Active Nanosystems Research Articles

Chitosan Nanoparticles for Targeted Cancer Therapy: A Review of Stimuli-Responsive, Passive, and Active Targeting Strategies.

Despite all major advancements in drug discovery and development in the pharmaceutical industry, cancer is still one of the most arduous challenges for the scientific community. The implications of nanotechnology have certainly resolved major issues related to conventional anticancer modalities; however, the undesired recognition of nanoparticles (NPs) by the mononuclear phagocyte system (MPS), their poor stability in biological fluids, premature release of payload, and low biocompatibility have restricted their clinical translation. In recent decades, chitosan (CS)-based nanodelivery systems (eg, polymeric NPs, micelles, liposomes, dendrimers, conjugates, solid lipid nanoparticles, etc.) have attained promising recognition from researchers for improving the pharmacokinetics and pharmacodynamics of chemotherapeutics. However, the specialty of this review is to mainly focus on and critically discuss the targeting potential of various CS-based NPs for treatment of different types of cancer. Based on their delivery mechanisms, we classified CS-based NPs into stimuli-responsive, passive, or active targeting nanosystems. Moreover, various functionalization strategies (eg, grafting with polyethylene glycol (PEG), hydrophobic substitution, tethering of stimuli-responsive linkers, and conjugation of targeting ligands) adapted to the architecture of CS-NPs for target-specific delivery of chemotherapeutics have also been considered. Nevertheless, CS-NPs based therapeutics hold great promise for improving therapeutic outcomes while mitigating the off-target effects of chemotherapeutics, a long-term safety profile and clinical testing in humans are warranted for their successful clinical translation.

Missing-Linker-Confined Single-Atomic Pt Nanozymes for Enzymatic Theranostics of Tumor.

Conventional nanozymes often possess low active site density. Pursuing effective strategies for constructing highly active single-atomic nanosystems with maximum atom utilization efficiency is exceptionally attractive. Herein, we develop a facile "missing-linker-confined coordination" strategy to fabricate two self-assembled nanozymes, i.e., conventional nanozyme (NE) and single-atomic nanozyme (SAE), which respectively consist of Pt nanoparticles and single Pt atoms as active catalytic sites anchored in metal-organic frameworks with encapsulated photosensitizers for catalase-mimicking enhanced photodynamic therapy. Compared to Pt nanoparticle-based conventional nanozyme, Pt single-atomic nanozyme shows enhanced catalase-mimicking activity in generating oxygen for overcoming tumor hypoxia, thus presenting more efficient reactive oxygen species generation and high tumor inhibition rate.

Microtubule Detachment in Gliding Motility Assays Limits the Performance of Kinesin-Driven Molecular Shuttles.

The creation of complex active nanosystems integrating cytoskeletal filaments propelled by surface-adhered motor proteins often relies on the filaments' ability to glide over up to meter-long distances. While theoretical considerations support this ability, we show that microtubule detachment (either spontaneous or triggered by a microtubule crossing event) is a non-negligible phenomenon that has been overlooked until now. The average gliding distance before spontaneous detachment was measured to be 30 ± 10 mm for a functional kinesin-1 density of 500 μm-2 and 9 ± 4 mm for a functional kinesin-1 density of 100 μm-2 at 1 mM ATP. Even microtubules longer than 3 μm detached, suggesting that spontaneous detachment is not caused by the stochastic absence of motors or their stochastic release due to a limited run length.

Towards polarization-based excitation tailoring for extended Raman spectroscopy.

Undoubtedly, Raman spectroscopy is one of the most elaborate spectroscopy tools in materials science, chemistry, medicine and optics. However, when it comes to the analysis of nanostructured specimens or individual sub-wavelength-sized systems, the access to Raman spectra resulting from different excitation schemes is usually very limited. For instance, the excitation with an electric field component oriented perpendicularly to the substrate plane is a difficult task. Conventionally, this can only be achieved by mechanically tilting the sample or by sophisticated sample preparation. Here, we propose a novel experimental method based on the utilization of polarization tailored light for Raman spectroscopy of individual nanostructures. As a proof of principle, we create three-dimensional electromagnetic field distributions at the nanoscale using tightly focused cylindrical vector beams impinging normally onto the specimen, hence keeping the traditional beam-path of commercial Raman systems. In order to demonstrate the convenience of this excitation scheme, we use a sub-wavelength diameter gallium-nitride nanostructure as a test platform and show experimentally that its Raman spectra depend sensitively on its location relative to the focal vector field. The observed Raman spectra can be attributed to the interaction with transverse and pure longitudinal electric field components. This novel technique may pave the way towards a characterization of Raman active nanosystems, granting direct access to growth-related parameters such as strain or defects in the material by using the full information of all Raman modes.

