Microparticles and nanoparticles for drug delivery

Particulate drug delivery systems have become important in experimental pharmaceutics and clinical medicine. The distinction is often made between micro- and nanoparticles, being particles with dimensions best described in micrometers and nanometers respectively. That size difference entails real differences at many levels, from formulation to in vivo usage. Here I will discuss those differences and provide examples of applications, for local and systemic drug delivery. I will outline a number of challenges of interest in particulate drug delivery.     

Cytotoxic activities of chitosan nanoparticles and copper-loaded nanoparticles

Chitosan nanoparticles and copper(II)-loaded chitosan nanoparticles were prepared based on the ionic gelation of chitosan with tripolyphosphate anions and copper ion sorption. In this study, the cytotoxic activities of the chitosan nanoparticles and copper(II)-loaded chitosan nanoparticles was investigated and a relationship between physiochemical properties and activity is suggested. The chitosan nanoparticles and copper(II)-loaded chitosan nanoparticles elicited dose-dependent inhibitory effects on the proliferation of tumor cell lines.     

Magnetic nanoparticles for gene and drug delivery

Investigations of magnetic micro- and nanoparticles for targeted drug delivery began over 30 years ago. Since that time, major progress has been made in particle design and synthesis techniques, however, very few clinical trials have taken place. Here we review advances in magnetic nanoparticle design, in vitro and animal experiments with magnetic nanoparticle-based drug and gene delivery, and clinical trials of drug targeting.     

Magnetic nanoparticles for multi-imaging and drug delivery

Various bio-medical applications of magnetic nanoparticles have been explored during the past few decades. As tools that hold great potential for advancing biological sciences, magnetic nanoparticles have been used as platform materials for enhanced magnetic resonance imaging (MRI) agents, biological separation and magnetic drug delivery systems, and magnetic hyperthermia treatment. Furthermore, approaches that integrate various imaging and bioactive moieties have been used in the design of multi-modality systems, which possess synergistically enhanced properties such as better imaging resolution and sensitivity, molecular recognition capabilities, stimulus responsive drug delivery with on-demand control, and spatio-temporally controlled cell signal activation. Below, recent studies that focus on the design and synthesis of multi-mode magnetic nanoparticles will be briefly reviewed and their potential applications in the imaging and therapy areas will be also discussed.     

Single plasmonic nanoparticles for biosensing

Along with remarkable progress of nanoplasmonics over the past 10 years, single plasmonic nanoparticle sensors have introduced a completely new dimension to the sensing scale, considering that nanoparticles are comparable in size to biomolecules such as nucleic acids or antibodies. Single particle sensing methods have recently shown the possibility of detecting the adsorption of single biomolecules, and have already provided information about conformational changes of single molecules. For practical application, arrays of such compact sensor units are expected to realize massive multiplexing and high throughput in diagnostics and drug discovery in the near future. In this review, recent achievements and perspectives of this emerging biosensing technique are discussed.     

Polymeric nanoparticles for optical sensing

Nanotechnology is a powerful tool for use in diagnostic applications. For these purposes a variety of functional nanoparticles containing fluorescent labels, gold and quantum dots at their cores have been produced, with the aim of enhanced sensitivity and multiplexing capabilities. This work will review progress in the application of polymeric nanoparticles in optical diagnostics, both for in vitro and in vivo detection, together with a discussion of their biodistribution and biocompatibility.     

New magnetic nanoparticles for biotechnology

Paramagnetic carriers, which are linked to antibodies enable highly specific biological cell separations. With the colloidal synthesis of superparamagnetic Co and FeCo nanocrystals with superior magnetic moments the question about their potential to replace magnetite as the magnetically responsive component of magnetic beads is addressed. Starting from a magnetic analysis of the corresponding magnetophoretic mobility of Co and FeCo based alloys their synthesis and resulting microstructural and magnetic properties as function of the underlying particle size distribution are discussed in detail. The stability of the oleic acid ligand of Co nanocrystals has been investigated. The oxidation kinetics were quantified using magnetic measurements. As a result, this ligand system provides sufficient protection against oxidation. Furthermore, the kinetics of the synthesis of Fe(50)Co(50) nanoparticles has been monitored employing Fourier transform infra red (FT-IR) spectroscopy and is modeled using a consecutive decomposition and growth model. This model predicts the experimentally realized FeCo nanoparticle composition as a function of the particle size fairly well. High-resolution transmission electron microscopy (HRTEM) was performed to uncover the resulting microstructure and composition on a nanometer scale.     

