Nanomedicine: Nanotechnology, Biology and Medicine

In vivo tumor imaging using a novel RNAi-based detection mechanism

2012-02-20

Abstract: A new concept of tumor imaging is introduced using a siRNA-based probe that is capable of amplifying a specific endogenous fluorescence emission in cancerous tissue. In previous studies, we demonstrated a significant downregulation of Ferrochelatase (FECH) mRNA-expression in colorectal carcinomas leading to the accumulation of protoporphyrin IX (PpIX), a fluorescent metabolite of the heme synthesis. In this article, we report on first in vivo experiments in xenografted nude mice using folate-coupled liposomes or dendritic polyglycerolamine nanoparticles carrying ferrochelatase-siRNA to enhance PpIX-derived fluorescence in the tumor tissue. Tiny tumor foci could be monitored by the emission of PpIX fluorescence in vivo. Due to the omnipresence of the heme synthesis pathway, targeted application of ferrochelatase-siRNA may provide a general means for molecular imaging.From the Clinical Editor: A new concept of tumor imaging is presented in this paper using a siRNA-based probe detecting protoporphyrin IX (PpIX), a fluorescent metabolite of the heme synthesis previously demonstrated to accumulate in cancer tissue.Graphical Abstract: How silencing of FECH leads to accumulation of fluorescent intracellular PpIX.

Nanoparticles in the treatment and diagnosis of neurological disorders: untamed dragon with fire power to heal

2011-09-05

Abstract: The incidence of neurological diseases of unknown etiology is increasing, including well-studied diseases such as Alzhiemer's, Parkinson's, and multiple sclerosis. The blood-brain barrier provides protection for the brain but also hinders the treatment and diagnosis of these neurological diseases, because the drugs must cross the blood-brain barrier to reach the lesions. Thus, attention has turned to developing novel and effective delivery systems that are capable of carrying drug and that provide good bioavailability in the brain. Nanoneurotechnology, particularly application of nanoparticles in drug delivery, has provided promising answers to some of these issues in recent years. Here we review the recent advances in the understanding of several common forms of neurological diseases and particularly the applications of nanoparticles to treat and diagnose them. In addition, we discuss the integration of bioinformatics and modern genomic approaches in the development of nanoparticles.From the Clinical Editor: In this review paper, applications of nanotechnology-based diagnostic methods and therapeutic modalities are discussed addressing a variety of neurological disorders, with special attention to blood-brain barrier delivery methods. These novel nanomedicine approaches are expected to revolutionize several aspects of clinical neurology.

Initial studies of mechanical compression on neurogenesis with neonatal neural stem cells

Leyla Esfandiari, Michelle Paff, William C. Tang — 2012-01-27

Abstract: In this article we demonstrate the effect of mechanical compression on the behavior of cultured neural stem cells using a microelectromechanical system platform. Polydimethylsiloxane (PDMS)-based stretchable substrates were used on a neurosphere (NS) assay to investigate the role of mechanical forces on the formation of radial glial processes and neuronal migration. To induce mechanical compression on NS, the PDMS culturing substrate was patterned with micron-sized wells. NS were cultured on the prestretched device. After 48 hours, when the NS had grown to the size of the well's width, the stretched substrate was released. The experimental results showed that applied mechanical compression on neural stem cells could be a factor accelerating the radial glial formation, which is associated with neurogenesis and neuronal migration.From the Clinical Editor: This study demonstrates that mechanical compression on neural stem cells could be a factor accelerating the radial glial formation, which is associated with neurogenesis and neuronal migration.Graphical Abstract: Polydimethylsiloxane (PDMS)-based stretchable platforms were used on neurosphere (NS) assay to investigate the role of mechanical forces on the formation of radial glial processes and neuronal migration. To induce mechanical compression on NS, the PDMS culturing substrate was patterned with micron-sized wells. NS were cultured on the prestretched device. After 48 hours, when the NS had grown to the size of the well’s width, the stretched substrate was released. The experimental results showed that applied mechanical compression on neural stem cells could be a factor accelerating the radial glial formation, which is associated with neurogenesis and neuronal migration.

