Recent Insights into NIR-Light-Responsive Materials for Photothermal Cell Treatments.

Controlling cells using photo-responsive materials is highly indispensable in the current biomedical sector. Considering the potential side effects of nanoparticles, it has become a challenge to control cells with photo-responsive materials. Recent studies have described several methods for controlling cell behavior using nanoparticles subjected to the near-infrared (NIR) laser light operating at the wavelength of 808 nm to 980 nm and at the power densities of 0.33 to 0.72 W·cm-2. The challenge here is the preparation of biocompatible nanoparticles for both in vivo and in vitro studies and understanding cell behavior with an external light source recommended for biological application. Earlier studies have well documented many approaches and associated mechanisms for controlling cell behavior and the interaction between nanoparticles, cells, and appropriate external light sources. In this review, various nanomaterials such as metal nanomaterials and carbon-based nanomaterials are compared systematically regarding the effects of controlling cell behavior and inflammation by studying their mechanisms, route of administration, dose, and adverse effects such as toxicity and the interaction of nanoparticles with a specific wavelength of the light. Future directions should focus on stable and efficient light-responsive materials with minimal cytotoxicity.

Gadolinium-based bimodal probes to enhance T1-Weighted magnetic resonance/optical imaging.

Gd3+-based contrast agents have been extensively used for signal enhancement of T1-weighted magnetic resonance imaging (MRI) due to the large magnetic moment and long electron spin relaxation time of the paramagnetic Gd3+ ion. The key requisites for the development of Gd3+-based contrast agents are their relaxivities and stabilities which can be achieved by chemical modifications. These modifications include coordinating Gd3+ with a chelator such as diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), encapsulating Gd3+ in nanoparticles, conjugation to biomacromolecules such as polymer micelles and liposomes, or non-covalent binding to plasma proteins. In order to have a coherent diagnostic and therapeutic approach and to understand diseases better, the combination of MRI and optical imaging (OI) techniques into one technique entity has been developed to overcome the conventional boundaries of either imaging modality used alone through bringing the excellent spatial resolution of MRI and high sensitivity of OI into full play. Novel MRI and OI bimodal probes have been extensively studied in this regard. This review is an attempt to shed some light on the bimodal imaging probes by summarizing all recent noteworthy publications involving Gd3+ containing MR-optical imaging probes. The several key elements such as novel synthetic strategy, high sensitivity, biocompatibility, and targeting of the probes are highlighted in the review. STATEMENT OF SIGNIFICANCE: The present article aims at giving an overview of the existing bimodal MRI and OI imaging probes. The review structured as a series of examples of paramagnetic Gd3+ ions, either as ions in the crystalline structure of inorganic materials or chelates for contrast enhancement in MRI, while they are used as optical imaging probes in different modes. The comprehensive review focusing on the synthetic strategies, characterizations and properties of these bimodal imaging probes will be helpful in a way to prepare related work.

Engineering nanoparticle strategies for effective cancer immunotherapy.

Cancer immunotherapy has been emerging in recent years, due to the inherent nature of the immune system. Although recent successes of immunotherapeutics in clinical application have attracted development of a novel immunotherapeutics, the off-target side effect and low immunogenicity of them remain challenges for the effective cancer immunotherapy. Theranostic nanoparticle system may one of key technology to address these issues by offering targeted delivery of various types of immunotherapeutics, resulting in significant improvements in the tumor immunotherapy. However, appropriate design or engineering of nanoparticles will be needed to improve delivery efficiency of antigen, adjuvant and therapeutics, resulting in eliciting antitumor immunity. Here, we review the current state of the art of cancer immunotherapeutic strategies, mainly based on nanoparticles (NPs). This includes NP-based antigen/adjuvant delivery vehicles to draining lymph nodes, and tumor antigen-specific T-lymphocytes for cancer immunotherapy. Several NP-based examples are shown for immune checkpoint modulation and immunogenic cell death. These overall studies demonstrate the great potential of NPs in cancer immunotherapy. Finally, engineering NP strategies will provide great opportunities to improve therapeutic effects as well as optimization of treatment processes, allowing to meet the individual needs in the cancer immunotherapy.

Recent advances in biocompatible semiconductor nanocrystals for immunobiological applications.