Intrinsic viscosity of bead models for macromolecules and nanoparticles

The calculation of the intrinsic viscosity by means of classical treatments of bead models, typically composed of a number of identical beads, presents some problems when applied to models where the beads are unequal and their number is not very large. A correction to this problem was proposed 10 years ago (García de la Torre and Carrasco in Eur Biophys J 27:549–557, 1998). This so-called volume correction, which consisted of adding a term proportional to the volume of the model, was proved to be rigorous in physico-mathemathical terms, and produced improved results in some circumstances, but not always. Recently, the volume correction is being reconsidered so that with some deduced or empirical modifications, it can allow for safer predictions of the intrinsic viscosity. This paper contributes a discussion and further improvements of that correction for the intrinsic viscosity.     

Peptidic nanoparticles: for cancer diagnosis and therapy

A challenging topic in cancer research is to create drug delivery system that can bring in a specific and noncytotoxic manner a therapeutic compound. Usually, tumor targeting requires very specific compounds. Currently, peptide analogues like somatostatin, neurotensin, or bombesin are used to target G-coupled receptors, which are overexpressed on tumor cells. However, many of those analogues are rapidly degraded in the plasma and are cytotoxic [1–2]. Due to the limited efficiency and high toxicity of conventional chemotherapy different strategies have been developed for non-cytotoxic cancer treatment and cancer localization [3–5]. The recent development in bio-nanotechnology offers new avenues for cancer therapy. A lot of studies have been devoted to nanoparticulate delivery systems (10–100nm) like lipid or polymer particles [6–8]. Due to the nanometer sized of such cargos, the transportation of therapeutic compounds in the blood stream is increased in terms of time circulation. But their surface functionalization to improve drug-targeting properties is usually complicated and rather uneffective. We have recently designed a novel type of functional nanoparticles with regular icosahedral symmetry, mimicking small, rigid viral capsids (Fig. 1 (A)) and a diameter of about 17 nm (Fig. 1 (C)) which self-assemble from single polypeptide chains (Fig. 1 (B)).     

Chitosan nanoparticles for oral drug and gene delivery

Chitosan is a widely available, mucoadhesive polymer that is able to increase cellular permeability and improve the bioavailability of orally administered protein drugs. It can also be readily formed into nanoparticles able to entrap drugs or condense plasmid DNA. Studies on the formulation and oral delivery of such chitosan nanoparticles have demonstrated their efficacy in enhancing drug uptake and promoting gene expression. This review summarizes some of these findings and highlights the potential of chitosan as a component of oral delivery systems.     

Photocontrolled nanoparticles for on-demand release of proteins

We describe here light-regulated swelling and degradation features of polymeric nanoparticles that are produced using an inverse microemulsion polymerization method. We demonstrate the phototriggered release characteristics of the nanoparticles by sequestering protein molecules and releasing them using light as a trigger. Furthermore, the intracellular translocation of the nanoparticles, along with its fluorescent protein payload, was achieved using a cell-penetrating peptide-based surface modification. We expect that the noncovalent encapsulation of proteins using nanoparticles and their photo triggered release using an external light would provide opportunities for achieving intracellular release of molecular therapeutics for on-demand requirements.     

Optimization of antibody-conjugated magnetic nanoparticles for target preconcentration and immunoassays

Biosensors based on antibody recognition have a wide range of monitoring applications that apply to clinical, environmental, homeland security, and food problems. In an effort to improve the limit of detection of the Naval Research Laboratory (NRL) Array Biosensor, magnetic nanoparticles (MNPs) were designed and tested using a fluorescence-based array biosensor. The MNPs were coated with the fluorescently labeled protein, AlexaFluor647–chicken IgG (Alexa647–chick IgG). Antibody-labeled MNPs (Alexa647–chick–MNPs) were used to preconcentrate the target via magnetic separation and as the tracer to demonstrate binding to slides modified with anti-chicken IgG as a capture agent. A full optimization study of the antibody-modified MNPs and their use in the biosensor was performed. This investigation looked at the Alexa647–chick–MNP composition, MNP surface modifications, target preconcentration conditions, and the effect that magnetic extraction has on the Alexa647–chick–MNP binding with the array surface. The results demonstrate the impact of magnetic extraction using the MNPs labeled with fluorescent proteins both for target preconcentration and for subsequent integration into immunoassays performed under flow conditions for enhanced signal generation.     