Vertically aligned carbon nanofiber as nano-neuron interface for monitoring neural function

2012-03-09

Abstract: Neural chips, which are capable of simultaneous multisite neural recording and stimulation, have been used to detect and modulate neural activity for almost thirty years. As neural interfaces, neural chips provide dynamic functional information for neural decoding and neural control. By improving sensitivity and spatial resolution, nano-scale electrodes may revolutionize neural detection and modulation at cellular and molecular levels as nano-neuron interfaces. We developed a carbon-nanofiber neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes and demonstrated its capability of both stimulating and monitoring electrophysiological signals from brain tissues in vitro and monitoring dynamic information of neuroplasticity. This novel nano-neuron interface may potentially serve as a precise, informative, biocompatible, and dual-mode neural interface for monitoring of both neuroelectrical and neurochemical activity at the single-cell level and even inside the cell.From the Clinical Editor: The authors demonstrate the utility of a neural chip with lithographically defined arrays of vertically aligned carbon nanofiber electrodes. The new device can be used to stimulate and/or monitor signals from brain tissue in vitro and for monitoring dynamic information of neuroplasticity both intracellularly and at the single cell level including neuroelectrical and neurochemical activities.

Preparation and characterization of recombinant human growth hormone–Zn2+-dextran nanoparticles using aqueous phase–aqueous phase emulsion

Weien Yuan, Zhenhua Hu, Jing Su, Fei Wu, Zhenguo Liu, Tuo Jin — 2012-02-27

Abstract: An effective and simple method was developed to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)–Zn2+-dextran nanoparticles (NPs) for a variety of delivery applications of the delicate protein. The results showed that the prepared rhGH-Zn2+-dextran particles were spherical, glassy, and uniform in size. rhGH recovered from the NPs maintained its structural integrity and its bioactivity well, as suggested by the Nb2-11 cell proliferation assay. Using polyethylene glycol and polysaccharide to mediate Zn2+-induced precipitation has proved to be a promising method to prepare spherical protein-loaded NPs with desired sizes and preserved protein stability.From the Clinical Editor: This basic science paper discusses a simple yet effective method to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)-Zn2+-dextran nanoparticles for a variety of delivery applications.Graphical Abstract: The objective of the study was to develop an rhGH-Zn2+-dextran nanoparticulate system with high encapsulating efficiency and preserved protein stability using two aqueous phase polymer solution emulsion of PEG solution and dextran solution, through being added rhGH and Zn2+ solution. The results showed that uniform size of rhGH-Zn2+-dextran spherical nanoparticles with high encapsulation efficiency and Nb2-11 cell proliferation activity were achieved.

Acute vascular effects of nanoparticle infusion in isolated perfused skin

Jim E. Riviere, Teresa L. Leavens, James D. Brooks, Nancy A. Monteiro-Riviere — 2012-03-09

Abstract: The majority of studies on the effect of nanomaterials on biological function involves either isolated in vitro cell systems or are concerned with in vivo effects after inhalational or dermal exposure. The current work reports on an intriguing observation of the vascular effects seen in an ex vivo perfused tissue preparation, the isolated perfused porcine skin flap (IPPSF), in studies conducted to assess nanomaterial biodistribution. Compared with a relatively large dataset involving organic chemical infusions (n = 53), infusion of six different nanoparticles of diverse sizes and composition (silica or dextran coated Fe2O3, silica or citrate coated silver, PEG or carboxylated quantum dots [QD]) resulted in statistically significant post-infusion flap weight gain and an increase in arterial perfusion pressure (especially with QD-PEG). In contrast, infusion with nC60 nanoparticles did not produce these effects. These observations suggest certain nanoparticle infusions may be associated with acute vascular physiologic effects that merit further attention.From the Clinical Editor: In this study utilizing a perfused porcine skin flap, specific nanoparticle infusions were demonstrated to be associated with significant acute vascular physiological effects.Graphical Abstract: Comparison of the weight gains of skin flaps among types of IPPSF experiments. The weight gain varied significantly among infusion types (ANOVA, P < 0.05) and all but nC60 differed significantly (P < 0.05) from the organic chemical infusions (⁎).

