Externally modulated nanoparticles comprise a rapidly advancing class of cancer nanotherapeutics, which combine the favorable tumor accumulation of nanoparticles, with external spatio-temporal control on therapy delivery via optical, magnetic, or ultrasound modalities. The local control on therapy enables higher tumor treatment efficacy, while simultaneously reducing off-target effects. The nanoparticle interactions with external fields have an additional advantage of frequently generating an imaging signal, and thus such agents provide theranostic (both diagnostic and therapeutic) capabilities. In this review, we classify the emerging externally modulated theranostic nanoparticles according to the mode of external control and describe the physiochemical mechanisms underlying the external control of therapy, and illustrate the major embodiments of nanoparticles in each class with proven biological efficacy: (I) electromagnetic radiation in visible and near-infrared range is being exploited for gold based and carbon nanostructures with tunable surface plasmon resonance (SPR) for imaging and photothermal therapy (PTT) of cancer, photochemistry based manipulations are employed for light sensitive liposomes and porphyrin based nanoparticles; (II) Magnetic field based manipulations are being developed for iron-oxide based nanostructures for magnetic resonance imaging (MRI) and magnetothermal therapy; (III) ultrasound based methods are primarily being employed to increase delivery of conventional drugs and nanotherapeutics to tumor sites.
Cancer nanotechnology; theranostics; hyperthermia; NIR therapy; gold nanoparticles (AuNPs)
Recent advances in theranostics have expanded our ability to design and construct multifunctional nanoparticles that will ultimately allow us to image and treat diseases in a single clinical procedure. Theranostic nanoparticles, combining targeting, therapeutic and diagnostic functions within a single nanoscale complex, have emerged as a result of this confluence of nanoscience and biomedicine. The theranostic capabilities of gold nanoshells -spherical, silica core, gold shell nanoparticles- have attracted tremendous attention over the past decade as nanoshells have emerged as a promising tool for cancer therapy and bioimaging enhancement. This account examines the design and synthesis of nanoshell-based theranostic agents, their plasmon-derived optical properties and their corresponding applications. Nanoshells illuminated with resonant light are either strong optical absorbers or scatterers, properties which give rise to their unique capabilities. In this account, we discuss the underlying physical principles contributing to the photothermal response of nanoshells. We elucidate the photophysics of nanoshell-induced fluorescence enhancement of weak near-infrared fluorophores. We then describe the application of nanoshells as a contrast agent for optical coherence tomography of breast carcinoma cells in vivo. We also examine the recent progress of nanoshells as a multimodal theranostic probe for near-infrared fluorescence and magnetic resonance imaging (MRI) combined with photothermal ablation of cancer cells. The design and preparation of nanoshell complexes is discussed, and their ability to enhance the photoluminescence of fluorophores while incorporating MR contrast is described. We show the theranostic potential of the multimodal nanoshells in vivo for imaging subcutaneous breast cancer tumors in animal models and their biodistribution in various tissues.
We then discuss the potential of nanoshells as light-triggered gene therapy vectors. The plasmonic properties of nanoshells make them highly effective as light controlled delivery vectors, adding temporal control to the spatial control characteristic of nanoparticle-based gene therapy approaches. We describe the fabrication of DNA-conjugated nanoshell complexes and compare the efficiency of light-induced and thermally-induced DNA release of DNA. We examine light-triggered release of DAPI (4',6-diamidino-2-phenylindole) molecules, which bind reversibly to double-stranded DNA, to visualize intracellular light-induced release. Finally, we look at future prospects of nanoshell-based theranostics, the potential impact and near-term challenges of theranostic nanomedicine in the next decade.
Nanoparticle-based drug delivery (NDD) has emerged as a promising approach to improving upon the efficacy of existing drugs and enabling the development of new therapies. Proof-of-concept studies have demonstrated the potential for NDD systems to simultaneously achieve reduced drug toxicity, improved bio-availability, increased circulation times, controlled drug release, and targeting. However, clinical translation of NDD vehicles with the goal of treating particularly challenging diseases, such as cancer, will require a thorough understanding of how nanoparticle properties influence their fate in biological systems, especially in vivo. Consequently, a model system for systematic evaluation of all stages of NDD with high sensitivity, high resolution, and low cost is highly desirable. In theory, this system should maintain the properties and behavior of the original NDD vehicle, while providing mechanisms for monitoring intracellular and systemic nanocarrier distribution, degradation, drug release, and clearance. For such a model system, quantum dots (QDots) offer great potential. QDots feature small size and versatile surface chemistry, allowing their incorporation within virtually any NDD vehicle with minimal effect on overall characteristics, and offer superb optical properties for real-time monitoring of NDD vehicle transport and drug release at both cellular and systemic levels. Though the direct use of QDots for drug delivery remains questionable due to their potential long-term toxicity, the QDot core can be easily replaced with other organic drug carriers or more biocompatible inorganic contrast agents (such as gold and magnetic nanoparticles) by their similar size and surface properties, facilitating translation of well characterized NDD vehicles to the clinic, maintaining NDD imaging capabilities, and potentially providing additional therapeutic functionalities such as photothermal therapy and magneto-transfection. In this review we outline unique features that make QDots an ideal platform for nanocarrier design and discuss how this model has been applied to study NDD vehicle behavior for diverse drug delivery applications.
