Clinical Editor Research Articles

Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer

The aim of this study was to assess the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with the anticancer drugs lonidamine and paclitaxel. Plasma, tumor, and tissue distribution profiles were quantified in an orthotopic animal model of multidrug-resistant breast cancer and were compared to treatment with nontargeted nanoparticles and to treatment with drug solution. A poly(d,l-lactide-co-glycolide)–poly(ethylene glycol)–EGFR targeting peptide (PLGA-PEG-EFGR peptide) construct was synthesized for incorporation in poly(ɛ-caprolactone) particles to achieve active EGFR targeting. An isocratic high-pressure liquid chromatography method was developed to quantify lonidamine and paclitaxel in mice plasma, tumors, and vital organs. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, particularly for lonidamine delivery. The first target site of accumulation was the liver, followed by the kidneys, and then the tumor mass; maximal tumor accumulation occured at 3 hours after administration. Lonidamine-paclitaxel combination therapy administered via EGFR-targeted polymer-blend nanocarriers may become a viable platform for the future treatment of multidrug-resistant cancer. From the Clinical EditorIn this study the biodistribution and pharmacokinetics of epidermal growth factor receptor (EGFR)–targeted polymer-blend nanoparticles loaded with lonidamine and paclitaxel were assessed. The targeted nanoparticles demonstrated a superior pharmacokinetic profile relative to drug solution and nontargeted nanoparticles, paving the way to new therapeutic approaches for multidrug-resistant malignancies.

Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA

We report the preparation of mannosylated nanoparticles loaded with messenger RNA (mRNA) that enhance the transfection of dendritic cells (DCs) in vivo and the anti-B16F10 melanoma vaccination in mice. Mannosylated and histidylated lipopolyplexes (Man11-LPR100) were obtained by adding mannosylated and histidylated liposomes to mRNA-PEGylated histidylated polylysine polyplexes. Upon intravenous injection, ∼9% of the radioactivity of technetium 99 m–labeled lipopolyplexes measured in the liver, spleen, lungs, and kidneys was found in the spleen. We demonstrate that spleen from mice injected with enhanced green fluorescent protein (EGFP) mRNA-loaded Man11-LPR100 contained four times more DCs expressing EGFP than that from mice injected with sugar-free LPR100. This better transfection of DCs is correlated with a better inhibition of B16F10 melanoma growth and an increased survival time when mice were immunized with MART-1 mRNA-loaded Man11-LPR100. These results indicate that mannosylated and histidylated LPR is an efficient system for the delivery of tumor antigen mRNA in splenic DCs aiming to induce an anticancer immune response. From the Clinical EditorThis paper discusses the preparation of mannosylated nanoparticles loaded with messenger RNA that enhance the transfection of dendritic cells (DCs) in vivo and the anti-B16F10 melanoma vaccination in mice. The authors describe an efficient system for the delivery of tumor antigen mRNA in splenic DCs aiming to induce an anticancer immune response.

A nanoemulsion formulation of dacarbazine reduces tumor size in a xenograft mouse epidermoid carcinoma model compared to dacarbazine suspension