Cell adhesion and focal contact formation on linear RGD molecular gradients: study of non-linear concentration dependence effects

2011-08-22

Abstract: Cell adhesion onto bioengineered surfaces is affected by a number of variables, including the former substrate derivatization process. In this investigation, we studied the correlation between cell adhesion and cell–adhesive ligand surface concentration and organization due to substrate modification. For this purpose, Arg-Gly-Asp (RGD) gradient surfaces were created on poly(methyl methacrylate) substrates by continuous hydrolysis and were then grafted with biotin-PEG-RGD molecules. Cell culture showed that adhesion behavior changes in a nonlinear way in the narrow range of RGD surface densities assayed (2.8 to 4.4 pmol/cm2), with a threshold value of 4.0 pmol/cm2 for successful cell attachment and spreading. This nonlinear dependence may be explained by nonhomogeneous RGD surface distribution at the nanometre scale, conditioned by the stochastic nature of the hydrolysis process. Atomic force microscopy analysis of the gradient surface showed an evolution of surface morphology compatible with this hypothesis.From the Clinical Editor: The authors observed by AFM nonlinear dependence of cell adhesion on RGD gradient surfaces with different surface densities. The nonlinear characteristics may be explained by non-homogeneous RGD surface distribution at the nanometer scale, conditioned by the stochastic nature of the hydrolysis process.Graphical Abstract: The Table of Contents image selected shows the plot of the percentage of adhered cells onto the gradient surface against the RGD density values for each sample position. Images superimposed denote how the clustering degree of the adhesive ligands (RGD), which varies along the gradient, may affect cell behavior: threshold observed in cell adhesion at the narrow range of RGD densities of 2.8 to 4.4 pmol/cm2.

Curcumin-loaded γ-cyclodextrin liposomal nanoparticles as delivery vehicles for osteosarcoma

2011-08-11

Abstract: The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-γ-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded γ-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin.From the Clinical Editor: Curcumin-loaded γ-cyclodextrin liposomes were demonstrated in vitro to have significant potential as delivery vehicles for the treatment of cancers of mesenchymal and epithelial origin. Differences between mechanisms of cell death were also evaluated.Graphical Abstract: In an osteosarcoma model (KHOS) liposomal curcumin induces apoptotic cell death, whereas DMSO-curcumin (free curcumin) induces autophagic cell death.

Characterization of biocompatible NiCo2O4 nanoparticles for applications in hyperthermia and drug delivery

2011-08-11

Abstract: Monodispersed, superparamagnetic nickel cobaltite (NCO) nanoparticles were functionalized using mercaptopropionic acid (MPA). MPA conjugates with NCO forming a metal-carboxylate linkage, with the MPA-MPA interaction occurring via formation of disulfide bonds, leaving another carboxyl end free for additional conjugation. The cytotoxicity studies on NCO-MPA show cell viability of ∼100% up to a dosage of 40 μg/mL on SiHa, MCF7, and B16F10 cell lines, and on mouse primary fibroblasts. Time-dependent cell viability studies done for a duration of 72 hours showed the cell lines’ viability up to 80% for dosages as high as 80 μg/mL. Negligible leaching (<5 ppm) of ionic Co or Ni was noted into the delivery medium. Upon subjecting the NCO-MPA dispersion (0.1 mg/mL) to radiofrequency absorption, the nanoparticles were heated to 75°C within 2 minutes, suggesting its promise as a magnetic hyperthermia agent. Furthermore, the amino acid lysine and the drug cephalexin were successfully adducted to the NCO system, suggesting its potential for drug delivery.From the Clinical Editor: NCO-MPA nanopartciles were found to be promising magnetic hyperthermia agents, suggesting potential future clinical applications.Graphical Abstract: Surface functionalization and molecular conjugation of nearly monodispersed nickel cobaltite nanoparticles (NiCo2O4) (NCO) and their evaluation as hyperthermia therapeutic agents and effective drug carriers.