Nanoparticle; Drug delivery vehicle; Nanocarrier; Quantum dot; Fluorescence imaging; Traceable drug delivery; Nanomedicine
Towards the goal of development of a generic nanomaterial delivery system and delivery of the ‘as prepared’ nanoparticles without ‘further surface modification’ in a generic way, we have fabricated a hybrid polymer capsule as a delivery vehicle in which nanoparticles are loaded within their cavity. To this end, a generic approach to prepare nanomaterials-loaded polyelectrolyte multilayered (PEM) capsules has been reported, where polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) polymer capsules were employed as nano/microreactors to synthesize variety of nanomaterials (metal nanoparticles; lanthanide doped inorganic nanoparticles; gadolinium based nanoparticles, cadmium based nanoparticles; different shapes of nanoparticles; co-loading of two types of nanoparticles) in their hollow cavity. These nanoparticles-loaded capsules were employed to demonstrate generic delivery of payload of nanoparticles intracellularly (HeLa cells), without the need of individual nanoparticle surface modification. Validation of intracellular internalization of nanoparticles-loaded capsules by HeLa cells was ascertained by confocal laser scanning microscopy. The green emission from Tb3+ was observed after internalization of LaF3:Tb3+(5%) nanoparticles-loaded capsules by HeLa cells, which suggests that nanoparticles in hybrid capsules retain their functionality within the cells. In vitro cytotoxicity studies of these nanoparticles-loaded capsules showed less/no cytotoxicity in comparison to blank capsules or untreated cells, thus offering a way of evading direct contact of nanoparticles with cells because of the presence of biocompatible polymeric shell of capsules. The proposed hybrid delivery system can be potentially developed to avoid a series of biological barriers and deliver multiple cargoes (both simultaneous and individual delivery) without the need of individual cargo design/modification.
Fe3O4-gold-chitosan core-shell nanostructure can be used in biotechnological and biomedical applications such as magnetic bioseparation, water and wastewater treatment, biodetection and bioimaging, drug delivery, and cancer treatment.
Magnetite nanoparticles with an average size of 9.8 nm in diameter were synthesized using the chemical co-precipitation method. A gold-coated Fe3O4 monotonous core-shell nanostructure was produced with an average size of 15 nm in diameter by glucose reduction of Au3+ which is then stabilized with a chitosan cross linked by formaldehyde. The results of analyses with X-ray diffraction (XRD), Fourier Transformed Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) indicated that the nanoparticles were regularly shaped, and agglomerate-free, with a narrow size distribution.
A rapid, mild method for synthesizing Fe3O4-gold nanoparticles using chitosan was investigated. A magnetic core-shell-chitosan nanocomposite, including both the supermagnetic properties of iron oxide and the optical characteristics of colloidal gold nanoparticles, was synthesized.
bioseparation; core-shell; Fe3O4-gold-chitosan; hydrogel; magnetic; nanocomposite; nanoparticle
Metallic nanoparticles have fascinated scientist for over a century and are now heavily utilized in biomedical sciences and engineering. They are a focus of interest because of their huge potential in nanotechnology. Today these materials can be synthesized and modified with various chemical functional groups which allow them to be conjugated with antibodies, ligands, and drugs of interest and thus opening a wide range of potential applications in biotechnology, magnetic separation, and preconcentration of target analytes, targeted drug delivery, and vehicles for gene and drug delivery and more importantly diagnostic imaging. Moreover, various imaging modalities have been developed over the period of time such as MRI, CT, PET, ultrasound, SERS, and optical imaging as an aid to image various disease states. These imaging modalities differ in both techniques and instrumentation and more importantly require a contrast agent with unique physiochemical properties. This led to the invention of various nanoparticulated contrast agent such as magnetic nanoparticles (Fe3O4), gold, and silver nanoparticles for their application in these imaging modalities. In addition, to use various imaging techniques in tandem newer multifunctional nanoshells and nanocages have been developed. Thus in this review article, we aim to provide an introduction to magnetic nanoparticles (Fe3O4), gold nanoparticles, nanoshells and nanocages, and silver nanoparticles followed by their synthesis, physiochemical properties, and citing some recent applications in the diagnostic imaging and therapy of cancer.