Quantum confinement in inorganic semiconductor nanocrystals produces brightly luminescent nanoparticles endowed with unique photo-physical properties, such as tunable optical properties. These have found widespread applications in nanotechnology. The ability to render such nanostructures biocompatible, while maintaining their tunable radiation in the visible range of the electromagnetic spectrum, renders them appropriate for bio-applications. Promising in vitro and in vivo diagnostic applications have been demonstrated, such as fluorescence-based detection of biological interactions, single molecule tracking, multiplexing and immunoassaying. In particular, these fluorescent inorganic semiconductor nanocrystals, generally known as quantum dots, have the potential of remarkable immunobiological applications. This review focuses on the current status of biocompatible quantum dots and their applications in immunobiology - immunosensing, immunofluorescent imaging and immunotherapy.

Highly Luminescent Heterostructured Copper-Doped Zinc Sulfide Nanocrystals for Application in Cancer Cell Labeling.

The structural characteristics of the seed-mediated synthesis of heterostructured CuS-ZnS nanocrystals (NCs) and Cu-doped ZnS (ZnS:Cu) NCs synthesized by two different protocols are compared and analyzed. At high Cu dopant concentrations, segregated subclusters of ZnS and CuS are observed. The photoluminescence quantum yield of ZnS:Cu NCs is about 50-80 %; a value much higher than that of ZnS NCs (6 %). Finally, these NCs are coated with a thin silica shell by using (3-mercaptopropyl)triethoxysilane in a reverse microemulsion to make them water soluble. Cytotoxicity experiments show that these silica-coated NCs have greatly reduced toxicity on both cancerous HeLa and noncancerous Chinese hamster ovary cells. The labeling of cancerous HeLa cells is also demonstrated.

Grafting of ZnS:Mn-Doped Nanocrystals and an Anticancer Drug onto Graphene Oxide for Delivery and Cell Labeling.

A facile method for the synthesis of highly fluorescent manganese-doped zinc sulfide (ZnS:Mn) nanocrystals covalently functionalized with polyethylene glycol conjugated graphene oxide (GO-PEG) for drug delivery and cell labeling is reported. First, covalently functionalized GO with PEG-bis(amine) to enhance the solubility and biocompatibility in water and physiological buffers. Second, glutathione (GSH)-coated ZnS:Mn-doped nanocrystals were covalently grafted onto GO-PEG. An acid-amidation process was employed to obtain GO-PEG/ZnS:Mn nanocomposites, which were characterized by UV/Vis, photoluminescence, and Fourier transform infrared spectroscopies, and transmission electron microscopy. Finally, the anticancer drug doxorubicin (DOX) was noncovalently loaded onto these GO-PEG/ZnS:Mn composite particles. High drug entrapment efficiency (100 % due to more GO surface available for binding), slow in vitro release of drug (ca. 40 % at acidic pH), better HeLa cancer cell killing efficiency (ca. 85 %), and cell labeling capability are the important traits of these DOX-loaded nanocomposites. It is believed these novel fluorescent [GO-PEG/ZnS:Mn]-DOX composite particles have great potential as theranostic agents in cancer diagnosis and therapy.

Fluorescence Retrieval of CdSe Quantum Dots by Self-Assembly of Supramolecular Aggregates of Reverse Micelles.

Life is restored to inactive (dead) quantum dots by means of the encapsulation into supramolecular aggregates of spherical nonionic Igepal micelles.

Core-shell upconversion nanoparticle - semiconductor heterostructures for photodynamic therapy.

Core-shell nanoparticles (CSNPs) with diverse chemical compositions have been attracting greater attention in recent years. However, it has been a challenge to develop CSNPs with different crystal structures due to the lattice mismatch of the nanocrystals. Here we report a rational design of core-shell heterostructure consisting of NaYF4:Yb,Tm upconversion nanoparticle (UCN) as the core and ZnO semiconductor as the shell for potential application in photodynamic therapy (PDT). The core-shell architecture (confirmed by TEM and STEM) enables for improving the loading efficiency of photosensitizer (ZnO) as the semiconductor is directly coated on the UCN core. Importantly, UCN acts as a transducer to sensitize ZnO and trigger the generation of cytotoxic reactive oxygen species (ROS) to induce cancer cell death. We also present a firefly luciferase (FLuc) reporter gene based molecular biosensor (ARE-FLuc) to measure the antioxidant signaling response activated in cells during the release of ROS in response to the exposure of CSNPs under 980 nm NIR light. The breast cancer cells (MDA-MB-231 and 4T1) exposed to CSNPs showed significant release of ROS as measured by aminophenyl fluorescein (APF) and ARE-FLuc luciferase assays, and ~45% cancer cell death as measured by MTT assay, when illuminated with 980 nm NIR light.