Effect of novel stabilizers—cationic polymers on the particle size and physical stability of poorly soluble drug nanocrystals

Wei Sun, Wei Tian, Yuyang Zhang, Jianyong He, Shirui Mao, Liang Fang — 2011-08-11

Abstract: In this study, a novel class of stabilizer, cationic polymer, was introduced into the system of nanocrystals. Taking itraconazole as a poorly soluble model drug, the influence of three cationic polymers—chitosan, N-trimethyl chitosan, and polyethyleneimine—on the properties of the nanocrystals prepared by high-pressure homogenization method was investigated. Physicochemical properties of the nanoparticles were characterized. It was demonstrated that the cationic polymers could act as both an electrostatic and steric stabilizer to facilitate particle size reduction. Factors influencing charge density and stretching state of the cationic polymers influenced the magnitude of the particle. The electrostatic stabilization effect is more prominent than that of the steric stabilizing mechanism. Drug crystalline state was not changed by the addition of cationic polymers. Physical stability of the nanocrystals with cationic polymers was remarkably improved. The in vivo antifungal efficacy of the nanocrystals was dependent on physicochemical properties and pH.From the Clinical Editor: Cationic polymer stabilizers were used to modify the surface of nanocrystals and the resulting stabilizing mechanisms were compared. The electrostatic stabilization effect was found to be stronger than the steric one. Crystallinity of itraconazole was unchanged by the addition of cationic polymers, while drug physical stability remarkably improved.Graphical Abstract: The particle size and zeta potential values of the itraconazole nanoparticles stabilized by 0.5% (w/w) Lutrol F68 with CS 50, TMC 50, or PEI 25 of different concentrations at pH 5.

Investigations into an alternate approach to target mannose receptors on macrophages using 4-sulfated N-acetyl galactosamine more efficiently in comparison with mannose-decorated liposomes: an application in drug delivery

Deepak Singodia, Ashwni Verma, Rahul K. Verma, Prabhat Ranjan Mishra — 2011-07-22

Abstract: In this study the potential of 2 different ligands, i.e., palmitoyl mannose (Man-Lip) and 4-SO4GalNAc (Sulf-Lip) to target resident macrophages was investigated after surface decoration of Amphotericin B (AmB) loaded liposomes. In the case of Sulf-Lip, the 4-SO4GalNAc was adsorbed through electrostatic interaction on cationic liposomes, which was confirmed by change in zeta potential from +48.2 ± 3.7 mV for Lip to +12.2 ± 1.3 mV for Sulf-Lip. The mean particle size of Sulf-Lip and Man-Lip was found to be 139.4 ± 7.4 nm and 147.4 ± 8.6 nm, respectively. Flow cytometric data reveal enhanced uptake of Sulf-Lip in both J774 and RAW cell lines in comparison with the uptake of Man-Lip. Intracellular localization studies indicate that the fluorescence intensity of Sulf-Lip was much higher in comparison with that of Man-Lip and Lip formulations. Sulf-Lip and Man-Lip showed significantly higher localization of AmB at all time points in comparison with Lip (P < 0.05) after intravenous (IV) administration. The studies provide evidence that 4-SO4GalNAc possesses a promising feature for targeting resident macrophages and its application in the conditions of leishmaniasis is in the offing.From the Clinical Editor: This in vivo study compares two different ligands to deliver Amphotericin B l(AmB) loaded liposomes to resident macrophages. Targeted approaches showed significantly higher localization of AmB at all time points in comparison to non-targeted liposomes, and future applications in leishmaniasis are already under preparation.Graphical Abstract: Schematic diagram presents mannose moiety attach with C-type carbohydrate recognition domain (CRD), while 4-sulfated galactosamine targets cysteine rich domain on mannose receptor. 3 and 4- hydroxyl group on mannose form hydrogen bond with C-type CRD while sulfate moiety on 4-sulfated galactosamine form six hydrogen bond with cysteine rich domain.