Fe3O4; gold nanoparticles; iron oxide nanoparticles; metallic nanoparticles; nanocages; nanoshells; silver nanoparticles
The optical properties of multi-functionalized cobalt ferrite (CoFe2O4), cobalt zinc ferrite (Co0.5Zn0.5Fe2O4), and zinc ferrite (ZnFe2O4) nanoparticles have been enhanced by coating them with silica shell using a modified Stöber method. The ferrites nanoparticles were prepared by a modified citrate gel technique. These core/shell ferrites nanoparticles have been fired at temperatures: 400°C, 600°C and 800°C, respectively, for 2 h. The composition, phase, and morphology of the prepared core/shell ferrites nanoparticles were determined by X-ray diffraction and transmission electron microscopy, respectively. The diffuse reflectance and magnetic properties of the core/shell ferrites nanoparticles at room temperature were investigated using UV/VIS double-beam spectrophotometer and vibrating sample magnetometer, respectively. It was found that, by increasing the firing temperature from 400°C to 800°C, the average crystallite size of the core/shell ferrites nanoparticles increases. The cobalt ferrite nanoparticles fired at temperature 800°C; show the highest saturation magnetization while the zinc ferrite nanoparticles coated with silica shell shows the highest diffuse reflectance. On the other hand, core/shell zinc ferrite/silica nanoparticles fired at 400°C show a ferromagnetic behavior and high diffuse reflectance when compared with all the uncoated or coated ferrites nanoparticles. These characteristics of core/shell zinc ferrite/silica nanostructures make them promising candidates for magneto-optical nanodevice applications.
nanostructures; oxides; cobalt ferrite; cobalt zinc ferrite; zinc ferrite; magnetic properties; diffuse reflectance.
Photothermal ablation is a minimally invasive approach, which typically involves delivery of photothermal sensitizers to targeted tissues. The purpose of our study was to demonstrate that gold nanoparticles are phagocytosed by pancreatic cancer cells, thus permitting magnetic resonance imaging (MRI) of sensitizer delivery and photothermal ablation.
Patients and methods
Iron-oxide core/gold-shell nanoparticles (GoldMag®, 30 nm diameter; Xi’an GoldMag Biotechnology Co, Xi’an, People’s Republic of China) were used. In a 96-well plate, 3 × 104 PANC-1 (human pancreatic cancer cell line) cells were placed. GoldMag (0, 25, or 50 μg/mL) was added to each well and 24 hours allowed for cellular uptake. Samples were then divided into two groups: one treated with photothermal ablation (7.9 W/cm2) for 5 minutes, the other not treated. Photothermal ablation was performed using laser system (BWF5; B&W Tek, Inc, Newark, DE, USA). Intraprocedural temperature changes were measured using a fiber optic temperature probe (FTP-LN2; Photon Control Inc, Burnaby, BC, Canada). After 24 hours, the remaining number of viable cells was counted using trypan blue staining; cell proliferation percentage was calculated based on the total number of viable cells after treatment compared with control. MRI of GoldMag uptake was performed using a 7.0T ClinScan system (Bruker BioSpin, Ettlingen, Germany).
Temperature curves demonstrated that with increased GoldMag uptake, laser irradiation produced higher temperature elevations in the corresponding samples; temperature elevations of 12.89°C, 35.16°C, and 79.51°C were achieved for 0, 25, and 50 μg/mL GoldMag. Without photothermal ablation, the cell proliferation percentage changed from 100% to 71.3% and 47.0% for cells treated with 25 and 50 μg/mL GoldMag. Photothermal ablation of PANC-1 cells demonstrated an effective treatment response, specifically a reduction to only 61%, 21.9%, and 2.3% cell proliferation for cells treated with 0, 25, and 50 μg/mL GoldMag. MRI was able to visualize GoldMag uptake within PANC-1 cells.
Our findings suggest that photothermal ablation may be effective in the treatment of pancreatic cancer. GoldMag nanoparticles could serve as photothermal sensitizers, and MRI is feasible to quantify delivery.
photothermal ablation therapy; hybrid nanoparticles; magnetic resonance imaging
In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nano-emulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and, most importantly, minimum toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/RNA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examined as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clinically successful formulations of currently available lipid-based nanoparticles.