Caged protein nanoparticles for drug delivery

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Protein-polymer nanoparticles for nonviral gene delivery

Protein-polymer conjugates were investigated as nonviral gene delivery vectors. BSA-poly(dimethylamino) ethyl methacrylate (PDMA) nanoparticles (nBSA) were synthesized using in situ atom transfer radical polymerization (in situ ATRP) and BSA as a macroinitiator. The diameter and charge of nBSA was a function of the ATRP reaction time and ranged from 5 to 15 nm and +8.9 to +22.5, respectively. nBSA were able to condense plasmid DNA (pDNA) and form polyplexes with an average diameter of 50 nm. nBSA/pDNA polyplexes transfected cells with similar efficiencies or better as compared to linear and branched PEI. Interestingly, the nBSA particle diameter and charge did not affect pDNA complexation and transgene expression, indicating that the same gene delivery efficiency can be achieved with lower charge ratios. We believe that with the use of protein-polymer conjugates additional functionality could be introduced to polyplexes by using different protein cores and, thus, they pose an interesting alternative to the design of nonviral gene delivery vectors.     

Magnetic nanoparticles for targeted vascular delivery

Magnetic targeting has shown promise to improve the efficacy and safety of different classes of therapeutic agents by enabling their active guidance to the site of disease and minimizing dissemination to nontarget tissues. However, its translation into clinic has proven difficult because of inherent limitations of traditional approaches inapplicable for deep tissue targeting in human subjects and a need for developing well-characterized and fully biocompatible magnetic carrier formulations. A novel magnetic targeting scheme based on the magnetizing effect of deep-penetrating uniform fields is presented as an example of a strategy providing a potentially clinically viable solution for preventing injury-triggered reobstruction of stented blood vessels (in-stent restenosis). The design of optimized magnetic carrier formulations and experimental results showing the feasibility of uniform field-controlled targeting for site-specific vascular delivery of small-molecule pharmaceuticals, biotherapeutics, and cells are discussed in the context of antirestenotic therapy. The versatility of this approach applicable to different classes of therapeutic agents exerting their antirestenotic effects through distinct mechanisms prompts exploring the utility of uniform field-mediated magnetic stent targeting for combination therapies with enhanced efficiencies and improved safety profiles. Additional improvements in terms of site specificity and protracted carrier retention at the site of injury may be expected from the development and use of magnetic carriers exhibiting affinity for arterial wall-specific antigens.     

Fluorescent nanoparticles for multiplexed bacteria monitoring

Rapid, sensitive, and selective detection of pathogenic bacteria is extremely important for proper containment, diagnosis, and treatment of diseases like foodborne illness, sepsis, and bioterrorism. Most current bacterial detection methods are time-consuming and laborious and can detect only one bacterial pathogen at a time. We have developed a method for sensitive, multiplexed monitoring of bacterial pathogens within 30 min using multicolored FRET (fluorescence resonance energy transfer) silica NPs (nanoparticles). By varying the ratio of three tandem dyes coencapsulated into the NPs, we have synthesized NPs that emit unique colors upon excitation with a single wavelength. When these NPs were conjugated to monoclonal antibodies specific for the pathogenic bacteria species Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus, and then incubated with small concentrations of the bacteria, simultaneous and sensitive detection of the multiple bacterial targets was achieved.     

Oligonucleotide and polymer functionalized nanoparticles for amplification-free detection of DNA

Sensitive and quantitative nucleic acid testing from complex biological samples is now an important component of clinical diagnostics. Whereas nucleic acid amplification represents the gold standard, its utility in resource-limited and point-of-care settings can be problematic due to assay interferants, assay time, engineering constraints, and costs associated with both wetware and hardware. In contrast, amplification-free nucleic acid testing can circumvent these limitations by enabling direct target hybridization within complex sample matrices. In this work, we grew random copolymer brushes from the surface of silica-coated magnetic nanoparticles using azide-modified and hydroxyl oligo ethylene glycol methacrylate (OEGMA) monomers. The azide-functionalized polymer brush was first conjugated, via copper-catalyzed azide/alkyne cycloaddition (CuAAC), with herpes simplex virus (HSV)-specific oligonucleotides and then with alkyne-substituted polyethylene glycol to eliminate all residual azide groups. Our methodology enabled control over brush thickness and probe density and enabled multiple consecutive coupling reactions on the particle grafted brush. Brush- and probe-modified particles were then combined in a 20 min hybridization with fluorescent polystyrene nanoparticles modified with HSV-specific reporter probes. Following magnetic capture and washing, the particles were analyzed with an aggregate fluorescence measurement, which yielded a limit of detection of 6 pM in buffer and 60 pM in 50% fetal bovine serum. Adoption of brush- and probe-modified particles into a particle counting assay will result in the development of diagnostic assays with significant improvements in sensitivity.