Nanoscalic silver possesses broad-spectrum antimicrobial activities and exhibits fewer toxicological side effects than silver sulfadiazine

2011-08-11

Abstract: Silver has been used successfully for decades as an antibacterial agent and has become a standard treatment for burns and bacterial skin infections. Silver-containing creams, particularly silver sulfadiazine (SSD), possess effective activities against bacteria and fungi. However, there is serious concern that silver ions applied to denuded skin might be absorbed in significant amounts, thus introducing the risk of silver deposition, potentially leading to internal organ injury. In view of these facts we compared the percutaneous absorption and the antimicrobial potency of SSD with a new composition, nanoscalic silver (NSAg). In a murine model topical application of NSAg resulted in significantly lower percutaneous absorption and internal organ deposition compared to SSD. Strikingly, antimicrobial activity of NSAg used as a 0.1% formulation was comparable not only with 0.1% SSD against different bacterial strains including methicillin-resistant Staphylococcus aureus, but also against different yeast and dermatophyte species.From the Clinical Editor: Nanoscale silver (NSAg) was demonstrated to have significantly lower percutaneous absorption and less accumulation in multiple organs when applied to denuded skin. Its antimicrobial activity against MRSA was not only comparable to silver sulfadiazine, but the formulation was also effective against different yeast and dermatophyte species.Graphical Abstract: In order to compare the percutaneous absorption of silver ions, hairless mice were treated topically for five consecutive days with either nanoscalic silver (NSAg), silver sulfadiazine (SSD), or remained untreated . After scarification, organs were prepared and further processed for ICP-MS analysis. Significantly lower concentrations of silver ions in the NSAg treated groups were detectable in liver, lung, kidney, blood, and faeces.In addition, NSAg used as a 0.1% formulation showed strong anti-bacterial activities against Methicillin-resistent Staphylococcus aureus (MRSA), Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa, as well as anti-fungal activities against yeasts (Candida albicans, Candida glabrata, Malassezia sympodialis) and dermatophytes (Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Microsporum canis). The observed anti-microbial activities for 0.1% NSAg were comparable with those shown for 0.1% SSD. Our results demonstrate that NSAg is a highly effective anti-microbial formulation, with a significantly lower risk for percutaneous absorption of silver ions.

Nanosized ethanolic vesicles loaded with econazole nitrate for the treatment of deep fungal infections through topical gel formulation