lipid-based nanoparticles; drug delivery; solid lipid nanoparticles; liposomes; nanostructured lipid carriers; bolaamphiphiles; cancer therapy
Nanooncology, the application of nanobiotechnology to the management of cancer, is currently the most important chapter of nanomedicine. Nanobiotechnology has refined and extended the limits of molecular diagnosis of cancer, for example, through the use of gold nanoparticles and quantum dots. Nanobiotechnology has also improved the discovery of cancer biomarkers, one such example being the sensitive detection of multiple protein biomarkers by nanobiosensors. Magnetic nanoparticles can capture circulating tumor cells in the bloodstream followed by rapid photoacoustic detection. Nanoparticles enable targeted drug delivery in cancer that increases efficacy and decreases adverse effects through reducing the dosage of anticancer drugs administered. Nanoparticulate anticancer drugs can cross some of the biological barriers and achieve therapeutic concentrations in tumor and spare the surrounding normal tissues from toxic effects. Nanoparticle constructs facilitate the delivery of various forms of energy for noninvasive thermal destruction of surgically inaccessible malignant tumors. Nanoparticle-based optical imaging of tumors as well as contrast agents to enhance detection of tumors by magnetic resonance imaging can be combined with delivery of therapeutic agents for cancer. Monoclonal antibody nanoparticle complexes are under investigation for diagnosis as well as targeted delivery of cancer therapy. Nanoparticle-based chemotherapeutic agents are already on the market, and several are in clinical trials. Personalization of cancer therapies is based on a better understanding of the disease at the molecular level, which is facilitated by nanobiotechnology. Nanobiotechnology will facilitate the combination of diagnostics with therapeutics, which is an important feature of a personalized medicine approach to cancer.
Nano dense-silica (dSiO2) has many advantages such as adjustable core–shell structure, multiple drug delivery, and controllable release behavior. Improving the gastric tumor-specific targeting efficiency based on the development of various strategies is crucial for anti-cancer drug delivery systems.
Superparamagnetic iron oxide nanoparticles (SPION) were coated with dSiO2 as core–shell nanoparticles, and labeled with near infra-red fluorescence (NIRF) dye 800ZW (excitation wavelength: 778 nm/emission wavelength: 806 nm) and anti-CD146 monoclonal antibody YY146 for magnetic resonance (MR)/NIRF imaging study in xenograft gastric cancer model. The morphology and the size of pre- and postlabeling SPION@dSiO2 core–shell nanoparticles were characterized using transmission electron microscopy. Iron content in SPION@dSiO2 nanoparticles was measured by inductively coupled plasma optical emission spectrometry. Fluorescence microscopy and fluorescence-activated cell sorter studies were carried out to confirm the binding specificity of YY146 and 800ZW–SPION@dSiO2–YY146 on MKN45 cells. In vivo and in vitro NIRF imaging, control (nanoparticles only) and blocking studies, and histology were executed on MKN45 tumor-bearing nude mice to estimate the affinity of 800ZW–SPION@dSiO2–YY146 to target tumor CD146.
800ZW–SPION@dSiO2–YY146 nanoparticles were uniformly spherical in shape and dispersed evenly in a cell culture medium. The diameter of the nanoparticle was 20–30 nm with 15 nm SPION core and ~10 nm SiO2 shell, and the final concentration was 1.7 nmol/mL. Transverse relaxivity of SPION@dSiO2 dispersed in water was measured to be 110.57 mM−1·s−1. Fluorescence activated cell sorter analysis of the nanoparticles in MKN45 cells showed 14-fold binding of 800ZW–SPION@dSiO2–YY146 more than the control group 800ZW–SPION@dSiO2. Series of NIRF imaging post intravenous injection of 800ZW–SPION@dSiO2–YY146 demonstrated that the MKN45 xenograft tumor model could be clearly identified as early as a time point of 30 minutes postinjection. Quantitative analysis revealed that the tumor uptake peaked at 24 hours postinjection.
This is the first successful study of functional nanoparticles for MR/NIRF imaging of cell surface glycoprotein CD146 in gastric cancer model. Our results suggest that 800ZW–SPION@dSiO2–YY146 nanoparticles will be applicable in tumor for image-guided therapy/surgery.
SPION; nanotechnology; EMT; SPION@dSiO2; xenograft; gastric cancer
Nanomaterials that interact with light provide a unique opportunity for biophotonic nanomedicine. Multifunctional nanoparticles (NPs) that have strong and tunable surface plasmon resonance absorption in the near-infrared region combined with visibility with multiple imaging modalities (magnetic resonance imaging, nuclear imaging, and photoacoustic imaging) have great potential in image-guided therapies. These novel nanostructures, once introduced, are expected to home to solid tumors via the enhanced permeability and retention effect (a passive targeting mechanism) or via targeting ligands bound to their surfaces (an active targeting mechanism). The primary mode of action for photothermal conducting NPs is to convert photoenergy into heat, causing temperature in the treatment volume to be elevated above the thermal damage threshold, which results in irreversible cell killing. It is now recognized that this process, termed photothermal ablation therapy or PTA, although very effective, is unlikely to kill all tumor cells when used alone. In addition to PTA, photothermal conducting NPs can also efficiently trigger drug release and activate RNA interference. Such a multimodal approach, which permits simultaneous PTA therapy, chemotherapy, and therapeutic RNA interference, should provide an opportunity for complete eradication of residual disease.