Magnetically active pNIPAM nanosystems as temperature-sensitive biocompatible structures for controlled drug delivery

Here, temperature-sensitive hybrid poly(N-isopropylacrylamide) (pNIPAM) nanosystems with magnetic response are synthesised and investigated for controlled release of 5-fluorouracil (5FU) and oxaliplatin (OXA). Initially, magnetic nanoparticles (@Fe3O4) are synthesised by co-precipitation approach and functionalised with acrylic acid (AA), 3-butenoic acid (3BA) or allylamine (AL) as comonomers. The thermo-responsive polymer is grown by free radical polymerisation using N-isopropylacrylamide (NIPAM) as monomer, N,N’-methylenbisacrylamide (BIS) as cross-linker, and 2,2’-azobis(2-methylpropionamidene) (V50) as initiator. We evaluate particle morphology by transmission electron microscopy (TEM) and particle size and surface charge by dynamic light scattering (DLS) and Z-potential (ZP) measurements. These magnetically active pNIPAM@ nanoformulations are loaded with 5-fluorouracil (5FU) and oxaliplatin (OXA) to determine loading efficiency, drug content and release as well as the cytotoxicity against T-84 colon cancer cells. Our results show high biocompatibility of pNIPAM nanoformulations using human blood cells and cultured cells. Interestingly, the pNIPAM@Fe3O4-3BA + 5FU nanoformulation significantly reduces the growth of T-84 cells (57% relative inhibition of proliferation). Indeed, pNIPAM-co-AL@Fe3O4-AA nanosystems produce a slight migration of HCT15 cells in suspension in the presence of an external magnetic field. Therefore, the obtained hybrid nanoparticles can be applied as a promising biocompatible nanoplatform for the delivery of 5FU and OXA in the improvement of colon cancer treatments.

Facile synthesis of Pd3Y alloy nanoparticles for electrocatalysis of the oxygen reduction reaction

Multielement nanocrystals made of noble metals and transition metals are at the focus of theoretical and experimental studies for their promising performances in several key electrochemical processes of the renewable energies landscape. However, the preparation of bimetallic nanocrystals often requires expensive and tedious procedures, sometimes resulting in nanocrystals contaminated at their surface by synthesis byproducts. In this paper we describe the synthesis of Pd3Y alloy nanoparticles (NPs) by a robust laser assisted method in pure organic solvents and their performances as electrocatalysts for oxygen reduction reaction (ORR). The electrochemical properties of Pd3Y NPs for ORR, investigated in acid and alkaline electrolytes, exhibited higher activity than standard Pd/C or Pt/C systems, in terms of half wave potential, mass activity and specific activity, in agreement with the predictions of the Nørskov d-band center model for Pd alloys. The effect of ClO4− and Cl− anions was also investigated revealing a surprising poisoning effect of both anions for the Pd3Y alloys. Overall, laser generated Pd3Y alloy NPs emerged as highly active nanosystems for ORR, opening the way to the realization of other nanoalloys of potential interest in the perspective of Pt replacement by the same synthetic route.

Engineering with Biomolecular Motors.

Biomolecular motors, such as the motor protein kinesin, can be used as off-the-shelf components to power hybrid nanosystems. These hybrid systems combine elements from the biological and synthetic toolbox of the nanoengineer and can be used to explore the applications and design principles of active nanosystems. Efforts to advance nanoscale engineering benefit greatly from biological and biophysical research into the operating principles of motor proteins and their biological roles. In return, the process of creating in vitro systems outside of the context of biology can lead to an improved understanding of the physical constraints creating the fitness landscape explored by evolution. However, our main focus is a holistic understanding of the engineering principles applying to systems integrating molecular motors in general. To advance this goal, we and other researchers have designed biomolecular motor-powered nanodevices, which sense, compute, and actuate. In addition to demonstrating that biological solutions can be mimicked in vitro, these devices often demonstrate new paradigms without parallels in current technology. Long-term trends in technology toward the deployment of ever smaller and more numerous motors and computers give us confidence that our work will become increasingly relevant. Here, our discussion aims to step back and look at the big picture. From our perspective, energy efficiency is a key and underappreciated metric in the design of synthetic motors. On the basis of an analogy to ecological principles, we submit that practical molecular motors have to have energy conversion efficiencies of more than 10%, a threshold only exceeded by motor proteins. We also believe that motor and system lifetime is a critical metric and an important topic of investigation. Related questions are if future molecular motors, by necessity, will resemble biomolecular motors in their softness and fragility and have to conform to the "universal performance characteristics of motors", linking the maximum force and mass of any motor, identified by Marden and Allen. The utilization of molecular motors for computing devices emphasizes the interesting relationship among the conversion of energy, extraction of work, and production of information. Our recent work touches upon these topics and discusses molecular clocks as well as a Landauer limit for robotics. What is on the horizon? Just as photovoltaics took advantage of progress in semiconductor fabrication to become commercially viable over a century, one can envision that engineers working with biomolecular motors leverage progress in biotechnology and drug development to create the engines of the future. However, the future source of energy is going to be electricity rather than fossil or biological fuels, a fact that has to be accounted for in our future efforts. In summary, we are convinced that past, ongoing, and future efforts to engineer with biomolecular motors are providing exciting demonstrations and fundamental insights as well as opportunities to wander freely across the borders of engineering, biology, and chemistry.

Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells

Targeted therapies have profoundly changed the clinical prospect in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In particular, the anti-HER2 monoclonal antibody trastuzumab represents the gold standard for the treatment of HER2+ breast cancer patients. Its contribution in dampening cancer progression is mainly attributed to the antibody-dependent cell-mediated cytotoxicity (ADCC) rather than HER2 blockade. Here, multiple half chains of trastuzumab were conjugated onto magnetic iron oxide nanoparticles (MNP-HC) to develop target-specific and biologically active nanosystems to enhance anti-HER2 therapeutic potential. HER2 targeting was assessed in different human breast cancer cell lines, where nanoparticles triggered site-specific phosphorylation in the catalytic domain of the receptor and cellular uptake by endocytosis. MNP-HC induced remarkable antiproliferative effect in HER2+ breast cancer cells, exhibiting enhanced activity compared to free drug. Accordingly, nanoparticles induced p27kip1 expression and cell cycle arrest in G1 phase, without loosing capability to prime ADCC. Finally, MNP-HC affected viability of trastuzumab-resistant cells, suggesting interference with the resistance machinery. Our findings indicate that multiple arrangement of trastuzumab half chain on the nanoparticle surface enhances anticancer efficacy in HER2+ breast cancer cells. Powerful inhibition of HER2 signaling could promote responsiveness of resistant cells, thus suggesting ways for drug sensitization.

Biologically active polymer nanosystems.

The methods of synthesis of biologically active nanostructured systems based on functional and natural polymers are reviewed. The formation of nanosystems in the process of interaction between synthetic water-soluble polyelectrolytes and amphiphilic ionic surfactants is discussed. The influence of structure and stability of these systems on their biological activity is considered. The complexation between DNA and polycations with the formation of compacted DNA molecules, and the transport of resulting complexes into the cells are discussed. The data on nanostructuring of hemoglobin using polyfunctional crosslinkers and the data on the use of the obtained nanoparticles as oxygen-transporting blood substitutes are summarized. Using nanodisperse silver stabilized with poly(vinylpyrrolidone) as an example it was demonstrated, that transferring silver into nanodisperse state results in widening its bioactivity.

Microscopic modeling of the effect of phonons on the optical properties of solid-state emitters

Understanding the effect of vibrations in optically active nano systems is crucial for successfully implementing applications in molecular-based electro-optical devices, quantum information communications, single photon sources, and fluorescent markers for biological measurements. Here, we present a first-principles microscopic description of the role of phonons on the isotopic shift presented in the optical emission spectrum associated to the negatively charged silicon-vacancy color center in diamond. We use the spin-boson model and estimate the electron-phonon interactions using a symmetrized molecular description of the electronic states and a force-constant model to describe molecular vibrations. Group theoretical arguments and dynamical symmetry breaking are presented in order to explain the optical properties of the zero-phonon line and the isotopic shift of the phonon sideband.

The Next Generation Non-competitive Active Polyester Nanosystems for Transferrin Receptor-mediated Peroral Transport Utilizing Gambogic Acid as a Ligand.

The current methods for targeted drug delivery utilize ligands that must out-compete endogenous ligands in order to bind to the active site facilitating the transport. To address this limitation, we present a non-competitive active transport strategy to overcome intestinal barriers in the form of tunable nanosystems (NS) for transferrin receptor (TfR) utilizing gambogic acid (GA), a xanthanoid, as its ligand. The NS made using GA conjugated poly(lactide-co-glycolide) (PLGA) have shown non-competitive affinity to TfR evaluated in cell/cell-free systems. The fluorescent PLGA-GA NS exhibited significant intestinal transport and altered distribution profile compared to PLGA NS in vivo. The PLGA-GA NS loaded with cyclosporine A (CsA), a model peptide, upon peroral dosing to rodents led to maximum plasma concentration of CsA at 6 h as opposed to 24 h with PLGA-NS with at least 2-fold higher levels in brain at 72 h. The proposed approach offers new prospects for peroral drug delivery and beyond.

