Nanoparticles and Microparticles

NANOPARTICLES History Richard Feynman, the Nobel-prize winning theoretical physicist, is often credited with conceptualizing the future field of nanotechnology in his lecture at the American Physical Society meeting at the California Institute of Technology in 1959: “There's plenty of room at the bottom.” According to Tourney,1 however, Feynman's actual role in catalyzing the nanotechnology field was more accurately actually applied retrospectively. The field came closer to reality with the invention of the scanning tunneling microscope in 1981. Nanotechnology may have been used first by Taniguchi in 1974 and recoined by Drexler in 1981.2 Early commercial applications were nanoparticle titanium dioxide and zinc oxide for sunscreens; silver nanoparticles in food packaging, clothes, and disinfectants; and carbon nanotubes used in stain-resistant cloth. A search of Medline using the term nanomedicine or nanotechnology detects the first publications in 1978, the subject of which was nanoparticle drug delivery systems. There has been exponential growth in the number of publications since then (Figure 1). A search of PubMed from 1970 to January 2015 with the word nanomedicine or nanoparticles showed no publications until 1978, increasing to 60084 from 2011 to 2015.FIGURE 1: A PubMed search from 1970 to January 2015 using the words nanomedicine and nanoparticles showed no publications until 1978, increasing to 60084 from 2011 to 2015.As of January 2012, there were 67 commercial nanodevices and 33 nanomedicine products (drugs and imaging agents) approved, mostly by the US Food and Drug Administration, and predominantly for treatment of different cancers.3,4 There were 1575 clinical trials of nanomedicines on http://www.clinicaltrials.gov as of December 2014, with 1381 focused on cancer. Definition and Characteristics One definition of nanotechnology encompasses designing and making materials, machines, and things that are between 1 and 100 nm in size.5 This is around the size of viruses and DNA. DNA is 1 to 3 nm in diameter, and a human chromosome is up to 85 nm long. Ion channel pores are usually around an Angstrom (0.1 nm) in diameter; some may be up to 3 nm. Strictly speaking, chemotherapeutic monoclonal antibodies like bevacizumab are within the nanotechnology size (10-15 nm), as are other proteins (2-10 nm). One way to distinguish nanotechnology from these native molecules is to require by definition a second step in the engineering of the molecule (attaching to another nanomaterial, encasing it within, etc) to be defined as nanotechnology. Nanomaterials may be metals (metallic), organic molecules (organic), or a combination of the two (semiconducting). Potential advantages of nanoparticles or nanostructures are the increase in the ratio of surface area to volume and unique physical and chemical characteristics compared with individual drug molecules or larger structures like microparticles (Table). The characteristics of nanoparticles can be engineered to produce more favorable drug pharmacokinetics (absorption, distribution, metabolism, and excretion, or what the body does to the drug), better pharmacodynamics (effects on enzymes, cell surface receptors, channels, plasma, or other proteins; disruption of cells and such; or what the drug does to the body), and thus a better therapeutic index. Similarly and related to distribution, they can accumulate in tissues such as tumors by passive or active targeting, which is useful for imaging and for drug delivery (Table).TABLE: Characteristics, Advantages and Disadvantages of NanoparticlesA high ratio of surface area to volume means that if nanoparticles are coated with a molecule, that molecule, whether it is an antibody, chemotherapy drug, or contrast agent, will be carried by the particle at a high concentration. A hollow nanoparticle such as a liposome can be loaded with hundreds of drug molecules. Thus, nanoparticles can carry high concentrations of drugs. Second, some nanomaterials preferentially permeate tumor vasculature (passive targeting), or they can be targeted to tumors or specific tissues by coating the particle with a molecule or antibody specific to the target (active targeting). Passive targeting is mediated in part by the enhanced permeation and retention (EPR) effect whereby drugs and drug-containing nanoparticles accumulate in tumors or cross the incompetent blood-brain barrier (BBB) that is found in the central nervous system after various injuries and in some intracranial neoplasms.6 The EPR effect is a consequence of there being pores up to several hundred nanometers in diameter in the endothelium of tumor blood vessels (and some normal tissues) that do not exist in most normal endothelium. Thus, if the nanoparticles have an increased half-life in the circulation, which they can be designed to have, they will accumulate in tumors. Second, there is impaired lymphatic drainage from tumors, leading to accumulation of some drugs and nanoparticles in tumors. Drug permeation into tissues and tumors, however, involves a complex interaction of concentration and pressure gradients, as well as permeability of the endothelium, lymphatic drainage, and active efflux of the drugs by transporter proteins. Passive targeting systems rely on the EPR and on prolonging the drug half-life. Another physical property of nanoparticles or of materials with at least 1 dimension in the nanometer range is that