In this Account, we provide an up-to-date review of the synthesis and characterization, functionalization, and in vitro and in vivo evaluation of NIR light-activatable multifunctional nanostructures used for imaging and therapy, with an emphasis on hollow gold nanospheres, magnetic core–shell gold nanoshells, and semiconductor copper monosulfide NPs. We discuss three types novel drug delivery systems in which hollow gold nanospheres are used to mediate controlled drug release.
Theranostics; hollow gold nanospheres; copper sulfide nanoparticles; near-infrared; drug delivery
As applications of nanoparticles in medical imaging and biomedicine rapidly expand, the interactions of nanoparticles with living cells have become an area of active interest. For example, intracellular trafficking of nanoparticles – an important part of cell-nanoparticle interaction, has been well studied using plasmonic nanoparticles and optical or optics-based techniques due to the change in optical properties of the nanoparticle aggregates. However, magnetic nanoparticles, despite their wide range of clinical applications, do not exhibit plasmonic-resonant properties and therefore their intracellular aggregation cannot be detected by optics-based imaging techniques. In this study, we investigated the feasibility of a novel imaging technique – pulsed magneto-motive ultrasound (pMMUS), to identify intracellular trafficking of endocytosed magnetic nanoparticles. In pulsed magneto-motive ultrasound imaging a focused, high intensity, pulsed magnetic field is used to excite the cells labeled with magnetic nanoparticles, and ultrasound imaging is then used to monitor the mechanical response of the tissue. We demonstrated previously that clusters of magnetic nanoparticles amplify the pMMUS signal in comparison to signal from individual nanoparticles. Here we further demonstrate that pMMUS imaging can identify interaction between magnetic nanoparticles and living cells, i.e. intracellular aggregation of nanoparticles within the cells. The results of our study suggest that pMMUS imaging can not only detect the presence of magnetic nanoparticles but also provides information about their intracellular trafficking non-invasively and in real-time.
Pulsed magneto-motive ultrasound imaging; superparamagnetic iron-oxide nanoparticles; macrophage; endocytosis; intracellular trafficking
Near infrared absorbing plasmonic nanoparticles enhance photothermal therapy of tumors. In this procedure, systemically delivered gold nanoparticles preferentially accumulate at the tumor site and when irradiated using laser light, produce localized heat sufficient to damage tumor cells. Gold nanoshells and nanorods have been widely studied for this purpose, and while both exhibit strong NIR absorption, their overall absorption and scattering properties differ widely due to their geometry. In this paper, we compared the photothermal response of both nanoparticle types including the heat generation and photothermal efficiency.
Tissue simulating phantoms, with varying concentrations of gold nanoparticles, were irradiated with a near-infrared diode laser while concurrently monitoring the surface temperature with an infrared camera. We calculated nanoshell and nanorod optical properties using the Mie solution and the discrete dipole approximation, respectively. In addition, we measured the heat generation of nanoshells and nanorods at the same optical density to determine the photothermal transduction efficiency for both nanoparticle types.
We found that the gold nanoshells produced more heat than gold nanorods at equivalent number densities (# of nanoparticles/mL), whereas the nanorods generated more heat than nanoshells at equivalent extinction values at the irradiance wavelength. To reach an equivalent heat generation, we found that it was necessary to have ~36x more nanorods than nanoshells. However, the gold nanorods were found to have two times the photothermal transduction efficiency than the gold nanoshells.
For the NPs tested, the nanoshells generated more heat, per nanoparticle, than nanorods, primarily due to their overall larger geometric cross section. Conversely, we found that the gold nanorods had a higher photothermal efficiency than the gold nanoshells. In conclusion, the ideal choice of plasmonic nanoparticle requires not only per particle efficiency, but also the in vivo particle targeting ability under study.
Cancer; Gold Nanorods; Gold Nanoshells; Infrared Imaging; Photothermal Therapy; Photothermal Efficiency
Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles with different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customized gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumors or preferential accumulation in tumors following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia.
Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanoparticles in the reticuloendothelial system when administered systemically, the inability to visualize or quantify the global concentration and spatial distribution of these particles within tumors, the lack of standardized thermal modeling and dosimetry algorithms, and the concerns regarding their biocompatibility. Nevertheless, novel particle compositions, geometries, activation strategies, targeting techniques, payload delivery strategies, and radiation dose enhancement concepts are unique attributes of this form of hyperthermia that warrant further exploration. Capitalizing on these opportunities and overcoming these challenges offers the possibility of seamless and logical translation of this nanoparticle-mediated hyperthermia paradigm from the bench to the bedside.
