Nanocarriers with Gentamicin to Treat Intracellular Pathogens

2006 ◽  
Vol 6 (9) ◽  
pp. 3296-3302 ◽  
Author(s):  
C. Lecaroz ◽  
C. Gamazo ◽  
M. J. Blanco-Prieto
Keyword(s):  
Macrophage Activation ◽  
Polymeric Nanoparticles ◽  
Current Treatment ◽  
Delivery Systems ◽  
Oxygen Intermediates ◽  
Water Solvent ◽  
Biodistribution Studies ◽  
Target Organs

Brucellosis is a worldwide zoonosis caused by different species of the genus Brucella. The intracellular localisation of this pathogen, particularly in macrophages, renders treatment difficult since most antibiotics known to be efficient in vitro do not actively pass through cellular membranes. As alternative to current treatment, polymeric drug delivery systems containing gentamicin have been developed. These particulate carriers target the drug into the mononuclear-phagocytic system, where the pathogen resides that will allow intracellular accumulation of the antibiotic after particle degradation. Besides, particle uptake may induce macrophage activation, increasing the production of reactive oxygen intermediates, involved in host defense against the intracellular pathogen. The aim of the present work was to study the suitability of polymeric nanoparticles for gentamicin entrapment in view to treat brucellosis. Different poly(lactide-co-glycolide) PLGA polymers were used to formulate the nanoparticles containing gentamicin by a water-oil-water solvent evaporation method. Furthermore, in vitro macrophage activation upon nanoparticles phagocytosis and in vivo distribution of the nanocarriers in the target organs for Brucella (liver and spleen) were also studied. The nanoparticle sizes were below 350 nm, the gentamicin encapsulation efficiency depended on the polymer type used for their preparation and the in vitro release of the antibiotic exhibited a continuos pattern (PLGA 502H). PLGA 502H nanoparticles were the most suitable due to the highest entrapment and the most sustained release. The nanoparticles were successfully phagocyted by a J774 murine monocytes cell line and biodistribution studies in mice after intravenous administration of the delivery systems revealed that the particles reached the target organs of Brucella (liver and spleen). All together, these results indicate that the nanocarriers described in this work may be suitable as gentamicin delivery system to control brucellosis.

68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

2019 ◽  
Vol 18 (9) ◽  
pp. 1289-1294 ◽  
Author(s):  
Kusum Vats ◽  
Rohit Sharma ◽  
Haladhar D. Sarma ◽  
Drishty Satpati ◽  
Ashutosh Dash
Keyword(s):  
Solid Phase ◽  
Evaluation Studies ◽  
Radiochemical Yield ◽  
In Vivo Evaluation ◽  
Peptide Conjugates ◽  
Biodistribution Studies ◽  
Target Organs ◽  
U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

scholarly journals Macrophage oxygen-dependent antimicrobial activity. III. Enhanced oxidative metabolism as an expression of macrophage activation.

1980 ◽  
Vol 152 (6) ◽  
pp. 1596-1609 ◽  
Author(s):  
H W Murray ◽  
Z A Cohn
Keyword(s):  
Antimicrobial Activity ◽  
Oxidative Metabolism ◽  
Macrophage Activation ◽  
Systemic Infection ◽  
Peritoneal Macrophages ◽  
H2o2 Production ◽  
Oxygen Intermediates ◽  
Cultivation In Vitro

