Nanomedicine: Nanotechnology, Biology and Medicine

The nanoscopic range and the effect of architecture on nanoproperties

Lajos P. Balogh — 2010-06-23

We know a lot about the physics and chemistry of atoms and molecules. They follow quantum rules and obey quantum laws. We have learned a lot about properties of bulk materials through chemical and materials engineering, and about architecture through civil engineering. These physical rules are always continuous in nature. Between the atomic-molecular range and the “macro” world there lies the nanoscopic range, about which many questions still exist. For example, what happens to the quantum laws, continuous rules, and laws governing properties in the molecular range and in bulk at the border? Do rules and properties in the nanoscopic range coexist, or do they exclude each other? These are very interesting and legitimate questions.

David versus Goliath

2010-04-23

In 2010 three new Nanomedicine Research Centers have been launched in Denmark. The three Centers of Excellence emerged via an open call for proposals posted by the private funding organization The Lundbeck Foundation. The foundation will provide a total financing of €13 million (US $17.7 million) for an initial period of 5 years to the three Centers. For a country like Denmark, this represents a massive investment into frontline research. The real dimension can best be visualized by relating it to the gross domestic product of Denmark and scaling it to the gross domestic products of Germany or the United States. Doing so, the financial support would correspond to investments of €139 million (US $189 million) and €540 million (US $735 million) for Germany and the United States, respectively, which is well in the scale of larger national programs. The three Centers will investigate novel strategies for exploiting nanoscaled biostructures in combating major human diseases, including cancer as well as neurological, infectious, cardiovascular, and musculoskeletal disorders.

Time-dependent measure of a nanoscale force-pulse driven by the axonemal dynein motors in individual live sperm cells

Michael J. Allen, Robert E. Rudd, Mike W. McElfresh, Rod Balhorn — 2010-01-07

Abstract: Nanoscale mechanical forces generated by motor proteins are crucial to normal cellular and organismal functioning. The ability to measure and exploit such forces is important to developing motile biomimetic nanodevices powered by biological motors for nanomedicine. Axonemal dynein motors positioned inside the sperm flagellum drive microtubule sliding and give rise to rhythmic beating. This force-generating action pushes the sperm cell through viscous media. Here we report new nanoscale information on how the propulsive force is generated by the sperm flagellum and how this force varies over time. Using a modified atomic force microscope, single-cell recordings reveal discrete ∼50-ms pulses oscillating with amplitude 9.8 ± 2.6 nN independent of pulse frequency (3.5–19.5 Hz). The average work carried out by each cell is 4.6 × 10-16 J per pulse, equivalent to the hydrolysis of ∼5500 molecules of adenosine triphosphate. The mechanochemical coupling at each active dynein head is ∼2.2 pN per adenosine triphosphate molecule and ∼3.9 pN per dynein arm.From the Clinical Editor: In this paper, nanoscale mechanical forces generated by axonemal dynein motors derived from sperm flagellum are examined and reported. These motor proteins are crucial to normal cellular and organismal functioning. The ability to measure and exploit such forces is important to developing motile biomimetic nanodevices powered by biological motors for nanomedicine.

Inorganic nanomedicine—Part 1

Bhupinder S. Sekhon, Seema R. Kamboj — 2010-04-23

Abstract: Inorganic nanomedicine refers to the use of inorganic or hybrid nanomaterials and nanosized objects to achieve innovative medical breakthroughs for drug and gene discovery and delivery, discovery of biomarkers, and molecular diagnostics. Potential uses for fluorescent quantum dots include cell labeling, biosensing, in vivo imaging, bimodal magnetic-luminescent imaging, and diagnostics. Biocompatible quantum dot conjugates have been used successfully for sentinel lymph node mapping, tumor targeting, tumor angiogenesis imaging, and metastatic cell tracking. Magnetic nanowires applications include biosensing and construction of nucleic acids sensors. Magnetic cell therapy is used for the repair of blood vessels. Magnetic nanoparticles (MNPs) are important for magnetic resonance imaging, drug delivery, cell labeling, and tracking. Superparamagnetic iron oxide nanoparticles are used for hyperthermic treatment of tumors. Multifunctional MNPs applications include drug and gene delivery, medical imaging, and targeted drug delivery. MNPs could have a vital role in developing techniques to simultaneously diagnose, monitor, and treat a wide range of common diseases and injuries.From the Clinical Editor: This review serves as an update about the current state of inorganic nanomedicine. The use of inorganic/hybrid nanomaterials and nanosized objects has already resulted in innovative medical breakthroughs for drug/gene discovery and delivery, discovery of biomarkers and molecular diagnostics, and is likely to remain one of the most prolific fields of nanomedicine.

Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies

Rebecca Klippstein, David Pozo — 2010-01-18

Abstract: Dendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and possess the ability to activate T cells and stimulate the growth and differentiation of B cells. DCs provide a direct connection between innate and adaptive immune response, and arise from bone marrow precursors that are present in immature forms in peripheral tissues, where they are prepared to capture antigens. DCs migrate from the peripheral tissues to the closest lymph nodes through afferent lymphatic vessels to present the foreign antigens, stimulating T-cell activation and initiating a cellular immune response. Moreover, it is known that DCs have an important role in various diseases and conditions involving the immune system, particularly in cancer and autoimmune disorders. For these reasons, targeting nanoparticles (NPs) to DCs provides a promising strategy for developing an efficient balanced and protective immune response. NPs can modulate the immune response and might be potentially useful as effective vaccine adjuvants for infectious disease and cancer therapy. The objective of this review is to present the latest advances in NP delivery methods targeting DCs, the mechanisms of action, potential effects, and therapeutic results of these systems and their future applications, such as improved vaccination strategies, cancer immunotherapy, and immunomodulatory treatments.From the Clinical Editor: Dendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and activating T and B cells. The role of DC-s can be considered as a bridge between innate and adaptive immunity. Targeting nanoparticles (NPs) to DCs can modulate the immune response and might be useful as vaccine adjuvants in infectious disease and cancer therapy.

Accurate quantitation of glutathione in cell lysates through surface-assisted laser desorption/ionization mass spectrometry using gold nanoparticles

Cheng-Kang Chiang, Yang-Wei Lin, Wen-Tsen Chen, Huan-Tsung Chang — 2010-02-05

Abstract: We developed a method for the determination of three aminothiols—cysteine, glutathione (GSH), and homocysteine—using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). The analytes were first captured using the unmodified 14-nm gold nanoparticles; N-2-mercaptopropionylglycine–modified gold nanoparticles serving as internal standard were sequentially added, and then the sample was analyzed using SALDI-MS. This approach provided good quantitative linearity of the three analytes (R2 = ∼0.99), with good reproducibility (relative standard deviations: <10%), in the analyses of GSH in the lysates of human red blood cells and MCF-7 cancer breast cells in the presence and absence of the anti-inflammatory drug sulfasalazine. The internal-standard SALDI-MS approach provides simplicity, accuracy, and precision to the determination of GSH in cells under drug invasion, to open an avenue for SALDI-MS to be used for the precise quantitative determination of a variety of analytes.From the Clinical Editor: This paper reports the development of a surface assisted laser desorption/ionization mass spectrometry method to precisely determine aminothiols-cysteine (Cys), glutathione (GSH), and homocysteine (HCys)

Landscape phage fusion protein-mediated targeting of nanomedicines enhances their prostate tumor cell association and cytotoxic efficiency

2010-02-05

Abstract: Tumor-specific cytotoxicity of drugs can be enhanced by targeting them to tumor receptors using tumor-specific ligands. Phage display offers a high-throughput approach to screen for the targeting ligands. We have successfully isolated phage fusion peptides selective and specific for PC3 prostate cancer cells. Also, we have demonstrated a novel approach of targeting liposomes through tumor-specific phage fusion coat proteins, exploiting the intrinsic properties of the phage coat protein as an integral membrane protein. Here we describe the production of Rhodamine-labeled liposomes as well as doxorubicin-loaded long-circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides, as an extension of our previous studies. Targeting of labeled liposomes was demonstrated using fluorescence microscopy as well as flow cytometry. Targeting of doxorubicin-loaded liposomes enhanced their cytotoxic effect against PC3 cells in vitro, indicating a possible therapeutic advantage. The simplicity of the approach for generating targeted liposomes coupled with the ability to rapidly obtain tumor-specific phage fusion proteins via phage display may contribute to a combinatorial system for the production of targeted liposomal therapeutics for advanced stages of prostate tumor.From the Clinical Editor: This paper demonstrates targeting cytotoxic agents to tumor receptors using tumor-specific ligands. The authors describe the production of Rhodamine-labeled liposomes as well as doxorubicin loaded long circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides. This approach may be especially relevant for advanced prostate tumors.