Nanoparticles; magnetic; optical; activatable; hyperthermia; prostate cancer
The propensity of nanoparticles to aggregate in aqueous media hinders their effective use in biomedical applications. Gold nanorods (GNRs) have been investigated as therapeutics, imaging agents, and diagnostics. We report that chemically generated gold nanorods rapidly aggregate in biologically relevant media. Depositing polyelectrolyte multilayers on gold nanorods enhanced the stability of these nanoparticles for at least up to four weeks. Dispersions of polyelectrolyte (PE)-gold nanorod assemblies (PE-GNRs) demonstrate a stable Arrhenius-like photothermal response, which was exploited for the hyperthermic ablation of prostate cancer cells in vitro. Sub-toxic concentrations of PE-GNR assemblies were also employed for delivering exogenous plasmid DNA to prostate cancer cells. PE-GNRs based on a cationic polyelectrolyte recently synthesized in our laboratory demonstrated higher transfection efficacy and lower cytotoxicity compared to those based on polyethyleneimine, a current standard for polymer-mediated gene delivery. Our results indicate that judicious engineering of biocompatible polyelectrolytes leads to multifunctional gold nanorod-based assemblies that combine high stability and low cytotoxicity with photothermal ablation, gene delivery, and optical imaging capabilities on a single platform.
gold nanorods; stability; photothermal; near infrared; polyelectrolytes; cationic polymers; non viral gene delivery; hyperthermia
We describe an innovative form of polymer micro-tubes with diverse functions including biodegradation, magnetic manipulation, and photothermal effect that employs and activates photothermal therapy to target cancer cells. The micro-tube comprised soybean protein isolate, poly-l-glutamic acid, magnetite nanoparticles, plus gold nanoparticles. Through electrostatic force, these components, with opposite charges, formed pairs of layers in the pores of the template, various bilayers of soybean protein isolate and poly-l-glutamic acid served as the biodegradable building wall to each micro-tube. The layers of magnetite nanoparticle functionalized micro-tubes enabled the micro-tube manipulate to target the cancer cells by using an external magnetic field. The photo-thermal effect of the layer of gold nanoparticles on the outer surface of the micro-tubes, when under irradiation and when brought about by the near infrared radiation, elevated each sample’s temperature. In addition, and when under the exposure of the near infrared radiation, the elevated temperature of the suspension of the micro-tubes, likewise with a concentration of 0.2 mg/mL, and similarly with a power of 2 W and as well maintained for 10 min, elevated the temperature of the suspension beyond 42 °C. Such temperatures induced apoptosis of target cancer cells through the effect of photothermal therapy. The findings assert that structured micro-tubes have a promising application as a photothermal agent. From this assertion, the implications are that this multifunctional agent will significantly improve the methodology for cancer diagnosis and therapy.
micro-tube; soybean protein isolate; magnetic manipulation; photothermal therapy
Surface functionalized nanoparticles have found their applications in several fields including biophotonics, nanobiomedicine, biosensing, drug delivery, and catalysis. Quite often, the nanoparticle surfaces must be post-coated with organic or inorganic layers during the synthesis before use. This work reports a generally one-pot synthesis method for the preparation of various inorganic-organic core-shell nanostructures (Au@polymer, Ag@polymer, Cu@polymer, Fe3O4@polymer, and TiO2@polymer), which led to new optical, magnetic, and catalytic applications. This green synthesis involved reacting inorganic precursors and poly(styrene-alt-maleic acid). The polystyrene blocks separated from the external aqueous environment acting as a hydrophobic depot for aromatic drugs and thus illustrated the integration of functional nanoobjects for drug delivery. Among these nanocomposites, the Au@polymer nanoparticles with good biocompatibility exhibited shell-dependent signal enhancement in the surface plasmon resonance shift, nonlinear fluorescence, and surface-enhanced Raman scattering properties. These unique optical properties were used for dual-modality imaging on the delivery of the aromatic photosensitizer for photodynamic therapy to HeLa cells.
Engineered multifunctional nanoparticles (NPs) have made a tremendous impact on the biomedical sciences, with advances in imaging, sensing and bioseparation. In particular, the combination of optical and magnetic responses through a single particle system allows us to serve as novel multimodal molecular imaging contrast agents in clinical settings. Despite of essential medical imaging modalities and of significant clinical application, only few nanocomposites have been developed with dual imaging contrast. A new method for preparing quantum dots (QDs) incorporated magnetic nanoparticles (MNPs) based on layer-by-layer (LbL) self-assembly techniques have developed and used for cancer cells imaging.