Multifunctional mesoporous silica nanocarriers for stimuli-responsive target delivery of anticancer drugs

By modifying the outer surface of MSNs with various functional groups or/and using a combination with other nanomaterials, stimuli-responsive and active targeting nanosystems can be designed for stimuli-responsive target delivery of anticancer drugs.

Enzyme-Powered Hollow Mesoporous Janus Nanomotors.

The development of synthetic nanomotors for technological applications in particular for life science and nanomedicine is a key focus of current basic research. However, it has been challenging to make active nanosystems based on biocompatible materials consuming nontoxic fuels for providing self-propulsion. Here, we fabricate self-propelled Janus nanomotors based on hollow mesoporous silica nanoparticles (HMSNPs), which are powered by biocatalytic reactions of three different enzymes: catalase, urease, and glucose oxidase (GOx). The active motion is characterized by a mean-square displacement (MSD) analysis of optical video recordings and confirmed by dynamic light scattering (DLS) measurements. We found that the apparent diffusion coefficient was enhanced by up to 83%. In addition, using optical tweezers, we directly measured a holding force of 64 ± 16 fN, which was necessary to counteract the effective self-propulsion force generated by a single nanomotor. The successful demonstration of biocompatible enzyme-powered active nanomotors using biologically benign fuels has a great potential for future biomedical applications.

Conceptual approach for developing sustainable, active antimicrobial-delivery nanosystems for microbial contamination removal in drinking and industrial water systems

Effective treatments for the removal of pathogenic microorganisms in drinking water and the reduction of biofouling/biocorrosion in industrial water are beneficial to public health and industry. This article proposed a conceptual approach for the development of target specific nano-carriers with encapsulated antimicrobial agents. Three types of nanocomposites including dendrimers, liposomes, and zeolite are proposed as suitable nano-carrier candidates. Bacteriophage lytic enzymes and quorum-sensing inhibitors could be alternative antimicrobial agents. Antibody-conjugated nano-carriers are able to specifically target the microorganisms responsible for waterborne-disease and biofouling/biocorrosion. Ultimately, the proposed conceptual approach, designed to be effective against target microorganisms in low concentrations of antimicrobial agents in water, could be economical and less/nontoxic for human and the environment.

Polymer Nanocompartments in Broad-Spectrum Medical Applications

The field of nanoscience is expected to make significant contributions to contemporary medicine by providing unique solutions to critical problems. These solutions require the design of hybrid materials/systems with new properties and functionalities. This review focuses on spherical polymer nanocompartments (capsules and vesicles) and describes their potential in a wide variety of medical applications that range from passive drug carriers to active nanoreactors to artificial organelles. Here, we place emphasis on the complex requirements that a polymer assembly must fulfill for consideration in the medical domain. In terms of stability and chemical diversity, synthetic polymer compartments are superior to currently marketed liposomes, thereby supporting their modification for targeting approaches, stimuli-responsiveness, and multifunctionality. The authors present the latest concepts and examples based on the encapsulation/entrapment of biomolecules (e.g., enzymes and proteins) for the development of active nanosystems for application in the medical domain.

Nanoionics: New materials and supercapacitors

The review presents the results of investigations of solid state nanomaterials and nanosystems with fast ion transport developed at the IMT RAS. The concept of a new branch of science, “nanoionics”, is proposed. New optically active physicochemical nanosystems Ag(Cu)I-M, with record high concentrations of rare-earth and transition metals (M) were discovered. The development of a new class of impulse high capacity sub-voltage devices with coherent heterojunctions, “nanoionic supercapacitors”, was initiated within the framework of a new direction, “nanoionics of advanced superionic conductors”. A search for areas of nanoionic device application was made with regard to the development of deep-sub-voltage nanoelectronics and related technologies in the nearest 5–10 years and the creation of high-density digital logics and memory, operating in hybrid nanostructures due to the combination of electron quantum transport and classical ion movement (nanoelionics) in the long future prospect.

Is there a shift to “active nanostructures”?

