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 Amphotericin B–intercalated liposomes Nanotechnology in drug delivery is a rapidly expanding field. Nanosized liposomal preparations are already in use for efficient drug delivery with better therapeutic indices. Existing methods of liposome preparation are limited by problems of scale-up, difficulty in controlling size, and intercalation efficiency. Here researchers prepare amphotericin B–intercalated liposomes by a novel process where amphotericin B and purified phosphatidyl choline are solubilized in suitable solvent and precipitated in supercritical fluid carbon dioxide (known as a gas antisolvent technique), to obtain microsized particles that are subsequently introduced into a buffer solution. The morphology of liposomes was characterized through a phase-contrast microscope, and the particle size distribution studied by laser technique showed nanosize with a narrow range of size distribution (between 0.5 and 15 µm) and a higher intercalation efficiency. In vitro studies conducted using Aspergillus fumigatus (MTCC 870) strain proved to be efficient in the retardation of the growth of the organism. [37] Diclofenac-loaded biopolymeric nanosuspensions Polymeric nanoparticle suspensions (NS) were prepared from poly(lactide-co- glycolide) and poly(lactide-co-glycolide-leucine) {poly[Lac (Glc- Leu)]} biodegradable polymers and loaded with diclofenac sodium (DS), with the aim of improving the ocular availability of the drug. NS were prepared by emulsion and solvent evaporation technique and characterized on the basis of physicochemical properties, stability, and drug release features. The nanoparticle system showed an interesting size distribution suitable for ophthalmic application. Stability tests (as long as 6 months' storage at 5°C or at 25°C/60% relative humidity) or freeze-drying were carried out to optimize a suitable pharmaceutical preparation. In vitro release tests showed a extended-release profile of DS from the nanoparticles. To verify the absence of irritation toward the ocular structures, blank NS were applied to rabbit eye and a modified Draize test performed. Polymer nanoparticles seemed to be devoid of any irritant effect on cornea, iris, and conjunctiva for as long as 24 hours after application, thus apparently a suitable inert carrier for ophthalmic drug delivery. [38] Paclitaxel nanoparticles Karmali et al have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA and LyP-1 (CGNKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands expressing its receptor, p32. Self-assembled mixed micelles carrying the homing peptide and the label on different subunits accumulated in the same areas of tumors as LyP-1-abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. Untargeted, FAM-abraxane was detected in the form of a faint meshwork in tumor interstitium. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared with untargeted abraxane. These results show that nanoparticles can be effectively targeted into extravascular tumor tissue and that targeting can enhance the activity of a therapeutic nanoparticle. [39] Nano–atropine sulfate dry powder inhaler The work of Raisuddin Ali et al was to develop, characterize, and carry out a clinical trial with nano–atropine sulfate (nano-AS) dry powder inhaler (DPI), because this route may offer several advantages over the conventional intramuscular route as an emergency treatment, including ease of administration and more rapid bioavailability. Different batches of nanoparticles of AS were produced using variants of nanoprecipitation method. The influence of the process parameters, such as the types and quantity of solvent and nonsolvent, the stirring speed, the solventto-nonsolvent volume ratio, and the drug concentration, was investigated. The methodology resulted in optimally sized particles. Bulk properties of the particles made by the chosen methodology 41
Cheng TF et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):27-49 were evaluated. A clinical trial was conducted in six healthy individuals using a single DPI capsule containing 6 mg nano-AS DPI in lactose. Early blood bioavailability and atropinization pattern confirmed its value as a potential replacement to parenteral atropine in field conditions. The formulation seems to have the advantage of early therapeutic drug concentration in blood due to absorption through the lungs as well as sustained action due to absorption from the gut of the remaining portion of the drug. [40] Drug delivery of siRNA therapeutics A review by Daniela Reischl and Andreas Zimmer focuses on different pathways for siRNA delivery and summarizes recent progress made in the use of vector-based siRNA technology. Gene therapy is a promising tool for the treatment of human diseases that cannot be cured by rational therapies. The major limitation for the use of small interfering RNA (siRNA), both in vitro and in vivo, is the inability of naked siRNA to passively diffuse through cellular membranes due to the strong anionic charge of the phosphate backbone and consequent electrostatic repulsion from the anionic cell membrane surface. Therefore, the primary success of siRNA applications depends on suitable vectors to deliver therapeutic genes. Cellular entrance is further limited by the size of the applied siRNA molecule. Multiple delivery pathways, both viral and nonviral, have been developed to bypass these problems and have been successfully used to gain access to the intracellular environment in vitro and in vivo, and to induce RNA interference (RNAi). [41] Translational implications for diagnosis and therapy: Esophageal adenocarcinoma arises in the backdrop of Barrett metaplasia-dysplasia sequence, with the vast majority of patients presenting with late-stage malignancy. Mesothelin, a glycophosphatidylinositol-anchored protein, is aberrantly overexpressed on the surface of many solid cancers. Mesothelin expression was assessed in esophageal tissue microarrays encompassing the entire histological spectrum of Barrett-associated dysplasia and adenocarcinoma. Mesothelin expression was observed in 24/84 (29%) of invasive adenocarcinomas and in 5/34 (15%) lymph node metastases. In contrast, normal squamous and cardiac mucosa, as well as noninvasive Barrett lesions, failed to label with mesothelin. Mesothelin was expressed in the esophageal adenocarcinoma cell line JH-EsoAd1 but not in primary human esophageal epithelial cells. Anti-mesothelin antibody–conjugated CdSe/CDS/ ZnS quantum rods were synthesized, and confocal bioimaging confirmed robust binding to JH-EsoAd1 cells. Anti-mesothelin antibody– conjugated nanoparticles can be useful for the diagnosis and therapy of mesothelin-overexpressing esophageal adenocarcinomas. [42] Research and development of nanomedicines in the future Nanotechnology will alter our relationship with molecules and matter profoundly. Research on productive nanosystems will eventually develop programmable, molecular-scale systems that make other useful nano-structured materials and devices. These systems will enable a new manufacturing base that can produce both small and large objects precisely and inexpensively. Nano-risk research is conducted by agencies that oversee health and environmental regulations. Nanotechnology, dealing with functional structures and materials smaller than 100nm, is emerging as a truly interdisciplinary research area spanning several traditional scientific disciplines. In keeping with the growing trend, there is a strong need for a platform to share original research related to applications of nanotechnology in biomedical fields. At the hearing, leaders of the Nanotechnology Environmental and Health Implications working group, an interagency panel that coordinates federal funding on health and environmental risks of nanotechnology, released a long-overdue report outlining research needed to buttress regulation of products in the field. There is far less agreement on how that money should be spent and coordinated. Research on Nanotech environmental health and safety in government agencies, academic institutions, and industry is being performed in an ad hoc fashion according to individual priorities. Yet the vast majority of nanotoxicology studies focus on those materials, while ignoring broad classes of other materials 42
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