title: Supercritical fluid technology based large porous celecoxib-PLGA microparticles do not induce pulmonary fibrosis and sustain drug delivery and efficacy for several weeks following a single dose.
abstract: Although pulmonary dosing of large porous particles has been shown to sustain drug delivery for a few days, there are no reports on safety or long term delivery. In this study we prepared large porous poly(lactide-co-glycolide) (PLGA) microparticles of celecoxib using supercritical fluid pressure-quench technology and demonstrated 4.8-, 15.7-, and 2.1-fold greater drug levels in lung, bronchoalveolar lavage fluid (BAL), and plasma compared to conventional microparticles on day 21 after a single intratracheal dosing of dry powders in A/J mice. Porous particle based delivery was 50.2-, 95.5-, and 7.7-fold higher compared to plain drug in the lung, BAL, and plasma, respectively. Toxicity of the formulations was assessed on day 21 following a fibrosis assessment protocol in A/J mice. There was no significant change in lactate dehydrogenase (LDH), total protein, and total cell counts in the BAL, and soluble collagen levels in the lung tissue following particle or drug treatments. Lung histology indicated no significant hyperplasia, granuloma, or collagen deposition in the treated groups. Chemopreventive potential of celecoxib porous particles was assessed in a benzo[a]pyrene (B[a]P) induced lung cancer model in A/J mice, on day 60 following a single intratracheal dose with or without single intravenous paclitaxel/carboplatin treatment. The combination group was more effective than individual groups, with the inhibition of tumor multiplicity and reduction of vascular endothelial growth factor in the BAL being 70 and 58%, respectively. Thus, large porous celecoxib-PLGA microparticles prepared using supercritical fluid technology exhibited sustained drug delivery and anti-tumor efficacy, without causing any significant toxicity.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, USA.
authors.forename: Devender S
authors.initials: DS
authors.lastname: Dhanda
authors.forename: Puneet
authors.initials: P
authors.lastname: Tyagi
authors.forename: Sidney S
authors.initials: SS
authors.lastname: Mirvish
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001564:Benzo(a)pyrene; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016190:Carboplatin / Q000008:administration & dosage; D000068579:Celecoxib; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D003692:Delayed-Action Preparations; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016062:Porosity; D011658:Pulmonary Fibrosis; D011720:Pyrazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D001564:Benzo(a)pyrene; D003094:Collagen; D016190:Carboplatin; D007770:L-Lactate Dehydrogenase; D000068579:Celecoxib; D017239:Paclitaxel