Dacarbazine (DAC) is an anticancer drug that has been used to treat various types of cancers. The aim of the current study was to test whether there is an increased efficacy of DAC as a nanoemulsion on reducing tumor size in an epidermoid carcinoma xenograft mouse model. Tumors were induced in 5-week-old nude mice by subcutaneous injection. The mice were untreated or treated with a suspension of DAC (0.1 mg/kg), a nanoemulsion of DAC (0.1 mg/kg), or Nano-Control (same composition as the suspension and nanoemulsion but no DAC), every 2 days by either intramuscular injection (IM) or topical application. After 40 days, the final tumor size of mice receiving the nanoemulsion of DAC IM (0.83 ± 0.55 mm 3) was significantly reduced compared to the suspension of DAC IM (4.75 ± 0.49 mm 3), Nano-Control IM (7.63 ± 0.91 mm 3), and untreated (10.46 ± 0.06 mm 3). The final tumor size of mice receiving the nanoemulsion of DAC topically (3.33 ± 0.63 mm3) was also significantly reduced compared to the suspension of DAC topically (7.64 ± 0.68 mm 3). This increased efficacy maybe partially attributed to: 1) the reduced particle size of the nanoemulsion in comparison with suspension (111 versus > 6000 nm), 2) reduction in zeta potential of the nanoemulsion compared to suspension (−3.2 versus −89.1 mV), 3) production of a stable water dispersion relative to unstable suspension, 4) decreased polydispersity index of the nanoemulsion compared to suspension, and 5) greater stability of drug with the nanoemulsion in comparison with the suspension. From the Clinical Editor In this clinically relevant study, the anti-tumor efficacy of dacarbazine was found to be significantly increased as a nanoemulsion in epidermoid carcinoma xenograft mice, both with IM and topical administration.

Targeted human serum albumin nanoparticles for specific uptake in EGFR-Expressing colon carcinoma cells

The specific application and transport of drugs into malignant tissue is a critical point during diagnosis and therapy. Nanoparticles are known as excellent drug carrier systems and offer the possibility of surface modification with targeting ligands, leading to a specific accumulation in the targeted tissue. First, the specificity of such a carrier system has to be proven. In this study, cetuximab-modified nanoparticles based on biodegradable human serum albumin (HSA) are investigated regarding their cellular binding and intracellular accumulation. Different EGFR-expressing colon carcinoma cells were used to test possible cytotoxic potential, specific binding and intracellular accumulation. A specific accumulation targeting the EGFR could be shown. These results emphasize that cetuximab-modified HSA-nanoparticles are a promising carrier system for later drug transport. To our knowledge, this is the first study investigating the specific accumulation of HSA nanoparticles into different EGFR-expressing colon carcinoma cells. From the Clinical EditorIn this study, cetuximab-modified nanoparticles based on human serum albumin (HSA) are investigated regarding their cellular binding and intracellular accumulation. The results suggest that these nanoparticles are a promising carrier system for EGFR overexpressing colon carcinoma cells.

Calcium phosphate drug nanocarriers with ultrahigh and adjustable drug-loading capacity: One-step synthesis, in situ drug loading and prolonged drug release

Calcium phosphates (CPs) are regarded as the most biocompatible inorganic biomaterials; however, they are limited in the drug-delivery applications, especially for hydrophobic drugs. Achieving high drug-loading capacity and a controllable drug-release property are two main challenges. In this study we report a strategy for the preparation of novel drug delivery systems based on a concerted process in which the formation of the CP nanocarriers and the drug storage are accomplished in one step in mixed solvents of water and ethanol. The key advantage of this strategy is that the formation of CP nanocarriers and in situ loading of the drug occur simultaneously in the same reaction system, which makes it possible to achieve ultrahigh drug-loading capacity and prolonged drug release due to ultrahigh specific surface area and numerous binding sites of the CP nanocarriers. A series of hydrophobic drug-delivery systems with adjustable drug-loading capacities and drug-release rates have been successfully synthesized. In addition, the drug-release kinetics of the as-prepared drug-delivery systems have been found in which the cumulative amount of drug release has a linear relationship with the natural logarithm of release time. From the Clinical EditorCalcium phosphates (CPs) are highly biocompatible inorganic biomaterials with thus far limited drug-delivery applications. This study reports the preparation of a novel drug delivery system where the formation of CP nanocarriers and in situ loading of the drug occur simultaneously in the same reaction, enabling ultra-high drug-loading.