they have unique electrical, magnetic, and optical properties.5 For example, iron oxide nanoparticles are used for magnetic resonance imaging. They have enhanced contrast because electrons spin in the same direction in the iron atoms in these particles, whereas in larger particles of iron oxide, the spins are not aligned, so the magnetic field and hence the contrast are reduced. Another example is cadmium selenide semiconductor nanoparticles (quantum dots) that can be synthesized to be <10 nm in diameter. Quantum dots of different diameters emit fluorescence at different wavelengths and have stronger fluorescence than traditional fluorescence dyes, which renders them useful for imaging. Current Applications Some examples approved by the US Food and Drug Administration include the use of nanostructures and nanotechnology for the diagnosis of various conditions because they can increase the sensitivity of the test and simplify the test.7 An example is the urine pregnancy test that detects human chorionic gonadotropin using a lateral flow in vitro diagnostic assay. Several other such biomarker assays are available, although the sensitivity is not necessarily higher than that of traditional assays, although they are faster and simpler to use. Imaging Approved products for imaging use superparamagnetic iron oxide crystals coated with dextran or carboxydextran (SPIONs) that are about 60 to 180 nm in diameter and are administered orally.8 They are selectively taken up in liver cells and are approved for liver imaging to detect liver metastases and for administration of iron to treat anemia in patients with chronic renal failure. Various other formulations also increased detection of metastatic disease. These particles also may be taken up by macrophages, which has led to interest in using them to image atherosclerotic plaques to detect unstable or vulnerable plaques. Hasan and coworkers9 administered a SPION imaging agent, ferumoxytol, to 30 patients with unruptured cerebral aneurysms. Ferumoxytol is taken up by macrophages and has been suggested to be useful for imaging macrophage-related inflammation. Among 7 of 30 patients (23%) who had marked early uptake of ferumoxytol in the aneurysm wall, all 3 who did not undergo aneurysm repair experienced aneurysm rupture within 6 months, suggesting that this imaging method, as well as the macrophage activity in unruptured aneurysm walls, indicates the aneurysm is unstable and prone to rupture. Furthermore, experimental studies show SPIONs can be targeted to specific tissues using magnetic fields and that they can be engineered to release a drug or other potential therapeutic agent in response to a magnetic field, which opens up another potential method for active targeting of therapeutic agents.10 Although the human applications are somewhat limited at present, nanotechnology has many experimental imaging applications. Mathieu and colleagues11 injected quantum dots into the cisterna magna and used in vivo hyperspectral imaging to demonstrate rapid clearance of the dots by undetermined but obviously novel pathways into the cervical lymph nodes (Figure 2).FIGURE 2: Quantum dots injected into the cisterna magna of a mouse and imaged in vivo with hyperspectral fluorescence imaging.11 Photographs are ventral views of the head and neck 20 minutes (A), 40 minutes (B), 1 hour (C), 2 hours (D), and 6 hours (E) after the injection. There is red quantum dot fluorescence in the submandibular area in the neck appearing as early as 20 minutes after injection. Green indicates skin/fur; blue, food autofluorescence. The spectral emission profile (gray dotted line, F) of the region indicated by the arrow in E shows the signal matches the quantum dot profile (red) and is different from autofluorescent green skin/fur and blue food (scale bar = 10 mm). Reproduced from Mathieu et al11 with permission from the publisher. Copyright © 2013 BioMed Central Ltd.Cancer The size, shape, and composition of nanoparticles affect the absorption, distribution, metabolism, and excretion of the particles. Wei et al3 noted that receptor-mediated cell uptake was optimal with 40- to 50-nm particles, whereas the EPR effect was best with 20-nm gold nanoparticles coated with polyethylene glycol (PEG). The optimal size of nanoparticles for delivery into tumors in some studies was 10 to 12 nm. On the other hand, excretion of the particles also depends in part on size and shape, with spheres <10 nm tending to be rapidly cleared by the kidneys. Clearance of larger particles tends to be by the reticuloendothelial system and liver, with differences in route of clearance determined by as little as 2 nm in diameter.3 The importance of such small differences highlights the potential difficulties in commercial manufacturing of nanoparticles for human use. Nanoparticles >10 nm that are taken up by macrophages and the reticuloendothelial system can accumulate in the liver, spleen, lungs, and kidneys. Smaller nanoparticles that are opsonized or that agglomerate also can be subject to clearance by this route. Metallic nanoparticles such as gold can remain in these tissues for months and potentially accumulate there. Nanoparticle coatings may prolong the half-life of drugs and favorably (or unfavorably) alter their pharmacokinetic and pharmacodynamic profile.12 Coatings may not be directed at specific targets (so-called passive targeting) or can be antibodies, aptamers (short oligonucleotide or peptide