The capacity of 15 separate populations of mouse peritoneal macrophages to generate and release H2O2 (an index of oxidative metabolism) was compared with their ability to inhibit the intracellular replication of virulent Toxoplasma gondii. Resident macrophages and those elicited by inflammatory agents readily supported toxoplasma multiplication and released 4-20X less H2O2 than macrophages activated in vivo by systemic infection with Bacille Calmette-Guérin or T. gondii, or by immunization with Corynebacterium parvum. Immunologically activated cells consistently displayed both enhanced H2O2 production and antitoxoplasma activity. Exposure to lymphokines generated from cultures of spleen cells from T. gondii immune mice and toxoplasma antigen preserved both the antitoxoplasma activity and the heightened H2O2 release of toxoplasma immune and immune-boosted macrophages, which otherwise were lost after 48-72 h of cultivation. In vitro activation of resident and chemically-elicited cells by 72 h of exposure to mitogen- and antigen-prepared lymphokines, conditions that induce trypanocidal (5) and leishmanicidal activity (14), stimulated O2- and H2O2 release, and enhanced nitroblue tetrazolium reduction in response to toxoplasma ingestion. Such treatment, however, failed to confer any antitoxoplasma activity, indicating that intracellular pathogens may vary in their susceptibility to macrophage microbicidal mechanisms, including specific oxygen intermediates. In contrast, cocultivating normal macrophages with lymphokine plus heart infusion broth for 18H rendered these cells toxoplasmastatic. This in vitro-acquired activity was inhibited by scavengers of O2-, H2O2, OH., and 1O2, demonstrating a role for oxidative metabolites in lymphokine-induced enhancement of macrophage antimicrobial activity. These findings indicate that augmented oxidative metabolism is an consistent marker of macrophage activation, and that oxygen intermediates participate in the resistance of both in vivo- and vitro-activated macrophages toward the intracellular parasite, T. gondii.

Stimuli-responsive Polymeric nanosystems for therapeutic applications

2021 ◽  
Vol 27 ◽  
Author(s):  
Mayank Handa ◽  
Ajit Singh ◽  
S.J.S. Flora ◽  
Rahul Shukla
Keyword(s):  
Drug Delivery ◽  
Metallic Nanoparticles ◽  
Drug Delivery Systems ◽  
Polymeric Nanoparticles ◽  
Drug Loading ◽  
Delivery Systems ◽  
Specific Drug ◽  
Stimuli Responsive

Background: Recent past decades have reported emerging of polymeric nanoparticles as a promising technique for controlled and targeted drug delivery. As nanocarriers, they have high drug loading and delivery to the specific site or targeted cells with an advantage of no drug leakage within en route and unloading of a drug in a sustained fashion at the site. These stimuli-responsive systems are functionalized in dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, quantum dots. Purpose of Review: The authors reviewed the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli like pH, temperature, redox, light, and magnet. These stimuli-responsive drug delivery systems behave differently in In vitro and In vivo drug release patterns. Stimuli-responsive nanosystems include both hydrophilic and hydrophobic systems. This review highlights the recent development of the physical properties and their application in specific drug delivery. Conclusion: The stimuli (smart, intelligent, programmed) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, lifestyle disorders. As development and innovation, the stimuli-responsive based nanocarriers are moving at a fast pace and huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.

scholarly journals Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics

2014 ◽  
Vol 2014 ◽  
pp. 1-23 ◽  
Author(s):  
Su-Eon Jin ◽  
Hyo-Eon Jin ◽  
Soon-Sun Hong
Keyword(s):  
Anticancer Drugs ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Anticancer Therapy ◽  
Delivery Systems ◽  
Specific Receptors ◽  
Targeted Delivery System ◽  
Targeted Delivery Systems

Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100 nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regardingin vitroandin vivoapplications and the translation of nanobiomaterials to nanomedicine in anticancer therapy.

scholarly journals Preclinical Evaluation of Radiolabeled Peptides for PET Imaging of Glioblastoma Multiforme

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2496 ◽  
Author(s):  
Zbynek Novy ◽  
Jana Stepankova ◽  
Michaela Hola ◽  
Dominika Flasarova ◽  
Miroslav Popper ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Tumor Imaging ◽  
Ex Vivo ◽  
Tumor Model ◽  
Rgd Peptides ◽  
Radiolabeled Peptides ◽  
Biodistribution Studies ◽  
Target Organs

In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.

Applications of Polymeric Nanoparticles in Oral Diseases: A Review of Recent Findings

2018 ◽  
Vol 24 (13) ◽  
pp. 1377-1394 ◽  
Author(s):  
Paula Chaves ◽  
Joao Oliveira ◽  
Alex Haas ◽  
Ruy Carlos Ruver Beck
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Polymeric Nanoparticles ◽  
Delivery Systems ◽  
Drug Uptake ◽  
Oral Diseases ◽  
Dental Biofilm ◽  
Treatment And Prevention