It has been suggested that an important transition in the long-run trajectory of nanotechnology development is a shift from passive to active nanostructures. Such a shift could present different or increased societal impacts and require new approaches for risk assessment. An active nanostructure “changes or evolves its state during its operation,” according to the National Science Foundation’s (2006) Active Nanostructures and Nanosystems grant solicitation. Active nanostructure examples include nanoelectromechanical systems (NEMS), nanomachines, self-healing materials, targeted drugs and chemicals, energy storage devices, and sensors. This article considers two questions: (a) Is there a “shift” to active nanostructures? (b) How can we characterize the prototypical areas into which active nanostructures may emerge? We build upon the NSF definition of active nanostructures to develop a research publication search strategy, with a particular intent to distinguish between passive and active nanotechnologies. We perform bibliometric analyses and describe the main publication trends from 1995 to 2008. We then describe the prototypes of research that emerge based on reading the abstracts and review papers encountered in our search. Preliminary results suggest that there is a sharp rise in active nanostructures publications in 2006, and this rise is maintained in 2007 and through to early 2008. We present a typology that can be used to describe the kind of active nanostructures that may be commercialized and regulated in the future.

The Challenge of Developing Oversight Approaches to Nanobiotechnology

This symposium of 19 articles grows out of a 4-year project funded by the National Science Foundation (NSF) (grant #SES-0608791) on “Evaluating Oversight Models for Active Nanostructures and Nanosystems: Learning from Past Technologies in a Societal Context” (Susan M. Wolf, Principal Investigator (PI); Co-PIs: Efrosini Kokkoli, Jennifer Kuzma, Jordan Paradise, Gurumurthy Ramachandran). The goal of this project was to develop oversight recommendations for nanobiotechnology grounded in historical analysis and evaluation of oversight approaches to five cognate technologies: drugs, devices, human gene transfer research (“gene therapy”), chemicals in the workplace, and genetically modified organisms in the food supply. The investigators utilized expert elicitation and literature analysis to develop a structured survey to aid analysis of the successes and failures of these prior oversight regimes. The methodology is presented in the symposium and described in depth in additional team publications cited here. The survey instrument devised represents a significant new tool for evaluating science and technology oversight, including regulatory regimes. This symposium publishes the five historical case studies plus commentaries, an article co-authored by the investigators comparing across the five case studies to derive overarching lessons for nanobio oversight, and seven articles on cross-cutting ideas including nanobio governance and oversight, risk communication, and approaches to expert elicitation. The symposium includes the work of 30 authors and breaks new ground on policy approaches to emerging science and technology.

Emerging trends of nanoparticles application in food technology: Safety paradigms

Nanotechnology has expanded its wings in various spheres of life. It has progressed from first-generation passive nanomaterial to active nanotechnology (e.g., drug delivery) and nanosystems (e.g., robotics). Although nanofood is still in its infancy; however, these particles are now finding application as a carrier of antimicrobial polypeptides required against microbial deterioration of food quality in the food industry. Another challenging area is nanoencapsulation of pesticides that releases the pesticides within the stomach of the insect, thus minimizing contamination of crops and vegetables. The current nanotechnology applications in food science provide the detection of food pathogens, through nanosensors, which are quick, sensitive and less labour-intensive procedures. With the increasing health consciousness among consumers, it is possible to use nanosensors in plastic packaging to detect gases released due to food spoilage. However, it is well known that the nanoparticles equipped with new chemical and physical properties that vary from normal macro particles of the same composition may interact with the living systems thereby causing unexpected toxicity. Limited toxicological/safety assessments have been carried out for a few nanoparticles; hence studies relevant to oral exposure risk assessment are required for particles to be used in food.

Optical manipulation of nanoparticles and biomolecules in sub-wavelength slot waveguides

The ability to manipulate nanoscopic matter precisely is critical for the development of active nanosystems. Optical tweezers are excellent tools for transporting particles ranging in size from several micrometres to a few hundred nanometres. Manipulation of dielectric objects with much smaller diameters, however, requires stronger optical confinement and higher intensities than can be provided by these diffraction-limited systems. Here we present an approach to optofluidic transport that overcomes these limitations, using sub-wavelength liquid-core slot waveguides. The technique simultaneously makes use of near-field optical forces to confine matter inside the waveguide and scattering/adsorption forces to transport it. The ability of the slot waveguide to condense the accessible electromagnetic energy to scales as small as 60 nm allows us also to overcome the fundamental diffraction problem. We apply the approach here to the trapping and transport of 75-nm dielectric nanoparticles and lambda-DNA molecules. Because trapping occurs along a line, rather than at a point as with traditional point traps, the method provides the ability to handle extended biomolecules directly. We also carry out a detailed numerical analysis that relates the near-field optical forces to release kinetics. We believe that the architecture demonstrated here will help to bridge the gap between optical manipulation and nanofluidics.