Here, citrate - capped negatively charged Fe3O4 NPs were prepared and coated with positively - charged hexadecyltrimethyl ammonium bromide (CTAB). Then, thiol - capped negatively charged CdTe QDs were electrostatically bound with CTAB. Morphological, optical and magnetic properties of the fluorescent magnetic nanoparticles (FMNPs) were characterized. Prepared FMNPs were additionally conjugated with hCC49 antibodies fragment antigen binding (Fab) having binding affinity to sialylated sugar chain of TAG-72 region of LS174T cancer cells, which was prepared silkworm expression system, and then were used for imaging colon carcinoma cells.
The prepared nanocomposites were magnetically responsive and fluorescent, simultaneously that are useful for efficient cellular imaging, optical sensing and magnetic separation. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the particle size is around 50 nm in diameter with inner magnetic core and outer CdTe QDs core-shell structure. Cytotoxicity test of prepared FMNPs indicates high viability in Vero cells. NPs conjugated with anti cancer antibodies were successfully labeled on colon carcinoma cells (LS174) in vitro and showed significant specificity to target cells.
The present report demonstrates a simple synthesis of CdTe QDs-Fe3O4 NPs. The surface of the prepared FMNPs was enabled simple conjugation to monoclonal antibodies by electrostatic interaction. This property further extended their in vitro applications as cellular imaging contrast agents. Such labeling of cells with new fluorescent-magneto nanoprobes for living detection is of interest to various biomedical applications and has demonstrated the potential for future medical use.
Core-shell structure; Magnetic nanoparticles; Quantum dots; Fluorescent nanoparticles; Cell imaging
During recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the “stealth” features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticle-based delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy.
small interfering RNA; nanoparticles; cancer therapy; delivery strategies; biological barriers; clinical trials
Photosensitizers (PSs) have shown great potentials as molecular contrast agents in photodynamic diagnosis (PDD) of cancer. While the diagnostic values of PSs have been proven previously, little efforts have been put into developing optical imaging and diagnostic algorithms. In this article, we review the recent development of optical probes that have been used in conjunction with a potent PS, hypericin (HY). Various fluorescence techniques such as laser confocal microscopy, fluorescence urine cytology, endoscopy and endomicroscopy are covered. We will also discuss about image processing and classification approaches employed for accurate PDD. We anticipate that continual efforts in these developments could lead to an objective PDD and complete surgical clearance of tumors. Recent advancements in nanotechnology have also opened new horizons for PSs. The use of biocompatible gold nanoparticles as carrier for enhanced targeted delivery of HY has been attained. In addition, plasmonic properties of nanoparticles were harnessed to induce localized hyperthermia and to manage the release of PS molecules, enabling a better therapeutic outcome of a combined photodynamic and photothermal therapy. Finally, we discuss how nanoparticles can be used as contrast agents for other optical techniques such as optical coherence tomography and surface-enhanced Raman scattering imaging.
Hypericin; Photodynamic diagnosis; Fluorescence; Endoscopy; Urine cytology; Endomicroscopy; Gold nanoparticle; Photothermal therapy
Advances in nanostructure materials are leading to novel strategies for drug delivery and targeting, contrast media for magnetic resonance imaging (MRI), agents for hyperthermia and nanocarriers. Superparamagnetic iron oxide nanoparticles (SPIONs) are useful for all of these applications, and in drug-release systems, SPIONs allow for the localization, direction and concentration of drugs, providing a broad range of therapeutic applications. In this work, we developed and characterized polymeric nanoparticles based on poly (3-hydroxybutyric acid-co-hydroxyvaleric acid) (PHBV) functionalized with SPIONs and/or the antibiotic ceftiofur. These nanoparticles can be used in multiple biomedical applications, and the hybrid SPION–ceftiofur nanoparticles (PHBV/SPION/CEF) can serve as a multifunctional platform for the diagnosis and treatment of cancer and its associated bacterial infections.
Morphological examination using transmission electron microscopy (TEM) showed nanoparticles with a spherical shape and a core-shell structure. The particle size was evaluated using dynamic light scattering (DLS), which revealed a diameter of 243.0 ± 17 nm. The efficiency of encapsulation (45.5 ± 0.6% w/v) of these polymeric nanoparticles was high, and their components were evaluated using spectroscopy. UV–VIS, FTIR and DSC showed that all of the nanoparticles contained the desired components, and these compounds interacted to form a nanocomposite. Using the agar diffusion method and live/dead bacterial viability assays, we demonstrated that these nanoparticles have antimicrobial properties against Escherichia coli, and they retain their magnetic properties as measured using a vibrating sample magnetometer (VSM). Cytotoxicity was assessed in HepG2 cells using live/dead viability assays and MTS, and these assays showed low cytotoxicity with IC50 > 10 mg/mL nanoparticles.
