Large (>6 microm) rigid microparticles (MPs) become passively entrapped within the lungs after intravenous (i.v.) injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In this study, PEGylated 6 microm polystyrene MPs with multiple copies of the norvaline (Nva) alpha-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope. CPT was released from the CPT-Nva-MPs over 24 h in rat plasma at 37 degrees C. In-vivo CPT plasma concentrations were low (approximately 1 ng/ml or less) and constant over a period of 4 days after a single i.v. injection of CPT-Nva-MPs as compared with high but short-lived systemic exposures after an i.v. injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anticancer efficacy was evaluated in an orthotopic lung cancer animal model and compared with a bolus injection of CPT. Animals receiving free CPT (2 mg/kg) and CPT-Nva-MPs (0.22 mg/kg CPT and 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05 and 0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was 10 times lower than after i.v. injection of free CPT, but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was 10 times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer.
[Show abstract][Hide abstract] ABSTRACT: The relationship between microparticle (MP) size and lung targeting efficiency, intra-lung distribution and retention time was systematically studied after intravenous administration of rigid fluorescent polystyrene MPs of various sizes (2, 3, 6 and 10 microm) to Sprague Dawley rats. Total fluorescence was assessed and it was found that 2 microm and 3 microm MPs readily passed through the lung to the liver and spleen while 10 microm MPs were completely entrapped in the lung for the one-week duration of the study. Approximately 84% of 6 microm MPs that were initially entrapped in the lung were cleared over the next 2 days and 15% were cleared over the remaining 5 days. A Caliper IVIS 100 small animal imaging system confirmed that 3 microm MPs were not retained in the lung but that 6 microm and 10 microm MPs were widely distributed throughout the lung. Moreover, histologic examination showed MP entrapment in capillaries but not arterioles. These studies suggest that for rigid MPs the optimal size range required to achieve transient but highly efficiently targeting to pulmonary capillaries after IV injection is >6 microm but <10 microm in rats and that systemic administration of optimally sized MPs may be an efficient alternative to currently used inhalation-based delivery to the lung.
[Show abstract][Hide abstract] ABSTRACT: The current study examines the passive pulmonary targeting efficacy and retention of 6μm polystyrene (PS) microparticles (MPs) covalently modified with different surface groups [amine (A-), carboxyl (C-) and sulfate (S-)] or single (PEG(1)-) and double (PEG(2)-) layers of α,ω-diamino poly(ethylene glycol) attached to C-MPs. The ζ-potential of A-MPs (-44.0mV), C-MPs (-54.3mV) and S-MPs (-49.6mV) in deionized water were similar; however PEGylation increased the ζ-potential for both PEG(1)-MPs (-18.3mV) and PEG(2)-MPs (11.5mV). The biodistribution and retention of intravenously administered MPs to male Sprague-Dawley rats was determined in homogenized tissue by fluorescence spectrophotometry. PEG(1)-MPs and PEG(2)-MPs demonstrated enhanced pulmonary retention in rats at 48h after injection when compared to unmodified A-MPs (59.6%, 35.9% and 17.0% of the administered dose, respectively). While unmodified MPs did not significantly differ in lung retention, PEGylation of MPs unexpectedly improved passive lung targeting and retention by modifying surface properties including charge and hydrophobicity but not size.
International Journal of Pharmaceutics 09/2010; 402(1-2):64-71. DOI:10.1016/j.ijpharm.2010.09.020 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past several years, great advances have been made on development of novel drug delivery systems (NDDS) for plant actives and extracts. The variety of novel herbal formulations like polymeric nanoparticles, nanocapsules, liposomes, phytosomes, nanoemulsions, microsphere, transferosomes, and ethosomes has been reported using bioactive and plant extracts. The novel formulations are reported to have remarkable advantages over conventional formulations of plant actives and extracts which include enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological activity, enhancement of stability, improved tissue macrophages distribution, sustained delivery, and protection from physical and chemical degradation. The present review highlights the current status of the development of novel herbal formulations and summarizes their method of preparation, type of active ingredients, size, entrapment efficiency, route of administration, biological activity and applications of novel formulations.
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