Multimodal imaging of dendritic cells using a novel hybrid magneto-optical nanoprobe

A transfecting agent-coated hybrid imaging nanoprobe (HINP) composed of visible and near-infrared (NIR) light emitting quantum dots (QDs) tethered to superparamagnetic iron oxide (SPIO) nanoparticles was developed. The surface modification of QDs and SPIO particles and incorporation of dual QDs within the SPIO were characterized by dynamic light scattering (DLS), quartz crystal microbalance (QCM) analysis and atomic force microscopy (AFM). The optical contrasting properties of HINP were characterized by absorption and photoluminescence spectroscopy and fluorescence imaging. Multicolor HINP was used in imaging the migration of dendritic cells (DCs) by optical, two-photon and magnetic resonance imaging techniques. From the Clinical EditorThe development of a transfecting agent-coated hybrid imaging nanoprobe (HINP) composed of visible and near-infrared light emitting quantum dots (QDs) tethered to superparamagnetic iron oxide nanoparticles is reported in this paper. Multicolor HINP was used in imaging the migration of dendritic cells by optical, two-photon and magnetic resonance imaging techniques.

Multifunctional silica nanoparticles with potentials of imaging and gene delivery

This article reports the method of preparation of gadolinium oxide-doped silica nanoparticles (NPs) whose surface has been functionalized to anchor DNA onto it. The silica NP's surface was modified by 3-aminopropyltrimethoxysilane for DNA to bind electrostatically. Silica NPs with low polydispersity and encapsulating gadolinium oxide were prepared in the aqueous core of the reverse micelles. The average size of these spherical silica NPs doped with gadolinium oxide and dispersed in water is ∼ 50 nm as measured by dynamic light scattering and transmission electron microscopy. The plasmid DNA electrostatically held over NP's surface was firmly immobilized and protected from DNase attack. The gadolinium oxide-doped silica NPs are paramagnetic as observed from the nuclear magnetic resonance (NMR) line-broadening effect on proton spectrum of the surrounding water. In vitro transfection efficiencies of these gadolinium oxide-doped and DNA-conjugated silica NPs in COS-7 and 293T cells were found to be about 75% and 77% respectively of that of ‘Polyfect®' as positive control. From the Clinical EditorThis article reports the method of preparation of gadolinium oxide-doped silica nanoparticles (NPs) whose surface has been functionalized to anchor DNA. These NPs are paramagnetic with in vitro transfection efficiencies in COS-7 and 293T cells of about 75% and 77% compared to ‘Polyfect®' as positive control.

Propidium iodide labeling of nanoparticles as a novel tool for the quantification of cellular binding and uptake

Because nanoparticles are promising tools in drug delivery, quantification of their cellular binding and uptake is an emerging question. Therefore, rhodamine B isothiocyanate–labeled silica nanoparticles with different sizes and surface modifications were investigated concerning their uptake in Caco-2 cells. Flow cytometry studies exhibited a size- and time-dependent association for unmodified nanoparticles (50 and 77 nm), whereas larger particles (94 nm) and polyethylene glycol–modified nanoparticles showed no cellular interaction. A second approach dealt with particles with adsorbed propidium iodide (PI) to distinguish between internalized and adsorbed nanoparticles. These particles only give a fluorescence signal when associated with nucleic acids inside the cell, whereas particles adsorbed to the outer cell surface are not detected. PI-labeled nanoparticles (21 nm) showed a time-dependent uptake, exhibiting a signal in the cytoplasm but less in the nucleus. These novel PI-labeled nanoparticles in combination with flow cytometry are innovative tools for the quantification of nanoparticulate uptake. From the Clinical EditorRhodamine B isothiocyanate–labeled silica nanoparticles with different sizes and surface modifications were investigated concerning their cellular uptake. Propidium iodide containing particles only give a fluorescence signal when associated with nucleic acids and are useful in detecting internalization of the particles. These novel nanoparticles in combination with flow cytometry are innovative tools for the quantification of nanoparticulate uptake.

