quantitative pharmacokinetics/efficacy or safety analysis of adoptive T cell therapy., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Purpose: 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., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Zhou et al.)

Background: Alzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN's). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities., Objectives: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer's disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs., Method: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data., Results: From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes., Conclusion: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2018 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

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 ( 99m Tc) 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 99m Tc-NC in stomach confirmed the in vivo stability of 99m Tc-NC. Accordingly, NC could be a worthy candidate for biological purposes and in vivo studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

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 dual-ligand 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., (© 2018 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.)

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.

Intravitreal (IVT) injection of ophthalmic therapeutics is the most widely used drug delivery route to the posterior segment of the eye. We employed this method to deliver our inorganic, catalytic antioxidant, cerium oxide nanoparticles (CeNPs), to rodent models of retinal degeneration. A single IVT of CeNPs delays disease progression. Even though we have shown that our synthesized CeNPs are retained in the retina for over a year, we still do not know which cell types in the retina preferentially take up these nanoparticles. In this study, we examined the temporal and spatial distribution of fluorescently labeled CeNPs in retinal sections after IVT. We detected elevated fluorescent signals in all the layers where retinal neurons and glia reside and retinal pigment epithelium (RPE) up to 90 days post injection. Additionally, we found that free fluorochrome accumulated in retinal vasculature instead of retinal cells. These data suggested that CeNP-conjugation mediated the targeting of the fluorochrome to retinal cells. We propose that CeNPs can be deployed as ophthalmic carriers to the retina.

The current strategies to treat different kinds of cancer are mainly based on chemotherapy, surgery and radiation therapy. Unfortunately, these approaches are not specific and rather invasive as well. In this scenario, metal nano-shells, in particular gold-based nanoshells, offer interesting perspectives in the effort to counteract tumor cells, due to their unique ability to tune Surface Plasmon Resonance in different light-absorbing ranges. In particular, the Visible and Near Infrared Regions of the electromagnetic spectrum are able to penetrate through tissues. In this way, the light absorbed by the gold nanoshell at a specific wavelength is converted into heat, inducing photothermal ablation in treated cancer cells. Furthermore, inert gold shells can be easily functionalized with different types of molecules in order to bind cellular targets in a selective manner. This review summarizes the current state-of-art of nanosystems embodying gold shells, regarding methods of synthesis, bio-conjugations, bio-distribution, imaging and photothermal effects (in vitro and in vivo), providing new insights for the development of multifunctional antitumor drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 ( 99m Tc) 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. 99m Tc-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. 99m Tc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99m Tc 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.

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., (Copyright © 2018. Published by Elsevier Inc.)

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 TiO 2 , 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 TiO 2 , ZnO and Ag NPs. We discussed about the bio-distribution of NPs following different exposure routes. We also discussed about the cardiovascular toxicity of TiO 2 , 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.