Poonam Verma, Kamla Pathak — 2011-08-11

Abstract: This project aimed at developing nanovesicles of econazole nitrate (EN) and formulating them as a suitable dermatological gel for improved therapeutic efficacy, better dispersity, and good storage stability. Ethosomes were prepared by cold method and evaluated for the mean diameter, surface charge, and entrapment efficiency. Optimized ethosomes with vesicle size and entrapment efficiency of 202.85 ± 5.10 nm and 81.05 ± 0.13%, respectively, were formulated as Carbopol 934 NF gels with varied permeation enhancers (G1–G7), and compared with liposomal and hydroethanolic gels. The pharmacotechnical evaluation of gels demonstrated G6 with a flux rate of 0.46 ± 0.22 μg/cm2 hr1/2 as the best formulation that was able to exhibit controlled release of EN for 12 hours across rat skin, and percent drug diffused from ethosomes was nearly twofold higher than liposomal and hydroethanolic gels. Confocal laser scanning microscopy demonstrated drug permeation as far as the last layer of epidermis (stratum basale). Stability profile of the prepared system assessed for 180 days revealed very low aggregation and insignificant growth in vesicular size. The results collectively suggest that because of the controlled drug release, better antifungal activity, and good storage stability, EN ethosomal gel has tremendous potential to serve as a topical delivery system.From the Clinical Editor: Ethosomal gel of econazole nitrate was found to have outstanding potential to serve as a topical delivery system, enabling controlled drug release, providing better antifungal activity, and good storage stability.Graphical Abstract: The TEM image of econazole nitrate–loaded ethosomes shows discrete spherical structures that are more or less uniform in size and penetrate the stratum corneum by dual mechanisms. First, the ethanol effect wherein ethanol interacts with lipid molecules in the polar head group region resulting in a reduction in the transition temperature of stratum corneum lipids, increase in their fluidity, and decrease in the density of the lipid multilayer. This is followed by the “ethosomes effect,” which includes lipid penetration and permeation by the opening of new pathways due to the malleability and fusion of ethosomes with skin lipids, resulting in the gradient penetration of econazole nitrate to the stratum basale.

Structure and biological activity of pathogen-like synthetic nanomedicines

2011-08-11

Abstract: Here we characterize the structure, stability and intracellular mode of action of DermaVir nanomedicine that is under clinical development for the treatment of HIV/AIDS. This nanomedicine comprises pathogen-like pDNA/PEIm nanoparticles (NPs) having the structure and function resembling spherical viruses that naturally evolved to deliver nucleic acids to the cells. Atomic force microscopy demonstrated spherical 100 – 200 nm NPs with a smooth polymer surface protecting the pDNA in the core. Optical absorption determined both the NP structural stability and biological activity relevant to their ability to escape from the endosome and release the pDNA at the nucleus. Salt, pH and temperature influence nanomedicine shelf-life and intracellular stability. This approach facilitates the development of diverse polyplex nanomedicines where the delivered pDNA-expressed antigens induce immune responses to kill infected cells.From the Clinical Editor: The authors investigated DermaVir nanomedicine comprised of pathogen-like pDNA/PEIm nanoparticles with structure and function resembling spherical viruses. DermaVir delivery of pDNA expresses antigens that induce immune responses to kill HIV infected cells.Graphical Abstract: “Pathogen-like” features of the nanomedicine correlate with efficient delivery of the pDNA to cells.

Bone biomimetic microenvironment induces osteogenic differentiation of adipose tissue-derived mesenchymal stem cells

ZuFu Lu, Seyed-Iman Roohani-Esfahani, Guocheng Wang, Hala Zreiqat — 2011-08-11

Abstract: A critical strategy for tissue engineering is to provide the signals necessary for tissue regeneration by mimicking the tissue microenvironment. In this study, we mimicked (1) the bone chemical and the physical microenvironment by fabricating a three-dimensional nanocomposite scaffold composed of biphasic calcium phosphates (BCP) coated with a nanocomposite layer of polycaprolactone (PCL) and hydroxyapatite nanoparticles (nHA) (BCP/PCL-nHA)), and (2) the bone's biological microenvironment by co-culturing with primary human osteoblasts (HOBs), and then investigated their effects on osteogenic differentiation of adipose tissue-derived stem cells (ASCs). In comparison with the ASCs cultured alone on BCP scaffolds that were coated only with PCL, early osteogenic differentiation of ASCs was induced by either seeding ASCs on BCP/PCL-nHA scaffolds or by co-culturing with HOBs; the combination of BCP/PCL-nHA scaffold and HOBs resulted in the synergistic enhancement of osteogenic gene expression. Moreover, we found that BCP/PCL-nHA scaffolds induced early osteogenic differentiation of ASCs through integrin-α2 and an extracellular signal-regulated kinase (ERK) signaling pathway.From the Clinical Editor: The authors mimicked the physico-chemical environment of bone by fabricating a nanocomposite scaffold, and then co-cultured it with human osteoblasts. Demonstrated enhancement of osteogenic gene expression and early osteogenic differentiation of adipose tissue derived stem cells were found using this approach.Graphical Abstract: Biomimetic scaffold (BCP/PCL-nHA scaffolds) that resembles the bone chemical and physical microenvironment acted in synergy with the bone biological microenvironment (coculturing with HOBs) in directing ASCs into osteogenic differentiation.

