Fast processes of nanoparticle blood clearance: Comprehensive study.

Blood circulation is the key parameter that determines the in vivo efficiency of nanoagents. Despite clinical success of the stealth liposomal agents with their inert and shielded surfaces, a great number of non-stealth nanomaterials is being developed due to their potential of enhanced functionality. By harnessing surface phenomena, such agents can offer advanced control over drug release through intricately designed nanopores, catalysis-propelled motion, computer-like analysis of several disease markers for precise target identification, etc. However, investigation of pharmacokinetic behavior of these agents becomes a great challenge due to ultra-short circulation (usually around several minutes) and impossibility to use the invasive blood-sampling techniques. Accordingly, the data on circulation of such agents has been scarce and irregular. Here, we demonstrate high-throughput capabilities of the developed magnetic particle quantification technique for nanoparticle circulation measurements and present a comprehensive investigation of factors that affect blood circulation of the non-stealth nanoparticles. Namely, we studied the following 9 factors: particle size, zeta-potential, coating, injection dose, repetitive administration, induction of anesthesia, mice strain, absence/presence of tumors, tumor size. Our fundamental findings demonstrate potential ways to extend the half-life of the agents in blood thereby giving them a better chance of achieving their goal in the organism. The study will be valuable for design of the next generation nanomaterials with advanced biomedical functionality.

Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes.

The rapid elimination of nanoparticles from the bloodstream by the mononuclear phagocyte system limits the activity of many nanoparticle formulations. Here, we show that inducing a slight and transient depletion of erythrocytes in mice (~5% decrease in haematocrit) by administrating a low dose (1.25 mg kg-1) of allogeneic anti-erythrocyte antibodies increases the circulation half-life of a range of short-circulating and long-circulating nanoparticle formulations by up to 32-fold. Treatment of the animals with anti-erythrocyte antibodies significantly improved the targeting of CD4+ cells in vivo with fluorescent anti-CD4-antibody-conjugated nanoparticles, the magnetically guided delivery of ferrofluid nanoparticles to subcutaneous tumour allografts and xenografts, and the treatment of subcutaneous tumour allografts with magnetically guided liposomes loaded with doxorubicin and magnetite or with clinically approved 'stealthy' doxorubicin liposomes. The transient and partial blocking of the mononuclear phagocyte system may enhance the performance of a wide variety of nanoparticle drugs.

Spindle-like MRI-active europium-doped iron oxide nanoparticles with shape-induced cytotoxicity from simple and facile ferrihydrite crystallization procedure.

Nanoparticles (NPs) that can provide additional functionality to the nanoagents derived from them, e.g., cytotoxicity or imaging abilities, are in high demand in modern nanotechnology. Here, we report new spindle-like iron oxide nanoparticles doped with Eu3+ that feature magnetic resonance imaging (MRI) contrasting properties together with shape-related cytotoxicity (unusual for such low 2.4% Eu content). The NPs were prepared by a novel procedure for doping of iron oxide nanoparticles based on the crystallization of amorphous ferrihydrite in the presence of hydrated europium(iii) oxide and were thoroughly characterized. Cytotoxicity of low Eu-doped spindle-like hematite nanoparticles was confirmed by MTT assay and further studied in detail by imaging flow cytometry, optical and electron microscopies. Additionally, enhancement of MRI contrast properties of NPs upon doping with europium was demonstrated. According to the MRI using mice as an animal model and direct inductively coupled plasma mass spectrometry (ICP-MS) 153Eu biodistribution measurements, these particles accumulate in the liver and spleen. Therefore, NPs present a novel example of a multimodal component combining magnetic imaging and therapeutic (cytotoxic) abilities for development of theranostic nanoagents.

Antibody-directed metal-organic framework nanoparticles for targeted drug delivery.

Nanosized metal-organic frameworks (nMOFs) have shown great promise as high-capacity carriers for a variety of applications. For biomedicine, numerous nMOFs have been proposed that can transport virtually any molecular drug, can finely tune their payload release profile, etc. However, perspectives of their applications for the targeted drug delivery remain relatively unclear. So far, only a few works have reported specific cell targeting by nMOFs exclusively through small ligands such as folic acid or RGD peptides. Here we show feasibility of targeted drug delivery to specific cancer cells in vitro with nMOFs functionalized with such universal tool as an antibody. We demonstrate ca. 120 nm magnetic core/MOFs shell nanoagents loaded with doxorubicin/daunorubicin and coupled with an antibody though a hydrophilic carbohydrate interface. We show that carboxymethyl-dextran coating of nMOFs allows extensive loading of the drug molecules (up to 15.7 mg/g), offers their sustained release in physiological media and preserves antibody specificity. Reliable performance of the agents is illustrated with trastuzumab-guided selective targeting and killing of HER2/neu-positive breast cancer cells in vitro. The approach expands the scope of nMOF applications and can serve as a platform for the development of potent theranostic nanoagents. STATEMENT OF SIGNIFICANCE: The unique combination of exceptional drug capacity and controlled release, biodegradability and low toxicity makes nanosized metal-organic frameworks (nMOFs) nearly ideal drug vehicles for various biomedical applications. Unfortunately, the prospective of nMOF applications for the targeted drug delivery is still unclear since only a few examples have been reported for nMOF cell targeting, exclusively for small ligands. In this work, we fill the important gap and demonstrate nanoagent that can specifically kill target cancer cells via drug delivery based on recognition of HER2/neu cell surface receptors by such universal and specific tool as antibodies. The proposed approach is universal and can be adapted for specific biomedical tasks using antibodies of any specificity and nMOFs of a various composition.

Smart materials on the way to theranostic nanorobots: Molecular machines and nanomotors, advanced biosensors, and intelligent vehicles for drug delivery.

BACKGROUND: Theranostics, a fusion of two key parts of modern medicine - diagnostics and therapy of the organism's disorders, promises to bring the efficacy of medical treatment to a fundamentally new level and to become the basis of personalized medicine. Extrapolating today's progress in the field of smart materials to the long-run prospect, we can imagine future intelligent agents capable of performing complex analysis of different physiological factors inside the living organism and implementing a built-in program thereby triggering a series of therapeutic actions. These agents, by analogy with their macroscopic counterparts, can be called nanorobots. It is quite obscure what these devices are going to look like but they will be more or less based on today's achievements in nanobiotechnology. SCOPE OF REVIEW: The present Review is an attempt to systematize highly diverse nanomaterials, which may potentially serve as modules for theranostic nanorobotics, e.g., nanomotors, sensing units, and payload carriers. MAJOR CONCLUSIONS: Biocomputing-based sensing, externally actuated or chemically "fueled" autonomous movement, swarm inter-agent communication behavior are just a few inspiring examples that nanobiotechnology can offer today for construction of truly intelligent drug delivery systems. GENERAL SIGNIFICANCE: The progress of smart nanomaterials toward fully autonomous drug delivery nanorobots is an exciting prospect for disease treatment. Synergistic combination of the available approaches and their further development may produce intelligent drugs of unmatched functionality.