Asian Journal of Pharmacodynamics and Pharmacokinetics

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Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49 Intraperitoneal injection of [Gd@C 82 (OH) 22 ] n nanoparticles decreased activities of enzymes associated with the metabolism of reactive oxygen species (ROS) in the tumor-bearing mice. Several physiologically relevant ROS were directly scavenged by nanoparticles, and lipid peroxidation was inhibited in this study. [Gd@C 82 (OH) 22 ] n nanoparticles significantly reduced the electron spin resonance (ESR) signal of the stable 2,2-diphenyl-1-picryhydrazyl radical measured by ESR spectroscopy. Like-wise, studies using ESR with spin-trapping demonstrated efficient scavenging of superoxide radical anion, hydroxyl radical, and singlet oxygen (1O2) by [Gd@C 82 (OH) 22 ] n nanoparticles. In vitro studies using liposomes prepared from bovine liver phosphatidylcholine revealed that nanoparticles also had a strong inhibitory effect on lipid peroxidation. Consistent with their ability to scavenge ROS and inhibit lipid peroxidation, we determined that [Gd@C 82 (OH) 22 ]n nanoparticles also protected cells subjected in vitro to oxidative stress. Studies using human lung adenocarcinoma cells or rat brain capillary endothelial cells demonstrated that [Gd@C 82 (OH) 22 ] n nanoparticles reduced H 2 O 2 - induced ROS formation and mitochondrial damage. [Gd@C 82 (OH) 22 ] n nanoparticles efficiently inhibited the growth of malignant tumors in vivo. In summary, the results obtained in this study reveal antitumor activities of [Gd@C 82 (OH) 22 ] n nanoparticles in vitro and in vivo. Because ROS are known to be implicated in the etiology of a wide range of human diseases, including cancer, the present findings demonstrate that the potent inhibition of [Gd@C 82 (OH) 22 ] n nanoparticles on tumor growth likely relates with typical capacity of scavenging reactive oxygen species. [13] Evaluation on pharmacology of nanomedicines Nanotechnology manifests itself in a wide range of materials that can be useful to medical application. Virtually all of these materials have been designed with chemically modifiable surfaces to attach a variety of legends that can turn these nanomaterials into biosensors, molecular-scale fluorescent tags, imaging agents, targeted molecular delivery vehicles, and other useful biological tools. The unprecedented freedom to design and modify nanomaterials to target cells, chaperone drugs, image biomolecular processes, sense and signal molecular responses to therapeutic agents, and guide surgical procedures is the fundamental capability offered by nanotechnology, which promises to impact drug development, medical diagnostics, and clinical applications profoundly (Fig 1). [14] Fig 1. Medical applications of nanotechnology. The size and tailorability of nanoparticles may lea to their widespread use in a variety of medical applications. [14] Engineered nanomaterials are at the leading edge of the rapidly developing nanosciences and are founding an important class of new materials with specific physicochemical properties different from bulk materials with the same compositions. The potential for nanomaterials is rapidly expanding with novel applications constantly being explored in different areas. The unique size-dependent properties of nanomaterials make them very attractive for pharmaceutical applications. Investigations of physical, chemical and biological properties of engineered nanomaterials have yielded valuable information. Cytotoxic effects of certain engineered nanomaterials towards malignant cells form the basis for one aspect of nanomedicine. It is inferred that size, three dimensional shape, hydrophobicity and electronic configurations make them an appealing subject in medicinal chemistry. Their unique structure coupled with immense scope for derivatization forms a base for exciting developments in therapeutics. This review article addresses the fate of absorption, distribution, metabolism and excretion (ADME) of engineered nanoparticles in vitro and in vivo. It updates the distinctive methodology used for studying the biopharmaceutics of nanoparticles. This review addresses the future potential and safety concerns and genotoxicity of nanoparticle formulations in 33