CNS regeneration after chronic injury using a self-assembled nanomaterial and MEMRI for real-time in vivo monitoring

To speed up the process of central nervous system (CNS) recovery after injury, the need for real-time measurement of axon regeneration in vivo is essential to assess the extent of injury, as well as the optimal timing and delivery of therapeutics and rehabilitation. It was necessary to develop a chronic animal model with an in vivo measurement technique to provide a real-time monitoring and feedback system. Using the framework of the 4 P's of CNS regeneration (Preserve, Permit, Promote and Plasticity) as a guide, combined with noninvasive manganese-enhanced magnetic resonance imaging (MEMRI), we show a successful chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. We also show that a chronic optic tract (OT) lesion is able to heal, and axons are able to regenerate, when treated with a self-assembling nanofiber peptide scaffold (SAPNS). From the Clinical Editor The authors of this study demonstrate the development of a chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. In addition, they determined that chronic optic tract lesions are able to heal with axonal regeneration when treated with a self-assembling nanofiber peptide scaffold (SAPNS).

Visualization and analysis of superparamagnetic iron oxide nanoparticles in the inner ear by light microscopy and energy filtered TEM

Nanoparticles as potential carriers for local drug transfer are an alternative to systemic drug delivery into the inner ear. We report on the first in vitro tests of a new ferrogel consisting of superparamagnetic iron oxide nanoparticles (SPIONs) and a Pluronic ® F127 (PF127) copolymer. Pluronic copolymers possess a unique viscosity-adjustable property that makes PF127 gels easy to handle compared to conventional cross-linked hydrogels. This ferrogel was successfully tested in cadaver human temporal bones as well as in organotypic explant cultures of mouse inner ears. SPIONs were identified by light microscopy and localized with different imaging modes in energy-filtered transmission electron microscopy. Our approach shows a promising possibility to use iron oxide nanoparticles, which are suitable for visualization and characterization at both the light- and electron-microscopic levels. From the Clinical Editor The authors report the first in vitro tests of a new ferrogel consisting of superparamagnetic iron oxide nanoparticles (SPIONs) and a Pluronic® F127 (PF127) copolymer for drug delivery in the inner ear, demonstrasting a promising possibility to use iron oxide nanoparticles, which are suitable for visualization and characterization at both the light- and electron-microscopic levels.

Practice Makes Perfect—Simulation Training for Perioperative Professionals

AORN JournalVolume 92, Issue S6 p. S112-S112 Practice Makes Perfect—Simulation Training for Perioperative Professionals Helen Starbuck Pashley MA, RN, CNOR, Helen Starbuck Pashley MA, RN, CNOR Clinical Editor AORNSearch for more papers by this author Helen Starbuck Pashley MA, RN, CNOR, Helen Starbuck Pashley MA, RN, CNOR Clinical Editor AORNSearch for more papers by this author First published: 01 December 2010 https://doi.org/10.1016/j.aorn.2010.09.003 Originally published in the AORN Journal. 2010;91(6):669–670. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume92, IssueS62011 OR Product DirectoryDecember 2010Pages S112-S112 RelatedInformation

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ChemInform Abstract: Aquasomes: A Promising Carrier for Peptides and Protein Delivery

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Production of magnetic multilamellar liposomes as highly T 2-efficient MRI contrast agents

Lipid-based multilamellar vesicles loaded with aminosilane-modified maghemite nanoparticles (a-MNPs), also called magnetonions (MO), were analyzed for their magnetic resonance imaging (MRI) contrast agent properties. They were shown to be better T 2-MRI contrast agents than commercial contrast agents and other reported liposome-based contrast agents as shown by their higher value of relaxivity ratio (r 2/r 1 = 17), although a lower magnetic field intensity was used (0.2 T). Their high efficiency was explained by the aggregation of a-MNPs in between multilamellar vesicles, bilayers induced by MO preparation, and evidenced by cryo-TEM imaging. Magnetonions are then a promising platform for diagnosis and therapy. From the Clinical Editor In this study, magnetonions (MO) are presented as a very potent T2 relaxation enhancing MRI contrast agents. Such agents may be used in cell labeling and molecular imaging applications.