β-casein–based nanovehicles for oral delivery of chemotherapeutic drugs: drug-protein interactions and mitoxantrone loading capacity

Alina Shapira, Gilad Markman, Yehuda G. Assaraf, Yoav D. Livney — 2010-01-25

Abstract: β-casein (β-CN), a major milk protein, is amphiphilic and self-associates into micelles in aqueous solutions. We have recently introduced a novel oral drug delivery system based on β-CN nanoparticles. The current research builds on and complements this work by studying the interactions of mitoxantrone (MX) and β-CN as they co-assemble into nanoparticles, using absorption and emission spectra, static and dynamic light scattering, and fluorescent emission of both MX and tryptophan 143 (Trp143) of β-CN. The optimal loading molar ratio was 3.3 MX/β-CN at 1 mg/mL β-CN, and the association constant was (2.45 ± 1.76) × 105 M–1 based on β-CN Trp143 fluorescence; independent MX fluorescence results provided supporting values. In these conditions a bimodal particle distribution was obtained (174.4 nm, 45.9%; 485.1 nm, 54.1%). The gastric digestibility of β-CN suggests possible targeting to stomach tumors. Hence, β-CN nanoparticles have potential to serve as effective vehicles of hydrophobic drugs for oral delivery preparations.From the Clinical Editor: Beta-casein (b-CN) is an amphiphilic milk protein that self-associates into micelles in aqueous solutions and can be utilized as a novel oral drug delivery system. This study investigates the basic properties of a mitoxantrone delivery system based on the above principles.

Poly(citric acid)-block-poly(ethylene glycol) copolymers—new biocompatible hybrid materials for nanomedicine

Ashkan Tavakoli Naeini, Mohsen Adeli, Manouchehr Vossoughi — 2010-01-13

Abstract: Linear-dendritic ABA triblock copolymers containing poly(ethylene glycol) (PEG) as B block and hyperbranched poly(citric acid) (PCA) as A blocks were synthesized through polycondensation. The molecular self-assembly of synthesized PCA-PEG-PCA copolymers in water led to formation of nanoparticles and fibers in different sizes and shapes depending on the time and size of PCA blocks. Ten days after dissolving PCA-PEG-PCA copolymers in water, the size of fibers had reached several millimeters. Mixing a water solution of fluorescein as a small guest molecule and PCA-PEG-PCA copolymers led to the encapsulation of fluorescein by products of molecular self-assembly. To investigate their potential application in nanomedicine and to understand the limitations and capabilities of these materials as nanoexcipients in biological systems, different types of short-term in vitro cytotoxicity experiments on the HT1080 cell line (human fibrosarcoma) and hemocompatibility tests were performed.From the Clinical Editor: This manuscript investigates the potentials of linear-dendritic ABA triblock copolymers containing poly(ethylene glycol) (PEG) as B block and hyperbranched poly(citric acid) (PCA) as A blocks for future applications in nanomedicine.

Identification of deregulated genes by single wall carbon-nanotubes in human normal bronchial epithelial cells

2010-01-07

Abstract: To identify genes affected by single-walled carbon nanotubes (SWCNTs) in human normal lung cells, we compared the gene expression profiles of untreated human normal bronchial epithelial (HNBE) cells to profiles of HNBE cells treated with SWCNTs. A complementary DNA microarray analysis consisting of 54,675 human genes revealed marked changes in the expression of 14,294 genes, with 7,029 genes being upregulated and 7,265 being downregulated. This comprehensive list of genes included those associated with cell cycle, apoptosis, cell survival, cell adhesion and motility, signal transduction, and transcription regulation. Additional analysis of 19 genes using reverse transcription–polymerase chain reaction confirmed the microarray analysis. More specifically, our study demonstrates to our knowledge for the first time, evidence that 9 of the 19 genes (most of which encode cell apoptotic, signal transduction, and transcription regulator products) are upregulated in the SWCNTs-treated HNBE cells as compared with untreated cells, whereas the remaining 10 of the 19 (involved in cell adhesion and motility, cell proliferation, and cell survival) are downregulated in SWCNTs-treated HNBE cells in comparison with untreated controls. These findings provide a large body of information regarding gene expression profiles associated with SWCNTs exposure in human lung bronchial epithelial cells, and also represent a source to investigate the mechanism of the effect of SWCNTs in human normal lung cells.From the Clinical Editor: In this study, the gene expression profile of human normal bronchial epithelial cells was compared with single-wall carbon nanotubes-treated cells. A cDNA microarray analysis consisting of 54,675 human genes revealed significant changes in the expression of 14,294 genes, with 7,029 genes being up-regulated and 7,265 being down-regulated. This serves as a first step in clarification of mechanisms of action and to investigate toxicity in this model.

