Transdermal delivery of macromolecules using skin electroporation.

PURPOSES: (1) To evaluate the feasibility of transdermal delivery of macromolecules by skin electroporation. (2) To assess the influence of the molecular weight of the permeant on transport and examine whether there exists a "cut-off" value of molecular weight. (3) To localize the transport pathways of the macromolecules in the skin. METHODS: FITC-dextran (FD) of increasing molecular weight (4.4, 12 and 38 kDa) were used as model macromolecules to study the extent of transport across hairless rats skin in vitro and to localize their distribution in the skin by confocal scanning laser microscopy. RESULTS: Electroporation enhanced the transport of the macromolecules as compared to passive diffusion. The transdermal delivery by skin electroporation of FITC and FD 4.4 was equivalent whereas transport of higher molecular weight FD was lower but significant. FITC and FD 38 were observed in the epidermis both around and in the keratinocytes. CONCLUSIONS: Transdermal and topical delivery of macromolecules of at least 40 kDa can be achieved by skin electroporation

Distribution and Cellular Uptake of PEGylated Polymeric Particles in the Lung Towards Cell-Specific Targeted Delivery

PURPOSE: We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung. METHODS: Three sizes of PRINT hydrogel particles (80×320 nm, 1.5 and 6 um donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging. RESULTS: Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80×320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles. CONCLUSIONS: Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics

Pulmonary Delivery of Voriconazole Loaded Nanoparticles Providing a Prolonged Drug Level in Lungs: A Promise for Treating Fungal Infection

Current therapies are insufficient to prevent recurrent fungal infection especially in the lower part of the lung. A careful and systematic understanding of the properties of nanoparticles plays a significant role in the design,development, optimization, and in vivo performances of the nanoparticles. In the present study, PLGA nanoparticles containing the antifungal drug voriconazole was prepared and two best formulations were selected for further characterization and in vivo studies. The nanoparticles and the free drug were radiolabeled with technetium-99m with 90% labelling efficiency, and the radiolabeled particles were administered to investigate the effect on their blood clearance, biodistribution, and in vivo gamma imaging. In vivo deposition of the drug in the lobes of the lung was studied by LC−MS/MS study. The particles were found to be spherical and had an average hydrodynamic diameter of 300 nm with a smooth surface. The radiolabeled particles and the free drug were found to accumulate in various major organs. Drug accumulation was more pronounced in the lung in the case of administration of the nanoparticles than that of the free drug. The free drug was found to be excreted more rapidly than the nanoparticle containing drug following the inhalation route as assessed by gamma scintigraphy study. Thus, the study reveals that pulmonary administration of nanoparticles containing voriconazole could be a better therapeutic choice even as compared to the iv route of administration of the free drug and/or the drug loaded nanoparticles