In vitro protein adsorption studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy

Nevirapine is a poorly water-soluble antiretroviral drug. Intravenous nevirapine nanosuspensions (NS) (457 ± 10 nm) were prepared by high-pressure homogenization. NS were surface modified by stabilizer adsorption, e.g., serum albumin, polysaccharide and polyethylene glycol (PEG) 1000. The NS were characterized for mean particle size, particle size distribution and polydispersity index. The targeting potential of the nonmodified and three surface-modified NS to the mononuclear phagocytic system (MPS) cells that serve as potent viral reservoirs was assessed by in vitro protein adsorption studies using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). The adsorption patterns were qualitatively identical, but showed quantitative differences. The relatively adsorbed high amounts of immunoglobulins indicate uptake by liver and spleen, observed quantitative differences (e.g., the amount of dysopsonin albumin and apolipoproteins) can modulate the organ distribution. Controlled in vitro optimization of the protein adsorption by surface modification of the nanocrystals can reduce the number of animals required for in vivo studies and accelerate development of targeted nanoparticles. From the Clinical Editor In this study, intravenous nevirapine (a poorly water-soluble antiretroviral drug) nanosuspensions were prepared by high-pressure homogenization and characterized.

Ag colloids and Ag clusters over EDAPTMS-coated silica nanoparticles: synthesis, characterization, and antibacterial activity against Escherichia coli

To produce better antibacterial water-insoluble nanocomposites of silver (Ag), silver–silicon dioxide (Ag-SiO 2) hybrid and silver colloid (Ag-c) nanoparticles (NPs) were studied. Ag-c NPs were synthesized using reduction of AgNO 3, and Ag-SiO 2 composites were prepared on a core of silica NPs functionalized with ethylenediamino-propyltrimethoxysilane, where Ag clusters were fabricated on amino groups using seed-mediated growth and characterized by transmission electron microscopy and ultraviolet-visible absorption spectroscopy. Antibacterial effectiveness of the Ag-SiO 2 NPs was tested against general Escherichia coli ( E. coli ATCC 25922) and E. coli O157:H7 by measuring the growth based on optical density and digital counting of live-dead cells using a fluorescent microscope, and a field emission scanning electron microscope. Minimum inhibitory concentration values were studied against four representative bacteria along with E. coli O157:H7. Results showed that Ag NPs of 6.6 ± 4.5 nm were attached to the surface of SiO 2 NPs (74 ± 13.5 nm), and the Ag-c NPs (3.5 ± 2 nm) showed excellent antibacterial properties. From the Clinical Editor In this paper, the synthesis of Ag colloids and Ag clusters over EDAPTMS-coated silica nanoparticles is reported. Both NPs were examined for antibacterial effectiveness against representative bacteria including E. coli O157:H7 and found to have excellent antibacterial properties.

Comparing cellular uptake and cytotoxicity of targeted drug carriers in cancer cell lines with different drug resistance mechanisms

The purpose of this study was to compare the cellular uptake and cytotoxicity of targeted and nontargeted doxorubicin (DOX)-loaded poly(d,l-lactide co-glycolide) (PLGA) nanoparticle (NP) drug delivery systems in drug-resistant ovarian (SKOV-3) and uterine (MES-SA/Dx5) cancer cell lines. The cellular uptakes of DOX from nonconjugated DOX-loaded NPs (DNPs) and from HER-2 antibody–conjugated DOX-loaded NPs (ADNPs) in MES-SA/Dx5 cancer cells were higher compared to free DOX. Results also showed higher uptake of DOX from ADNPs in SKOV-3 cells compared with both free DOX and DNPs treatment. Cytotoxicity results at 10 μM extracellular DOX concentration were consistent with the cellular uptake results. Our study concludes that cellular uptake and cytotoxicity of DOX can be improved in MES-SA/Dx5 cells by loading DOX into PLGA NPs. DNPs targeted to membrane receptors may enhance cellular uptake and cytotoxicity in SKOV-3 cells. From the Clinical Editor The authors of this study compare the cellular uptake and cytotoxicity of targeted and nontargeted doxorubicin loaded PLGA nanoparticle delivery systems in drug-resistant ovarian and uterine cancer cell lines, concluding that cellular uptake and cytotoxicity of doxorubicin can be improved by the proposed methods.