Synthesis of small-sized, porous, and low-toxic magnetite nanoparticles by thin POSS silica coating.

In this communication, we report the synthesis of small-sized (<10 nm), water-soluble, magnetic nanoparticles (MNPs) coated with polyhedral oligomeric silsesquioxanes (POSS), which contain either polyethylene glycol (PEG) or octa(tetramethylammonium) (OctaTMA) as functional groups. The POSS-coated MNPs exhibit superparamagnetic behavior with saturation magnetic moments (51-53 emu g(-1)) comparable to silica-coated MNPs. They also provide good colloidal stability at different pH and salt concentrations, and low cytotoxicity to MCF-7 human breast epithelial cells. The relaxivity data and magnetic resonance (MR) phantom images demonstrate the potential application of these MNPs in bioimaging.

"Turn-on" fluorescence probe integrated polymer nanoparticles for sensing biological thiol molecules.

A "turn-on" thiol-responsive fluorescence probe was synthesized and integrated into polymeric nanoparticles for sensing intracellular thiols. There is a photo-induced electron transfer process in the off state of the probe, and this process is terminated upon the reaction with thiol compounds. Configuration interaction singles (CIS) calculation was performed to confirm the mechanism of this process. A series of sensing studies were carried out, showing that the probe-integrated nanoparticles were highly selective towards biological thiol compounds over non-thiolated amino acids. Kinetic studies were also performed to investigate the relative reaction rate between the probe and the thiolated amino acids. Subsequently, the Gibbs free energy of the reactions was explored by means of the electrochemical method. Finally, the detection system was employed for sensing intracellular thiols in cancer cells, and the sensing selectivity could be further enhanced with the use of a cancer cell-targeting ligand in the nanoparticles. This development paves a path for the sensing and detection of biological thiols, serving as a potential diagnostic tool in the future.

"Smart" theranostic lanthanide nanoprobes with simultaneous up-conversion fluorescence and tunable T1-T2 magnetic resonance imaging contrast and near-infrared activated photodynamic therapy.

The current work reports a type of "smart" lanthanide-based theranostic nanoprobe, NaDyF4:Yb(3+)/NaGdF4:Yb(3+),Er(3+), which is able to circumvent the up-converting poisoning effect of Dy(3+) ions to give efficient near infrared (980 nm) triggered up-conversion fluorescence, and offers not only excellent dark T2-weighted MR contrast but also tunable bright and T1-weighted MR contrast properties. Due to the efficient up-converted energy transfer from the nanocrystals to chlorin e6 (Ce6) photosensitizers loaded onto the nanocrystals, cytotoxic singlet oxygen was generated and photodynamic therapy was demonstrated. Therefore, the current multifunctional nanocrystals could be potentially useful in various image-guided diagnoses where bright or dark MRI contrast could be selectively tuned to optimize image quality, but also as an efficient and more penetrative near-infrared activated photodynamic therapy agent.

Mimicking cellular transport mechanism in stem cells through endosomal escape of new peptide-coated quantum dots.

Protein transport is an important phenomenon in biological systems. Proteins are transported via several mechanisms to reach their destined compartment of cell for its complete function. One such mechanism is the microtubule mediated protein transport. Up to now, there are no reports on synthetic systems mimicking the biological protein transport mechanism. Here we report a highly efficient method of mimicking the microtubule mediated protein transport using newly designed biotinylated peptides encompassing a microtubule-associated sequence (MTAS) and a nuclear localization signaling (NLS) sequence, and their final conjugation with streptavidin-coated CdSe/ZnS quantum dots (QDs). Our results demonstrate that these novel bio-conjugated QDs enhance the endosomal escape and promote targeted delivery into the nucleus of human mesenchymal stem cells via microtubules. Mimicking the cellular transport mechanism in stem cells is highly desirable for diagnostics, targeting and therapeutic applications, opening up new avenues in the area of drug delivery.

MicroRNAs -the next generation therapeutic targets in human diseases.