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., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To establish a platform for the possibility of effective and safe delivery of Temozolomide (TMZ) to brain via surface engineered (polyamidoamine) PAMAM dendrimer for the treatment of glioblastoma., Methods: The present study aims to investigate the efficacy of PAMAM-chitosan conjugate based TMZ nanoformulation (PCT) against gliomas in vitro as well as in vivo. The prepared nanoconjugated formulation was characterized by 1 H NMR, FT-IR spectroscopy and for surface morphological parameters. The reported approach was also designed in such a way to ensure toxicity before in vivo delivery through conducting the hemolytic study., Result: Surface morphology was found as per nanoformulation via size, pdi and zeta potential measurement. PCT was more efficacious in terms of IC 50 values compared to pure TMZ against U-251 and T-98G glioma cell lines. The in vivo pharmacokinetic parameters proved sustained release fashion such as half-life (t 1/2 ) of 22.74 h (PCT) rather than15.35 h (TMZ) only. Higher concentration was found in heart than brain in bio-distribution studies. This study exhibits the potential applicability of dendrimer and CS in improving the anticancer activity and delivery of TMZ to brain., Conclusion: The attractive ex vivo cytotoxicity against two glioma cell lines; U-251 and T-98G and phase solubility studies of TMZ revealed remarkable results. In vivo studies of prepared nanoformulation were significant and promising that explored the double concentration of TMZ in brain due to surface functionality of dendrimer. The reported work is novel and non- obvious as none of such approaches using chitosan anchored dendrimer for TMZ delivery has been reported earlier.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recombinant Elastin-Like Polypeptides (ELPs) serve as attractive scaffolds for nanoformulations because they can be charge-neutral, water soluble, high molecular weight, monodisperse, biodegradable, and decorated with functional proteins. We recently reported that fusion of the FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) reduces rapamycin (Rapa) toxicity and enables intravenous (IV) therapy in both a xenograft breast cancer model and a murine autoimmune disease model. Rapa has poor solubility, which leads to variable oral bioavailability or drug precipitation following parenteral administration. While IV administration is routine during chemotherapy, cytostatic molecules like Rapa would require repeat administrations in clinical settings. To optimize FKBP/Rapa for subcutaneous (SC) administration, this manuscript expands upon first-generation FSI nanoparticles ( R h ~ 25 nm) and compares them with two second-generation carriers (FA and FAF) that: i) do not self-assemble; ii) retain a hydrodynamic radius ( R h ~ 7 nm) above the renal filtration cutoff; iii) increase tumor accumulation; and iv) have either one (FA) or two (FAF) drug-binding FKBP domains per ELP protein. Methods: The carriers were compared and evaluated for temperature-concentration phase behavior by UV-Vis spectrophotometry; equilibrium binding and thermodynamics by Isothermal Titration Calorimetry; drug retention and formulation stability by Dialysis and Dynamic Light Scattering; in vitro efficacy using a cell proliferation assay; in vivo efficacy in human MDA-MB-468 orthotopic breast cancer xenografts; downstream target inhibition using western blot; tissue histopathology; and bio-distribution via optical imaging in the orthotopic xenograft mouse model. Results: Named after the two-headed bird in Hindu mythology, the 'Berunda polypeptide' FAF with molecular weight of 97 kDa and particle size, R h ~ 7 nm demonstrated polypeptide conformation of a soluble hydrated coiled polymer, retained formulation stability for one month post Rapa loading, eliminated toxicity observed with free Rapa after SC administration, suppressed tumor growth, decreased phosphorylation of a downstream target, and increased tumor accumulation in orthotopic breast tumor xenografts. Conclusion: This comprehensive manuscript demonstrates the versatility of recombinant protein-polymers to investigate drug carrier architectures. Furthermore, their facilitation of SC administration of poorly soluble drugs, like Rapa, may enable chronic self-administration in patients., Competing Interests: Competing Interests: J.P.D., S.P., and J.A.M are inventors on a patent describing subcutaneous delivery of small molecules using protein polymer fusions related to this work. All other authors declare no competing financial interests.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objective: Nanoparticles have special properties, such as higher surface-to-volume ratio and higher reactivity, which increases cell penetrability and enhance their applicability in the field of medicine, especially in the case where other drugs are ineffective. Calcium phosphate nanoparticles (CPNP) and their encapsulation with therapeutic and/or diagnostic agents is such an agent synthesized. However, there are concerns related to the colloidal stability of these nanoparticles, which are reflected in their tendency to form aggregates in the physiological milieu. Therefore, successful translation of these nanoparticles from laboratory to the clinic requires studies of biodistribution and biocompatibility of nanoparticles for in vivo biomedical applications., Method: Calcium phosphate nanoparticles synthesized and were tagged with a fluorophore and surface stabilized with trisilanol for stable aqueous dispersion. The in vivo biodistribution and sub-acute toxicological studies were done for orally-administered calcium phosphate nanoparticles., Results: The biodistribution studies indicated that these nanoparticles were not prone to rapid degradation or excretion in the body, were long-circulating, and could appreciably permeate to the brain. Body/organ weight and biochemical analyses did not reveal much difference between nanoparticle-administered and saline-administered (control) groups. Finally, histopathological analyses of major organs such as liver, lungs, heart, stomach and kidney, did not reveal significant abnormalities in the treatment groups., Conclusion: Thus, it is evident from these sub-acute toxicity studies that the nanoparticles appear to be non-toxic to rats following oral administration. These observations can have significant implications in calcium-phosphate nanoparticle-mediated non-toxic drug delivery to target organs, such as brain, via non-invasive, oral route., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The production of layered double hydroxide(LDH) nanocomposite as an alternative drug delivery system against various ailments is on the increase. Their toxicity potential is usually dose and time dependent with particle sizes, shapes and surface charge playing some role both in the in vitro and in vivo studies. The reticular endothelial system of especially the liver and spleen were shown to sequestrate most of these nanocomposite, especially those with sizes greater than 50 nm. The intracellular drug delivery by these particles is mainly via endocytotic pathways aided by the surface charges in most cases. However, structural modification of these nanocomposite via coating using different types of material may lower the toxicity where present. More importantly, the coating may serve as targeting ligand hence, directing drug distribution and leading to proper drug delivery to specific area of need; it equally decreases the unwanted nanocomposite accumulation in especially the liver and spleen. These nanocomposite have the advantage of wider bio-distribution irrespective of route of administration, excellent targeted delivery potential with ease of synthetic modification including coating.

