Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).

Stimuli-responsive nanocarriers for drug delivery

https://dash.harvard.edu/bitstream/handle/1/29293165/Cancer%20Nanotechnology.pdf?sequence=1

Cancer Nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

This tutorial review provides an outlook on nanomaterials that are currently being used for theranostic purposes, with a special focus on mesoporous silica nanoparticle (MSNP) based materials. MSNPs with large surface area and pore volume can serve as efficient carriers for various therapeutic agents. The functionalization of MSNPs with molecular, supramolecular or polymer moieties, provides the material with great versatility while performing drug delivery tasks, which makes the delivery process highly controllable. This emerging area at the interface of chemistry and the life sciences offers a broad palette of opportunities for researchers with interests ranging from sol–gel science, the fabrication of nanomaterials, supramolecular chemistry, controllable drug delivery and targeted theranostics in biology and medicine.

Mesoporous silica nanoparticles in biomedical applications

In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.

Engineered Nanoparticles for Drug Delivery in Cancer Therapy

Atomically precise pieces of matter of nanometer dimensions composed of noble metals are new categories of materials with many unusual properties. Over 100 molecules of this kind with formulas such as Au25(SR)18, Au38(SR)24, and Au102(SR)44 as well as Ag25(SR)18, Ag29(S2R)12, and Ag44(SR)30 (often with a few counterions to compensate charges) are known now. They can be made reproducibly with robust synthetic protocols, resulting in colored solutions, yielding powders or diffractable crystals. They are distinctly different from nanoparticles in their spectroscopic properties such as optical absorption and emission, showing well-defined features, just like molecules. They show isotopically resolved molecular ion peaks in mass spectra and provide diverse information when examined through multiple instrumental methods. Most important of these properties is luminescence, often in the visible–near-infrared window, useful in biological applications. Luminescence in the visible region, especially by clusters prot...

Atomically Precise Clusters of Noble Metals: Emerging Link between Atoms and Nanoparticles

Magnetoresponsive Therapy Nohyun Lee, Dongwon Yoo, Daishun Ling,†,‡,⊥ Mi Hyeon Cho, Taeghwan Hyeon,*,†,‡ and Jinwoo Cheon* †Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Korea ‡School of Chemical and Biological Engineering, Seoul National University, Seoul 151-742, Korea Department of Chemistry, Yonsei University, Seoul 120-749, Korea School of Advanced Materials Engineering, Kookmin University, Seoul 136-702, Korea Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China

Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy.

Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.

Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles

On application of a focused magnetic field, zinc-doped iron oxide nanoparticles with targeting antibodies attached are shown to activate cell death signalling in a spatially controlled manner. This triggering of apoptosis signalling, via the magnetically activated aggregation of receptors, is observed in both in vitro and in vivo systems.

/pdf/a-magnetic-switch-for-the-control-of-cell-death-signalling-2kh7452lpb.pdf

A magnetic switch for the control of cell death signalling in in vitro and in vivo systems