Silver nanoparticles as a safe preservative for use in cosmetics

2010-01-08

Abstract: Concern is continuously raised regarding the safety of preservatives, which are crucial in most cosmetic preparations. The antimicrobial effects of silver (Ag) are well recognized; however, Ag has some limitations as a preservative, such as its interference with salts. In this study, we investigated the effects of recently synthesized Ag nanoparticles on microorganisms, the permeability of Ag nanoparticles in human skin, and the cytotoxicity of Ag nanoparticles in human keratinocytes under ultraviolet B irradiation. Ag nanoparticles were found to be very stable, and they did not exhibit sedimentation for over 1 year. Ag nanoparticles showed sufficient preservation efficacy against mixed bacteria and mixed fungi, and did not penetrate normal human skin. At concentrations of 0.002–0.02 parts per million, Ag nanoparticles had no effect on HaCaT keratinocytes and did not enhance ultraviolet B-induced cell death. These results suggest that Ag nanoparticles may have potential for use as a preservative in cosmetics.From the Clinical Editor: In this study, the effects of recently synthesized Ag nanoparticles were investigated on microorganisms, along with the skin permeability and the cytotoxicity in human keratinocytes under UVB-irradiation. Ag nanoparticles were found to be very stable, showed sufficient preservation efficacy against mixed bacteria and mixed fungi, and did not penetrate normal human skin. Ag nanoparticles appear to be suitable for use as a preservative in cosmetics.

Uptake and distribution of fullerenes in human mast cells

2010-02-05

Abstract: Fullerenes are carbon cages of variable size that can be derivatized with various side chain moieties resulting in compounds that are being developed into nanomedicines. Although fullerene use in several preclinical in vitro and in vivo models of disease has demonstrated their potential as diagnostic and therapeutic agents, little is known about how they enter cells, what organelles they target, and the time course for their cellular deposition. Fullerenes (C70) that have already been shown to be potent inhibitors of mast cell (MC)–mediated allergic inflammation were conjugated with Texas red (TR) and used in conjunction with confocal microscopy to determine mechanisms of uptake, the organelle localization, and the duration they can be detected in situ. We show that C70-TR are nonspecifically endocytosed into MCs, where they are shuttled throughout the cytoplasm, lysosomes, mitochondria, and into endoplasmic reticulum at different times. No nuclear or secretory granule localization was observed. The C70-TR remained detectable within cells at 1 week. These studies show that MCs endocytose fullerenes, where they are shuttled to organelles involved with calcium and reactive oxygen species production, which may explain their efficacy as cellular inhibitors.From the Clinical Editor: Fullerenes are carbon cages of variable size that have already been shown to be potent inhibitors of mast cell (MC)-mediated allergic inflammation. These were conjugated with Texas red (TR) and used in conjunction with confocal microscopy to determine mechanisms of uptake, the organelle localization, and duration, demonstrating that MCs endocytose fullerenes, which are shuttled to organelles involved with calcium and reactive oxygen species production. This intracellulac trafficking may explain the efficacy of fullerenes as cellular inhibitors.

Hepatoma-targeted gene delivery using a tumor cell–specific gene regulation system combined with a human liver cell–specific bionanocapsule

2010-02-05

Abstract: Hepatoma (hepatocellular carcinoma) is the most common type of malignant tumor originating in the liver and has a relatively low 5-year survival rate. The development of hepatoma-targeted therapy is needed to increase treatment efficiency and to reduce the incidence of undesirable side effects. In this study we developed a novel hepatoma-targeted gene delivery system. The gene delivery system was prepared by combining a human liver cell–specific bionanocapsule (BNC) and a tumor cell–specific gene regulation polymer, which responds to hyperactivated protein kinase Cα in hepatoma cells. The complex of the polymer-DNA with BNCs was delivered into cells and tissues. The developed system showed increased transfection efficiency and resulted in cell-specific gene expression in hepatoma cells and tissues (HuH-7), but no gene expression in normal human hepatocytes or human epidermoid tumor cells (A431). The combination of a tumor cell-specific gene regulation system responding to protein kinase Cα and BNCs showed excellent potential for the selective treatment of hepatomas. The system could be a useful method with applications in hepatoma-specific gene therapy and molecular imaging.From the Clinical Editor: Hepatocellular carcinoma is the most common type of malignant tumor in the liver with a low 5-year survival rate. In this study, a novel hepatoma-targeted gene delivery system was prepared by combining a human liver cell-specific bionanocapsule and a tumor cell-specific gene regulation polymer, which responds to hyperactivated protein kinase C (PKC)a in hepatoma cells. The system could be a useful in hepatoma-specific gene therapy and molecular imaging.