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49 general. It particularly emphasizes the effects of nanoparticles on metabolic enzymes as well as the parenteral or inhalation administration routes of nanoparticle formulations. This paper illustrates the potential of nanomedicine by discussing biopharmaceutics of fullerene derivatives and their suitability for diagnostic and therapeutic purposes. Future direction is discussed as well. [15] With the rapid development of quantum dot (QD) technology, water-soluble QDs have the prospect of being used as a biological probe for specific diagnoses, but their biological behaviors in vivo are little known. Our recent in vivo studies concentrated on the bio-kinetics of QDs coated by hydroxyl group modified silica networks (the QDs are 21.3±2.0 nm in diameter and have maximal emission at 570 nm). Male ICR mice were intravenously given the water-soluble QDs with a single dose of 5 nmol/mouse. Inductively coupled plasma-mass spectrometry was used to measure the (111)Cd content to indicate the concentration of QDs in plasma, organs, and excretion samples collected at predetermined time intervals. Meanwhile, the distribution and aggregation state of QDs in tissues were also investigated by pathological examination and differential centrifugation. The plasma half-life and clearance of QDs were 19.8±3.2 h and 57.3±9.2 ml·h -1·kg -1 , respectively. The liver and kidney were the main target organs for QDs. The QDs metabolized in three paths depending on their distinct aggregated states in vivo. A fraction of free QDs, maintaining their original form, could be filtered by glomerular capillaries and excreted via urine as small molecules within five days. Most QDs bound to protein and aggregated into larger particles that were metabolized in the liver and excreted via feces in vivo. After five days, 8.6% of the injected dose of aggregated QDs still remained in hepatic tissue and it was difficult for this fraction to clear. [16] There is growing interest in developing tissue-specific multifunctional drug delivery systems with the ability to diagnose or treat several diseases. One class of such agents, composite nanodevices (CNDs), is multifunctional nanomaterials with several potential medical uses, including cancer imaging and therapy. Nanosized metal-dendrimer CNDs consist of poly(amidoamine) dendrimers (in various sizes, surface substituents, and net charges) and inorganic nanoparticles, properties of both of which can be individually modified and optimized. In this study we examine effects of size and surface charge on the behavior of Au-dendrimer CNDs in mouse tumor models. Quantitative biodistribution and excretion analyses including 5-nm and 22-nm positive surface, 5-nm and 11-nm negative surface, and a 5-nm neutral surface CNDs were carried out in the B16 mouse melanoma tumor model system. Results seen with the 22-nm CND in the B16 melanoma model were corroborated in a prostate cancer mouse tumor model system. Quantitative in vivo studies confirm the importance of charge and show for the first time the importance of size in affecting CND biodistribution and excretion. Interestingly, CNDs of different size and/or surface charge had high levels of uptake (“selective targeting”) to certain organs without specific targeting moieties placed on their surfaces. Researchers conclude that size and charge greatly affect biodistribution of CNDs. These findings have significance for the design of all particle-based nanodevices for medical uses. The observed organ selectivity may make these nanodevices exciting for several targeted medical applications. [17] Study on responses of Ferric oxide nanoparticles: Ferric oxide (Fe 2 O 3 ) nanoparticles are of considerable interest for application in nanotechnology related fields. However, as iron being a highly redox-active transition metal, the safety of iron nanomaterials need to be further studied. In this study, the size, dose and time dependent of Fe 2 O 3 nanoparticle on pulmonary and coagulation system have been studied after intratracheal instillation. The Fe 2 O 3 nanoparticles with mean diameters of 22 and 280 nm, respectively, were intratracheally instilled to male Sprague Dawley rats at low (0.8 mg·kg -1 ) and high (20 mg/kg) doses. The toxic effects were monitored in the post-instilled 1, 7 and 30 days. Our results showed that the Fe 2 O 3 nanoparticle exposure could induce oxidative stress in lung. Alveolar macrophage (AM) over-loading of phagocytosed nanoparticle by high dose treatment had occurred, 34
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