Nanomedicine and personalized medicine toward the application of pharmacotyping in clinical practice to improve drug-delivery outcomes

Recent technological advances in nanomedicine and nanotechnology in parallel with knowledge accumulated from the clinical translation of disease- and drug-related genomic data have created fertile ground for personalized medicine to emerge as the new direction in diagnosis and drug therapy. To this end, the development of sophisticated nano-based systems for targeted drug delivery, along with the advent of pharmacogenomics, moves the drug-prescription process toward pharmacotyping, e.g., the individualized adjustment of drug selection and dosage. However, the clinical validity and utility of pharmacogenomic testing must be demonstrated by cost-effectiveness analysis and establishment of clinical-practice reimbursement codes. Within this framework, and to achieve major benefits for all patients worldwide, a multidisciplinary scientific and technological infrastructure has to be organized in the healthcare system to address better the issues affecting regulatory environment, clinical pharmacology guidelines, education, bioethics and genomics data dissemination. From the Clinical Editor Individualized pharmacotyping, patient and disease-specific delivery of drugs, combining nanotechnology and pharmagenomics-based approaches would result in much more specific and efficient treatment of a variety of illnesses. While this clearly is one of the main cornerstones of individualized medicine; the cost effective integration of this complex technology is far from trivial, as discussed in details in this opinion paper.

Cancer targeting potential of some ligand-anchored poly(propylene imine) dendrimers: a comparison

The present investigation was aimed at developing and comparing the cancer-targeting potential of ligand-anchored dendrimers. Folate-, dextran-, and galactose-anchored poly(propylene imine) dendrimers were synthesized and characterized. Dendritic formulations were evaluated for ex vivo cytotoxicity on HeLa and SiHa cell lines. Flow cytometry studies were performed on the HeLa cell line. An ex vivo MTT assay on HeLa cells indicated IC 50 values of 0.05, 0.2, 0.8, and 0.08 μM for folate, dextran, and galactose formulations, and for free paclitaxel (PTX), respectively. An analogous observation was carried out in SiHa cells, where IC 50 values of 0.6, 0.8, 10, and 6 μM were observed by folate, dextran, and galactose formulations, and free PTX, respectively. The outcome of the MTT assay and flow cytometry suggested the order of targeting potential of various ligands under investigation as folate > dextran > galactose. The outcome is deemed to be of scientific value and is believed to assist drug delivery scientists during selection of targeting ligands. From the Clinical Editor The cancer targeting potential of folate, dextran and galactose functionalized polypropyleneimine (PPI) dendrimers was studied by this group of investigators, reporting the order of targeting potential as folate > dextran > galactose.

Copper complex of a pyridine-modified poly(amidoamine) dendrimer as a chemical nuclease: synthetic and catalytic study

[Cu Y((G:2-6)- dendri-PAMAM-(Py) n)] 2Y+ complexes (3) were prepared, and their ability to generate oxygen radical anions was investigated. The maximum catalytic efficiency ( k′ cat/ K M) was found to be 0.32 min –1·μM –1, and a positive dendritic effect was observed. The saturated kinetics revealed that the improved catalytic efficiency resulted from an enhanced binding affinity toward molecular oxygen. From the Clinical Editor In this basic science study, the oxygen radical anion generating ability of specific copper complex of a pyridine-modified poly(amidoamine) dendrimer was investigated and reported in details.