fragments that are designed to bind to specific target molecules), peptides, proteins, oligonucleotides, or other molecules (folic acid, carbohydrates) that are designed to lead to active targeting. Coating with PEG tends to reduce clearance from the circulation and probably decreases immunological effects (Nanoparticles can activate immune responses or, in the case of fullerenes, have immunosuppressant effects).3,13 Coating of liposomes (spherical lipid bilayers that can be filled with drugs like chemotherapy drugs) with PEG was the key to prolonging their circulation time, which permitted accumulation in tumors by the EPR effect. Cationic nanoparticles have a positive surface charge or zeta potential and tend to be more toxic; anionic ones tend to be less so, possibly because they are less prone to cause protein aggregation and membrane permeation. Clearance of nanoparticles and smaller microparticles can be by opsonization (adsorption of plasma proteins onto the particle surface, which leads to phagocytosis by macrophages and the reticuloendothelial system) and by nonopsonization pathways. Nanoparticles and some microparticles also may be removed from the circulation by being taken up by the scavenging receptor macrophage receptor with collagenous structure on inflammatory monocytes. Thus, nanoparticle formulations of drugs may lead to less toxicity, higher tumor exposure, and more optimal pharmacokinetics, although this has not always been reproduced in vivo. Most passive targeting relies on coatings nanoparticles with chemicals such as PEG. Passive targeting relies in part on the EPR effect. Many nanoparticle drugs being developed rely on this, including many different chemotherapy drugs complexed in liposomes or as polymer drug conjugates using polymers like PEG, N-(2-hydroxypropyl) methacrylamide, and human albumin, among others. One of the first examples was 130-nm nanoparticles composed of albumin and paclitaxel that increase tumor delivery by the EPR effect plus the additional mechanism that albumin may accumulate in tumors; they are used for metastatic breast and non–small-cell lung cancer in which increased efficacy has been demonstrated.14 Combined passive and stabilization strategies can be used; for example, there is a formulation of 20- to 50-nm micelles composed of PEG and poly-D,L-lactide polymers that are filled with paclitaxel. This formulation allows a higher dose of paclitaxel to be administered to patients because of reduced toxicity, but this has so far not been associated with increased survival from a variety of cancers.14 An early nanoparticle formulation was doxorubicin liposomes, which have reduced toxicity compared with native doxorubicin, although Stirland and colleagues14 questioned whether there was any evidence for enhanced efficacy. Nanoparticle chemotherapy delivery systems are approved for breast cancer and acute lymphocytic leukemia. Active targeting involves coating nanoparticles with antibodies or ligands to cell surface receptors that in theory would increase delivery of the particles to the desired cells, a strategy that has often been effective in vitro.12 On the other hand, in vivo, targeted nanoparticles have to cross the endothelial cell layer, including its surface glycocalyx and the basement membrane, and then diffuse to the cells that are targeted, with the diffusion affected by tissue pressure gradients.3 The strategy has been difficult to translate to humans. One formulation of gemtuzumab ozogamicin (a humanized monoclonal antibody to CD33 linked to calicheamicin, an antibody that damages DNA), was initially approved for use but then withdrawn after postmarketing studies showed limited evidence for efficacy and increased toxicity.14 An example of a targeted formulation being studied clinically is 27-nm gold nanoparticles coated with recombinant human tumor necrosis factor-α and PEG. Intravenous injection into humans with malignancies showed selective uptake of the nanoparticles in tumors.15 There was reduced exposure of the rest of the patient to tumor necrosis factor-α, permitting administration of up to 20 times as much tumor necrosis Although many studies have been and several products are clinical no targeted nanoparticle drugs are approved for use in humans. et a complex to nanoparticle for targeted delivery of They size, PEG coating and number of ligands was a membrane drug drug release ratio of to and A nanoparticle was synthesized with pharmacokinetics and efficacy experimental cancer in is being in clinical trials in and non–small-cell lung cancer. to target tumors with this active targeting have not Drug delivery to tumors is by all of the noted of lymphatic drainage, drug and by the The may be in tumors, although of active tumor may have a The other to for drug delivery to the is that the endothelial cells of the that can drugs and efflux such as breast and protein 2 that drugs of the The EPR effect has been suggested to the increased uptake of and other nanoparticles chemotherapeutic in of et experimental studies using nanoparticle drug formulations to drugs to the and that was limited so One way to the is to drugs into the or delivery of drugs and nanoparticles into the was by et in is potentially to many conditions but has been applied for tumors. include that the pressure in the or tissue at the of will affect diffusion and that the is in size and to be small nm). 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