Our results indicate that hybrid and multifunctional PHBV/SPION/CEF nanoparticles are suitable as a superparamagnetic drug delivery system that can guide, concentrate and site–specifically release drugs with antibacterial activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0077-5) contains supplementary material, which is available to authorized users.
PHBV; SPION; Ceftiofur; Polymeric nanoparticles; Drug delivery; Superparamagnetic nanoparticles
Gold nanoparticles are useful tools for biological applications due to their attractive physical and chemical properties. Their applications can be further expanded when they are functionalized with biological molecules. The biological molecules not only provide the interfaces for interactions between nanoparticles and biological environment, but also contribute their biological functions to the nanoparticles. Therefore, we used self-assembling protein nanoparticles (SAPNs) to encapsulate gold nanoparticles. The protein nanoparticles are formed upon self-assembly of a protein chain that is composed of a pentameric coiled-coil domain at the N-terminus and trimeric coiled-coil domain at the C-terminus. The self-assembling protein nanoparticles form a central cavity of about 10 nm in size, which is ideal for the encapsulation of gold nanoparticles with similar sizes.
We have used SAPNs to encapsulate several commercially available gold nanoparticles. The hydrodynamic size and the surface coating of gold nanoparticles are two important factors influencing successful encapsulation by the SAPNs. Gold nanoparticles with a hydrodynamic size of less than 15 nm can successfully be encapsulated. Gold nanoparticles with citrate coating appear to have stronger interactions with the proteins, which can interfere with the formation of regular protein nanoparticles. Upon encapsulation gold nanoparticles with polymer coating interfere less strongly with the ability of the SAPNs to assemble into nanoparticles. Although the central cavity of the SAPNs carries an overall charge, the electrostatic interaction appears to be less critical for the efficient encapsulation of gold nanoparticles into the protein nanoparticles.
The SAPNs can be used to encapsulate gold nanoparticles. The SAPNs can be further functionalized by engineering functional peptides or proteins to either their N- or C-termini. Therefore encapsulation of gold nanoparticles into SAPNs can provide a useful platform to generate a multifunctional biodevices.
Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables no-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and biological system, and a therapeutic payload that performs designated function in vivo. Often, a targeting ligand is also included in the design that recognizes the receptors over-expressed on cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the proper design of the iron oxide core to ensure MRI detectability and more critically, the coating to render the ability to bypass these barriers.
Strategies to bypass the physiological barriers such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells, and employing materials that promote desired intracellular trafficking and enable controlled drug release.
The payload can be genes, proteins, chemotherapy drugs, or a combination of them. Each therapeutic requires a specific coating design to maximize the loading and achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body’s defense system and provide examples of how these design parameters have been implemented to produce therapeutic SPIONs for specific therapeutic applications.
Although there are still challenges to be addressed, SPIONs show great promise in successful diagnosis and treatment of the most devastating cancers. Once critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as a truly multi-functional theranostic agent that not only performs a therapeutic function, but provides instant treatment feedback for the physician to adjust the treatment plan.
Polymeric nanoparticles are promising delivery platforms for various biomedical applications. One of the main challenges toward the development of therapeutic nanoparticles is the premature disassembly and release of the encapsulated drug. Among the different strategies to enhance the kinetic stability of polymeric nanoparticles, shell- and core-crosslinking have been shown to provide robust character, while creating a suitable environment for encapsulation of a wide range of therapeutics, including hydrophilic, hydrophobic, metallic, and small and large biomolecules, with gating of their release as well. The versatility of shell- and core-crosslinked nanoparticles is driven from the ease by which the structures of the shell- and core-forming polymers and crosslinkers can be modified. In addition, postmodification with cell-recognition moieties, grafting of antibiofouling polymers, or chemical degradation of the core to yield nanocages allow the use of these robust nanostructures as “smart” nanocarriers. The building principles of these multifunctional nanoparticles borrow analogy from the synthesis, supramolecular assembly, stabilization, and dynamic activity of the naturally driven biological nanoparticles such as proteins, lipoproteins, and viruses. In this review, the chemistry involved during the buildup from small molecules to polymers to covalently stabilized nanoscopic objects is detailed, with contrast of the strategies of the supramolecular assembly of polymer building blocks followed by intramicellar stabilization into shell-, core-, or core–shell-crosslinked knedel-like nanoparticles versus polymerization of polymers into nanoscopic molecular brushes followed by further intramolecular covalent stabilization events. The rational design of shell-crosslinked knedel-like nanoparticles is then elaborated for therapeutic packaging and delivery, with emphasis on the polymer chemistry aspects to accomplish the synthesis of such nanoparticulate systems.
biomimetic; biomimetic nanoparticles; block copolymers; nanocages; nanoparticles; polymer brushes; shell-crosslinked knedel-like nanoparticles