MicroRNAs (miRNAs), an abundant class of ~22-nucleotide non-coding RNAs, regulate the expression of genes at post transcriptional level. MiRNAs are important regulators of eukaryotic gene expression and therefore implicated in a wide range of biological processes. The miRNA-related genetic alterations are possibly more implicated human diseases than currently appreciated. Genetic variants in miRNA target sites, called miRNA genes are identified to be associated with human diseases. This review discusses about the role of micro-RNA genes in various human diseases such as neurodegenerative disorders, cardio-vascular diseases, and metabolic disorders, and how they can be targeted as a new therapeutic tool in future with reference to drug discoveries/ development.

Multifunctional iron oxide nanoparticles for diagnostics, therapy and macromolecule delivery.

In recent years, multifunctional nanoparticles (NPs) consisting of either metal (e.g. Au), or magnetic NP (e.g. iron oxide) with other fluorescent components such as quantum dots (QDs) or organic dyes have been emerging as versatile candidate systems for cancer diagnosis, therapy, and macromolecule delivery such as micro ribonucleic acid (microRNA). This review intends to highlight the recent advances in the synthesis and application of multifunctional NPs (mainly iron oxide) in theranostics, an area used to combine therapeutics and diagnostics. The recent applications of NPs in miRNA delivery are also reviewed.

An anti-clogging 3D porous membrane for sorting and patterning of micro-entities.

A 3D porous membrane containing pyramidal microstructures around funnel-like pores is demonstrated as a unique anti-clogging porous membrane for high efficiency sorting and patterning of cells/beads. The membrane exhibits four interesting features: anti-clogging, patterning of micro-entities of different sizes, bi-directional separation and simultaneous separation and patterning of micro-entities.

Bimodal magnetic-fluorescent probes for bioimaging.

Fluorescent optical probes have been intensively used in the area of bio-imaging. In this review article, we describe the recent advancements in the synthesis and application of bimodal magnetic-fluorescent probes for bioimaging. The bimodal probes consist of fluorescent [semiconducting quantum dots (e.g., CdSe/ZnS) or rare-earth doped (e.g., NaYF(4) :Yb,Er)] nanoparticles (NPs) and magnetic (iron oxide or gadolinium based) NPs for optical and magnetic resonance (MR) imaging.

Silica-coated quantum dots and magnetic nanoparticles for bioimaging applications (Mini-Review).

Fluorescent quantum dots (e.g., CdSe-ZnS) and magnetic nanoparticles (e.g., Fe(2)O(3) or Fe(3)O(4)) are two important candidate systems that have been emerging as potential probes for bioimaging applications. This review focuses on the development of silica-coated inorganic probes (optical and magnetic) that are originated mainly from the author's laboratory for bioimaging applications. The recent developments in the synthesis of rare earth nanoparticles for multimodality imaging are also delineated.

Gadolinium oxide ultranarrow nanorods as multimodal contrast agents for optical and magnetic resonance imaging.

We demonstrate a simple synthetic strategy for the fabrication of single-phase rare earth (RE) doped gadolinium oxide (Gd(2)O(3):RE where RE = terbium (Tb), ytterbium (Yb), and erbium (Er)) nanorods (NRs) as multimodal imaging probes. The NRs are ultranarrow and exhibit both emission and magnetic characteristics. The Tb-doped and Yb/Er-codoped Gd(2)O(3) NRs exhibit down- and up-conversion fluorescence respectively, and also exhibit paramagnetism. Importantly, these codoped NRs possess excellent magnetic characteristics, as shown in their longitudinal relaxation time (T1) -weighted image contrast, which is closer to that of commercial Gadovist for magnetic resonance imaging (MRI) applications. This property opens up new avenues in the development of contrast agents.

Functional and multifunctional nanoparticles for bioimaging and biosensing.

Herein, we describe the synthesis of functional and multifunctional nanoparticles (NPs), derived from our recent work, for bioimaging and biosensing applications. The functionalized NPs involve quantum dots (QDs), magnetic particles (MPs) and noble metal NPs for the aforementioned applications. A diverse silica coating approaches (reverse microemulsion and thin silanization) are delineated for the design of water-soluble NPs. We also review the synthesis of silica-coated bifunctional NPs consisting of MPs and QDs for live cell imaging of human liver cancer cells (HepG2) and mouse fibroblast cells (NIH-3T3). Using silica coated NPs, various NPs that are functionalized with antibody, oligonucleotide, biotin and dextran are efficiently used for protein detection.