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Sosnik A.,Technion - Israel Institute of Technology | Carcaboso A.M.,Preclinical Therapeutics and Drug Delivery Research Program
Advanced Drug Delivery Reviews | Year: 2014

Nanotechnology has become a key tool to overcome the main (bio)pharmaceutical drawbacks of drugs and to enable their passive or active targeting to specific cells and tissues. Pediatric therapies usually rely on the previous clinical experience in adults. However, there exists scientific evidence that drug pharmacokinetics and pharmacodynamics in children differ from those in adults. For example, the interaction of specific drugs with their target receptors undergoes changes over the maturation of the different organs and systems. A similar phenomenon is observed for toxicity and adverse effects. Thus, it is clear that the treatment of disease in children cannot be simplified to the direct adjustment of the dose to the body weight/surface. In this context, the implementation of innovative technologies (e.g., nanotechnology) in the pediatric population becomes extremely challenging. The present article overviews the different attempts to use nanotechnology to treat diseases in the pediatric population. Due to the relevance, though limited available literature on the matter, we initially describe from preliminary in vitro studies to preclinical and clinical trials aiming to treat pediatric infectious diseases and pediatric solid tumors by means of nanotechnology. Then, the perspectives of pediatric nanomedicine are discussed. © 2014 Elsevier B.V. Source


Cockle J.V.,University of Leeds | Cockle J.V.,Yorkshire Regional Center for Paediatric Oncology and Haematology | Picton S.,Yorkshire Regional Center for Paediatric Oncology and Haematology | Levesley J.,University of Leeds | And 7 more authors.
British Journal of Cancer | Year: 2015

Background:Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed.Methods:Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays.Results:All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging.Conclusions:Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours. © 2015 Cancer Research UK. Source


Daryani V.M.,St Jude Childrens Research Hospital | Patel Y.T.,St Jude Childrens Research Hospital | Tagen M.,Genentech | Turner D.C.,Merck And Co. | And 5 more authors.
CPT: Pharmacometrics and Systems Pharmacology | Year: 2016

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. Source


Monterrubio C.,Hospital Sant Joan de Deu Barcelona | Monterrubio C.,Preclinical Therapeutics and Drug Delivery Research Program | Paco S.,Hospital Sant Joan de Deu Barcelona | Paco S.,Preclinical Therapeutics and Drug Delivery Research Program | And 13 more authors.
Pharmaceutical Research | Year: 2015

Abstract Purpose: To develop a reproducible microdialysis-tumor homogenate method for the study of the intratumor distribution of a highly hydrophobic anticancer drug (SN-38; 7-ethyl-10-hydroxycamptothecin) in neuroblastoma patient-derived xenografts. Methods: We studied the nonspecific binding of SN-38 to the microdialysis tubing in the presence of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the perfusate. We calibrated the microdialysis probes by the zero flow rate (ZFR) method and calculated the enhancement factor (f=extrapolated SN-38 concentration at the ZFR / SN-38 concentration in the dialysed solution) of HPBCD. We characterized the extravasation of HPBCD to tumors engrafted in mice. In vivo microdialysis and terminal homogenate data at the steady state (subcutaneous pump infusions) were used to calculate the volume of distribution of unbound SN-38 (Vu,tumor) in neuroblastoma. Results: HPBCD (10%w/v) in the perfusate prevented the nonspecific binding of SN-38 to the microdialysis probe and enhanced SN-38 recovery (f=1.86). The extravasation of HPBCD in the tumor during microdialysis was lower than 1%. Vu,tumor values were above 3 mL/g tumor for both neuroblastoma models and suggested efficient cellular penetration of SN-38. Conclusions: The method contributes to overcome the limitations of the microdialysis technique in hydrophobic drugs and provides a powerful tool to characterize compartmental anticancer drug distribution in xenografts. © 2015 Springer Science+Business Media New York. Source


Ordonez J.L.,University of Seville | Ordonez J.L.,University of Salamanca | Amaral A.T.,University of Seville | Amaral A.T.,University of Salamanca | And 18 more authors.
Oncotarget | Year: 2015

Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting. Source

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