Nobiliside A (Nob) is a new triterpenoid saponin separated from Holothuria noblilis. In this article, a liquid chromatography-electrospray ionization-tandem mass spectrometry method was established to quantify Nob, a hemolytic saponin, in rat blood and tissue homogenates. Standard curves were linear (r=0.9988-0.9995) over the range 50-5000ng/mL in blood and 100-10000ng/g in tissues. The lower limit of quantification (LLOQ) was 50ng/mL for Nob. The novel method was rapid, accurate, highly sensitive and highly selective. Using this method, the pharmacokinetics and biodistribution of Nob liposome and Nob solution in Sprague-Dawley rats after a single intravenous dose of 1mg/kg were then investigated. Nob was cleared slowly from circulation. There was no significant difference of the pharmacokinetic parameters in blood between Nob solution and Nob liposome. The highest AUC of Nob was observed in liver for the two groups, followed by spleen, lungs, kidney and heart. Compared with Nob solution, Nob liposome showed much higher AUC in liver and spleen and much lower AUC in kidney, heart and lung, which might be one important reason for the decreased toxicity of Nob., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A simple, rapid and sensitive LC-UV method was developed and validated for the determination of paclitaxel (PTX) in rabbit plasma and tissues. A 2 mL aliquot of acetonitrile and 10 μL ammonium acetate (pH 5.0, 6 m) as extraction agents were used to markedly increase the extraction recoveries and greatly reduce the endogenous substances. The separation was achieved on a C18 column at 30 °C using an acetonitrile-ammonium acetate buffer (pH 5.0, 0.02 m; 55:45, v/v) at a flow rate of 1.0 mL/min; UV detection was used at 227 nm. Good linearity was obtained between 0.025 and 10,000 µg/mL for plasma and between 0.025-200,000 µg/g for tissue samples (r > 0.999). The limit of detection was 6 ng/mL in plasma, 8 ng/g in heart and 12.5 ng/g in other tissues. The limit of quantitation was 25 ng/mL in plasma and heart, 125 ng/g in other tissues. The intra- and inter-day assays of precision and accuracy for all bio-samples ranged from 1.38 to 9.60% and from 83.6 to 114.5%, respectively. The extraction recoveries ranged from 70.1 to 109.5%. Samples were stable during three freeze-thaw cycles or stored in a freezer at -20 °C for 30 days. The assay method was successfully applied to a study of the pharmacokinetics and tissue distribution of novel PTX lung targeting liposomes., (Copyright © 2013 John Wiley & Sons, Ltd.)

Within the framework of the fight against cancer, oncolytic viruses inducing the specific death of represent tumour cells, a new therapeutic approach. If some viruses such as the reovirus, the parvovirus or the vesicular stomatitis virus are naturally oncotropic, most of viruses assessed for their property to specifically lyse cancer cells are genetically modified. Mostly, these modifications consist in deleting genes which are necessary for replication in normal cells but dispensable in a neoplasic context. Thus, the adenovirus Onyx-015 or the herpes virus G207 are already prone to clinical studies. However, efficiency of these modified viruses is limited by the host's immune system. Moreover, these modified agents derived from their disease-induced wild-type counterparts could potentially evolved in vivo and cause unexpected adverse effects. Therefore, future research will focus on generating safer and tolerated viral tools. In that context, a better knowledge of the biology and the bio-distribution of these viruses is required.