Oriented conjugates of single-domain antibodies and quantum dots: toward a new generation of ultrasmall diagnostic nanoprobes

2011-08-11

Abstract: Common strategy for diagnostics with quantum dots (QDs) utilizes the specificity of monoclonal antibodies (mAbs) for targeting. However QD-mAbs conjugates are not always well-suited for this purpose because of their large size. Here, we engineered ultrasmall nanoprobes through oriented conjugation of QDs with 13-kDa single-domain antibodies (sdAbs) derived from llama IgG. Monomeric sdAbs are 12 times smaller than mAbs and demonstrate excellent capacity for refolding. sdAbs were tagged with QDs through an additional cysteine residue integrated within the C terminal of the sdAb. This approach allowed us to develop sdAbs-QD nanoprobes comprising four copies of sdAbs coupled with a QD in a highly oriented manner. sdAbs-QD conjugates specific to carcinoembryonic antigen (CEA) demonstrated excellent specificity of flow cytometry quantitative discrimination of CEA-positive and CEA-negative tumor cells. Moreover, the immunohistochemical labeling of biopsy samples was found to be comparable or even superior to the quality obtained with gold standard protocols of anatomopathology practice. sdAbs-QD–oriented conjugates as developed represent a new generation of ultrasmall diagnostic probes for applications in high-throughput diagnostic platforms.From the Clinical Editor: The authors report the development of sdAbs-QD–oriented conjugates, comprised of single domain antibodies that are 12 times smaller than regular mAb-s and quantum dots. These ultrasmall diagnostic probes represent a new generation of functionalized ODs for applications in high-throughput diagnostic platforms.Graphical Abstract: “Anatomy” of ultra-small diagnostic nanoprobe engineered from the CdSe-ZnS quantum-dot and single-domain antibodies (sdAbs or VhH) via sdAbs-oriented conjugation through His-Cys linker.

Nanoparticle augmented radiation treatment decreases cancer cell proliferation

Helen E. Townley, Elizabeth Rapa, Gareth Wakefield, Peter J. Dobson — 2011-08-22

Abstract: We report significant and controlled cell death using novel x-ray-activatable titania nanoparticles (NPs) doped with lanthanides. Preferential incorporation of such materials into tumor tissue can enhance the effect of radiation therapy. Herein, the incorporation of gadolinium into the NPs is designed to optimize localized energy absorption from a conventional medical x-ray. This result is further optimized by the addition of other rare earth elements. Upon irradiation, energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species (ROS).From the Clinical Editor: The authors report significant and controlled cell death using x-ray-activated titania nanoparticles doped with lanthanides as enhancers. Upon irradiation X-ray energy is transferred to the titania crystal structure, resulting in the generation of reactive oxygen species.Graphical Abstract: Schematic illustrating the mechanism and action of ROS-generated by doped nanoparticles (NPs). (1) X rays absorbed by the gadolinium K-edge eject an electron and create a free hole (h+) in the titania valence band (2) The hole mobility and lifetime are governed by the electronic structure of titania allowing (3) migration to the particle surface and creation of ROS (4) passive uptake of the NPs allows passage through the outer cell membrane (5) the generated ROS interacts with cellular components, affecting nucleic acids, lipids and proteins (6) cell death as a result of irreparable damage.

Cover 1

2012-05-01

About the Cover

2012-05-01

Editorial Board

2012-05-01