Enhanced transdermal delivery of an anti-HIV agent via ethanolic liposomes

Vaibhav Dubey, Dinesh Mishra, Manoj Nahar, Vikas Jain, Narendra Kumar Jain — 2010-01-20

Abstract: Indinavir, as a protease inhibitor with a short biological half life, variable pH-dependent oral absorption, and extensive first-pass metabolism, presents a challenge with respect to its oral administration. The current work aims to formulate and characterize indinavir-bearing ethanolic liposomes (ethosomes), and to investigate their enhanced transdermal delivery potential. The prepared ethanolic liposomes were characterized to be spherical, unilamellar structures having low polydispersity, nanometric size range, and improved entrapment efficiency over other delivery formulations. Permeation studies of indinavir across human cadaver skin resulted in enhanced transdermal flux from ethanolic liposomes that was significantly (P < 0.05) greater than that with ethanolic drug solution, conventional liposomes, or plain drug solution. Additionally, the ethanolic liposomes showed the shortest lag time for indinavir, thus presenting a suitable approach for transdermal delivery of this protease inhibitor.From the Clinical Editor: This study characterizes indinavir bearing ethanolic liposomes (ethosomes), and investigate their enhanced transdermal delivery potential, demonstrating a potentially a suitable approach for transdermal delivery of this protease inhibitor for HIV treatment, which typically has been associated with limited bioavailability via the oral route.

Delivery of amphotericin B nanosuspensions to the brain and determination of activity against Balamuthia mandrillaris amebas

Andreas Lemke, Albrecht F. Kiderlen, Boris Petri, Oliver Kayser — 2010-01-08

Abstract: Amphotericin B was formulated as nanosuspensions to develop a nanoparticulate brain delivery system. Nanosuspensions were produced with different surfactant solutions by high-pressure homogenization and then characterized by laser diffractometry and photon correlation spectroscopy. Before in vitro and in vivo testing all nanosuspensions were investigated for protein adsorption by two-dimensional polyacrylamide gel electrophoresis to predict brain-targeting capacities. Selected nanosuspensions were tested for amebicidal activity against Balamuthia mandrillaris, an agent of lethal encephalitis. Our results indicate that nanosuspensions coated with polysorbate 80 and sodium cholate markedly increased drug brain delivery and inhibited the parasite in vitro, though less in vivo.From the Clinical Editor: The antifungal Amphotericin B was formulated as nanosuspensions to develop a nanoparticulate brain delivery system. The results indicate that nanosuspensions coated with polysorbate 80 and sodium cholate markedly increased drug brain delivery and inhibited the parasite in vitro, though less in vivo.

Cover 1

2010-08-01

Editorial Board

2010-08-01

Nanomedicine: Nanotechnology, Biology and Medicine

The nanoscopic range and the effect of architecture on nanoproperties

David versus Goliath

Time-dependent measure of a nanoscale force-pulse driven by the axonemal dynein motors in individual live sperm cells

Inorganic nanomedicine—Part 1

Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies

Accurate quantitation of glutathione in cell lysates through surface-assisted laser desorption/ionization mass spectrometry using gold nanoparticles

Landscape phage fusion protein-mediated targeting of nanomedicines enhances their prostate tumor cell association and cytotoxic efficiency

β-casein–based nanovehicles for oral delivery of chemotherapeutic drugs: drug-protein interactions and mitoxantrone loading capacity

Poly(citric acid)-block-poly(ethylene glycol) copolymers—new biocompatible hybrid materials for nanomedicine

Identification of deregulated genes by single wall carbon-nanotubes in human normal bronchial epithelial cells

Silver nanoparticles as a safe preservative for use in cosmetics

Uptake and distribution of fullerenes in human mast cells

Hepatoma-targeted gene delivery using a tumor cell–specific gene regulation system combined with a human liver cell–specific bionanocapsule

Enhanced transdermal delivery of an anti-HIV agent via ethanolic liposomes

Delivery of amphotericin B nanosuspensions to the brain and determination of activity against Balamuthia mandrillaris amebas

Cover 1

Editorial Board

Table of Contents