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Nanoparticles effectively deliver therapeutic agent by penetrating into the rat skin in vivo. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. Indomethacin (IM) and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied in vivo. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied at 0.05 mA/cm(2), permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal systemic delivery of therapeutic agents., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Macrophages and their phagocytotic abilities play a dominant role for defense against infected organisms. However, Mycobacterium tuberculosis can survive in the phagosomes of macrophages. In this study, the effective delivery of a drug and the killing effect of tubercle bacilli within macrophages were investigated utilizing the phagocytotic uptake of rifampicin (RFP) that had been incorporated into poly(DL-lactic-co-glycolic) acid (PLGA) microspheres. The microspheres were composed of PLGA that had a monomer ratio (lactic acid/glycolic acid) of either 50/50 or 75/25. They had molecular weights from 5000 to 20,000, and diameters of 1.5, 3.5, 6.2 and 8.9 microm. The most significant factor for phagocytotic activity of macrophages was the diameter of the microspheres. By contrast, molecular weight and monomer ratio of PLGA did not influence phagocytosis. The amount of RFP delivered into cells was also investigated. RFP-PLGA microspheres composed of PLGA with a molecular weight of 20,000 and monomer ratio of 75/25 showed the highest amount of delivery (4 microg/1 x 10(6) cells). Fourteen days after infection, the survival rate of treated intracellular bacilli was 1% when compared with untreated cells. There was almost no killing effect of free RFP (4 or 15 microg/ml) on intracellular bacilli. In vivo efficacy of RFP-PLGA was also examined in rats infected with M. tuberculosis Kurono. Intratracheal administration of RFP-PLGA microspheres was shown to be superior to free RFP for killing of intracellular bacilli and preventing granuloma formation in some lobes. These results suggest that phagocytotic activity could be part of a new drug delivery system that selectively targeted macrophages.

Poly(lactide- co -glycolide) has been widely used and studied because of its biocompatibility and biodegradability. Many drug-loaded particles have been developed using this copolymer, however, information on its release behavior is lacking, especially for nanoparticles prepared using poly( l -lactide- co -glycolide). In this study, we used poly( dl -lactide- co -glycolide) (PLGA) and poly( l -lactide- co -glycolide) (PLLGA) with a 75/25 and 90/10 monomer composition of lactic acid/glycolic acid and molecular weights of 10,000. We determined the crystalline states, glass transition temperatures, and activation energies of the copolymers. Rifampicin-loaded PLGA7510, PLLGA7510, PLGA9010, or PLLGA9010 nanoparticles with 100-, 200- and 400-nm diameters were prepared, and in vitro release tests were carried out in phosphate-buffered saline at 37 °C or 25 °C for a week. The cumulative release ratio of rifampicin from nanoparticles using poly( l -lactide- co -glycolide) as a drug carrier was significantly lower than the release ratio from nanoparticles using poly( dl -lactide- co -glycolide), since the glass transition temperature of poly( l -lactide- co -glycolide) was 7 °C higher than that of poly( dl -lactide- co -glycolide) at the same monomer composition. In addition, we found that the glass transition temperatures of the copolymers exerted a considerable influence on the initial release burst from the drug-loaded nanoparticles. [ABSTRACT FROM AUTHOR]

Indomethacin-loaded poly(lactide- co-glycolide) (PLGA) nanoparticles with an average diameter of 100 nm were prepared by using a combination of an antisolvent diffusion method with preferential solvation (bare nanoparticles). Polyvinyl alcohol (PVA)-coated indomethacin-loaded PLGA nanoparticles with an average diameter of 100 nm were also prepared by emulsification and the solvent evaporation method (PVA-coated nanoparticles). Bare nanoparticles do not have a hydrophilic stabilizer on the surface; therefore, they have high hydrophobicity and negative charges. Electrophoretic mobility of bare nanoparticles at 5 mM NaCl solution was about 68 times higher than that of PVA-coated nanoparticles. Permeability of bare nanoparticles through rat skin was significantly higher than that of PVA-coated nanoparticles when iontophoresis was applied ex vivo. Indomethacin amount inside the skin after the permeation study by using bare nanoparticles was much higher than that by using PVA-coated nanoparticles. Indomethacin transition to circulation and accumulation in muscle by the transdermal delivery of indomethacin-loaded PLGA nanoparticles were significantly enhanced by using the combination of bare nanoparticles and iontophoresis in vivo. As for transdermal route of nanoparticles, both bare and PVA-coated nanoparticles were revealed to penetrate through the transfollicular pathway, and the migration of nanoparticles to follicles was enhanced by the application of iontophoresis. PLGA nanoparticles prepared by the antisolvent diffusion with preferential solvation are beneficial for iontophoretic transdermal delivery of therapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract: Estradiol is a therapeutic agent for treatment of perimenopausal symptoms and osteoporosis. Conventional oral or intravenous administration of estradiol has many problems, such as, metabolization in gastrointestinal tract and liver, pain by using an injection needle, rapid increase of drug levels in blood and fast clearance with unwanted side effects including thrombosis, endometriosis and uterus carcinoma. The use of nanocarriers for transdermal delivery has been studied because of their ability to deliver therapeutic agents for long time with a controlled ratio, escaping from the first pass effect by liver. In this study, permeability of estradiol-loaded PLGA nanoparticles through rat skin was studied. Higher amount of estradiol was delivered through skin when estradiol was loaded in nanoparticles than estradiol was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied, permeability of estradiol-loaded PLGA nanoparticles was much higher than that obtained by simple diffusion of them through skin, since they have negative surface charges. They were found to penetrate through follicles mainly. Also, enhanced permeability effect of estradiol by using nanoparticle system and iontophoresis were observed in vivo. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents. [Copyright &y& Elsevier]

Abstract: Nanoparticles effectively deliver therapeutic agent by penetrating into the skin. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100nm. IM and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis with 3V/cm was applied, permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents. [Copyright &y& Elsevier]

Abstract: Nanoparticles have widely been studied in drug delivery research for targeting and controlled release. The aim of this article is application of nanoparticles as an inhalable agent for treatment of lung cancer. To deposit effectively deep the particles in the lungs, the PLGA nanoparticles loaded with the anticancer drug 6-{[2-(dimethylamino)ethyl]amino}-3-hydroxyl-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) were prepared in the form of nanocomposite particles. The nanocomposite particles consist of the complex of drug-loaded nanoparticles and excipients. In this study, the anticancer effects of the nanocomposite particles against the lung cancer cell line A549. Also, the concentration of TAS-103 in blood and lungs were determined after administration of the nanocomposite particles by inhalation to rats. TAS-103-loaded PLGA nanoparticles were prepared with 5% and 10% of loading ratio by spray drying method with trehalose as an excipient. The 5% drug-loaded nanocomposite particles were more suitable for inhalable agent because of the sustained release of TAS-103 and higher FPF value. Cytotoxicity of nanocomposite particles against A549 cells was higher than that of free drug. When the nanocomposite particles were administered in rats by inhalation, drug concentration in lung was much higher than that in plasma. Furthermore, drug concentration in lungs administered by inhalation of nanocomposite particles was much higher than that after intravenous administration of free drug. From these results, the nanocomposite particle systems could be promising for treatment of lung cancer. [Copyright &y& Elsevier]

Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (P-GEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics. [ABSTRACT FROM AUTHOR]