Mechanical stresses on biological objects can lead to changes in a wide range of cellular properties, such as cell shape, cytoskeletal organization, and cell fate, by means of physical stimulations using dielectricity, optical trapping, and magnetic cytometry. In particular, micrometer-sized magnetic beads have been useful since their first utilization by Crick and Hughes to draw mechanical stresses on biological objects by developing techniques such as magnetic twisting, pulling, and cell-stretching cytometry. With the use of such magnetic stimulations, the roles of mechanical stresses for cell characteristics have been studied, which include cytoplasmic viscosity, cytoskeletal mechanotransduction, and mechanical calcium responses. Further scientific breakthroughs in this research field have depended on molecular-level understanding of mechanobiological processes and the induction of changes in cellular functions and/or cytoskeletal structures. The goal is to bring about single-cell or subcellular-level imaging and actuation of biological objects with high target specificity. Nanoscale probes and actuators are important because of their small sizes, which are comparable to those of many biologically meaningful molecules such as DNAs and proteins. In addition, their ability to attach multivalence functional groups would be another advantage. By employing nanoparticles, difficult challenges associated with currently used micrometer-scale magnetic particles, such as probing and manipulation of a single receptor without disturbing any other rheological or cytoskeletal properties of the entire cell, can be overcome. Recently, the groups of Ingber and Dobson have independently demonstrated that activation of ion channels is possible by using nanoscale magnetic particles. These efforts have demonstrated that FceRI, a cellular membrane receptor, can be magnetically agglomerated to activate the Ca signal. On the other hand, TREK-1, a membrane protein for the K ion channel, is specifically activated by magnetic nanoparticles with size as small as 130 nm. While these two pioneering works focused on ion-channel activations, new conceptual advances and other applications of nanoscale magneto-activated cellular signaling (N-MACS) are widely open to exploration. Herein, we demonstrate for the first time that receptormediated artificial triggering of cell growth in the preangiogenesis stage is possible by the N-MACS approach. Angiogenesis is a vital process both for the growth and development of blood vessels and for tumor metastasis. Conventionally, this process is initiated by several interactions that take place between specific receptors and ligands on the cell surface. The Tie2/angiopoietin(Ang) pair, in which one Ang molecule binds to clusterize three to five Tie2 receptors, is regarded as one of the important receptor–ligand interactions. This cluster formation is critical to activate multiple signaling steps and eventually participates in the angiogenic processes. Instead of using such ligands, in our study a TiMo214 monoclonal antibody(mAb)-conjugated Zn-doped ferrite magnetic nanoparticle (Ab-Zn-MNP) is employed to target and magnetically manipulate Tie2 receptors through the steps in Figure 1a–c. To achieve this result, two permanent NdFeB magnets are positioned to exert an external magnetic field of about 0.15 T, with horizontal magnetic field lines that are oriented in the manner shown in Figure 1d. At this magnetic field strength, magnetization of Ab-Zn-MNPs can be saturated in plane (Figure 1e), which induces strong attractive forces between the dipoles of neighboring nanoparticles. This phenomenon results in the aggregation of Ab-Zn-MNPs. For successful magnetic manipulation under mild external magnetic field conditions, we utilized a high-performance 15 nm Zn-doped ferrite magnetic nanoparticle (Zn-MNP) instead of a conventional magnetic nanoparticle, since it exhibits a very high saturation magnetization (Figure 1e,f) [*] J.-H. Lee, M. H. Cho, Prof. J. Cheon Department of Chemistry, Yonsei University Seoul 120-749 (Korea) Fax: (+ 82)2-364-7050 E-mail: jcheon@yonsei.ac.kr E. S. Kim, M. Son, S.-I. Yeon, Prof. J.-S. Shin Department of Microbiology Institute for Immunology and Immunological Diseases College of Medicine, Yonsei University Seoul 120-752 (Korea) Fax: (+ 82)2-392-7088 E-mail: jsshin6203@yuhs.ac [] These authors contributed equally to this work.

Artificial control of cell signaling and growth by magnetic nanoparticles

Cell-based therapies are attractive for treating various degenerative disorders and cancer but delivering functional cells to the region of interest in vivo remains difficult. The problem is exacerbated in dense biological matrices such as solid tissues because these environments impose significant steric hindrances for cell movement. Here, we show that neural stem cells transfected with zinc-doped ferrite magnetic nanoparticles (ZnMNPs) can be pulled by an external magnet to migrate to the desired location in the brain. These magnetically labeled cells (Mag-Cells) can migrate because ZnMNPs generate sufficiently strong mechanical forces to overcome steric hindrances in the brain tissues. Once at the site of lesion, Mag-Cells show enhanced neuronal differentiation and greater secretion of neurotrophic factors than unlabeled control stem cells. Our study shows that ZnMNPs activate zinc-mediated Wnt signaling to facilitate neuronal differentiation. When implemented in a rodent brain stroke model, Mag-Cells ...

Mi Hyeon Cho

Papers

Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy.

Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles

A magnetic switch for the control of cell death signalling in in vitro and in vivo systems

Artificial control of cell signaling and growth by magnetic nanoparticles

Design of Magnetically Labeled Cells (Mag-Cells) for in Vivo Control of Stem Cell Migration and Differentiation.