Polymeric nanoparticles are promising drug delivery systems due to their physicochemical properties, which may be explored to improve the treatment and prevention of several diseases, including oral conditions. Moreover, the pharmacological effects of polymers may be improved by nanostructuration. Therefore, this article provides a detailed review of the studies published between 2010 and 2017 covering the use of polymeric nanoparticles in the treatment and/or prevention of oral diseases. A brief description about the dental biofilm and oral diseases is presented in first part of the article. The following section includes an important discussion about the strategies studied to improve the treatment and prevention of these diseases using polymeric nanoparticles: (i) a better drug antibacterial effect, (ii) the release of the drug in a time-controlled way, (iii) the increase of drug uptake by cells, (iv) the cytotoxicity in tumor cells and solubility in water, and (v) mucoadhesive drug delivery systems. Furthermore, the composition and size of the polymeric nanoparticles explored by these strategies were described. Finally, in the last part of this review, the in vitro and in vivo results which demonstrate the effect of these systems in the treatment and/or prevention of the most prevalent oral disorders were highlighted: dental carious lesions, oral cancer, and periodontal and endodontic diseases.

Biodegradable Polymeric Nanoparticles for Tumor-Selective Tamoxifen Delivery: In Vitro and in Vivo Studies

2004 ◽  
Vol 845 ◽  
Author(s):  
Dinesh B. Shenoy ◽  
Jugminder S. Chawla ◽  
Mansoor M. Amiji
Keyword(s):  
Cellular Uptake ◽  
Polymeric Nanoparticles ◽  
Therapeutic Benefit ◽  
In Vivo Studies ◽  
Tumor Mass ◽  
Biodistribution Studies ◽  
Poly Ethylene ◽  
Surface Modified

1. ABSTRACT: This study was performed to evaluate the in-vitro and in-vivo tumor-cellular uptake and biodistribution pattern of tamoxifen when administered intravenously as a simple solution and upon encapsulation into biodegradable, surface-modified poly(ε-caprolactone) (PCL) nanoparticles. PCL (MW ∼ 15, 000) nanoparticles were prepared by the solvent displacement method and characterized for particle size/charge and surface morphology (by scanning electron microscopy). We investigated the nanoparticle-surface modification potential of the hydrophilic stabilizer (Pluronic® F-68 and F-108) employed during the preparation by electron spectroscopy for chemical analysis (ESCA). Quantitative in-vitro cellular uptake of tritiated (3H) tamoxifen in solution form and as nanoparticulate formulation was assessed in MCF-7 breast cancer cells. In-vivo biodistribution studies for the same formulations were carried out in Nu/Nu mice bearing MDA-MB-231 human breast carcinoma xenograft. Spherical nanoparticles having positive zeta potential (∼25 mV) were obtained in the size range of 200-300 nm. Pluronics (both F-68 and F-108), the triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) induced surface hydrophilization of the nanoparticles via adsorption as evident by ESCA. Nanoparticulate formulations of tamoxifen achieved higher intracellular concentrations when exposed at therapeutic concentrations to tumor cells in-vitro compared to solutions. The in-vivo biodistribution studies carried out in nude mice bearing experimental breast tumor suggested increased tumor concentrations for the drug administered as nanoparticulate formulations besides longer retention times within tumor mass. This type of delivery system is expected to provide better therapeutic benefit by dual means: preferential concentration within the tumor mass via enhanced permeation and retention pathway, and; subsequent controlled release, thus maintaining the local drug concentration for longer periods of time to achieve maximal cell-kill.

scholarly journals Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

2021 ◽  
Author(s):  
Naresh Damuka ◽  
Miranda Orr ◽  
Paul W. Czoty ◽  
Jeffrey L. Weiner ◽  
Thomas J. Martin ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Ex Vivo ◽  
Neuroblastoma Cells ◽  
Proper Function ◽  
Brain Functions ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
Vitro Binding

AbstractMicrotubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

scholarly journals Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

2021 ◽  
Vol 7 (2) ◽  
pp. 113
Author(s):  
Anne-Laure Bidaud ◽  
Patrick Schwarz ◽  
Guillaume Herbreteau ◽  
Eric Dannaoui
Keyword(s):  
Animal Models ◽  
Fungal Infections ◽  
Acquired Resistance ◽  
Adequate Treatment ◽  
Combination Treatments ◽  
Target Organs ◽  
Fungal Load ◽  
Time Kill

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

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