Intratracheal budesonide-poly (lactide-co-glycolide) microparticles reduce oxidative stress, VEGF expression, and vascular leakage in a benzo(a)pyrene-fed mouse model

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Abstract
The purpose of this study was to determine whether intratracheally instilled polymeric budesonide microparticles could sustain lung budesonide levels for one week and inhibit early biochemical changes associated with benzo(a)pyrene (B[a]P) feeding in a mouse model for lung tumours. Polymeric microparticles of budesonide-poly (dl-lactide-co-glycolide) (PLGA 50:50) were prepared using a solvent evaporation technique and characterized for their size, morphology, encapsulation efficiency, and in-vitro release. The microparticles were administered intratracheally (i.t.) to B[a]P-fed A/J mice. At the end of one week drug levels in the lung tissue and bronchoalveolar lavage (BAL) were estimated using HPLC and compared with systemic (intramuscular) administration. In addition, in-vivo end points including malondialdehyde (MDA), glutathione (GSH), total protein levels and vascular endothelial growth factor (VEGF) in BAL, and VEGF and c-myc mRNA levels in the lung tissue were assessed at the end of one week following intratracheal administration of budesonide microparticles. Budesonide-PLGA microparticles (1–2 μm), with a budesonide loading efficiency of 69–94%, sustained in-vitro budesonide release for over 21 days. Compared with the intramuscular route, intratracheally administered budesonide-PLGA microparticles resulted in higher budesonide levels in the BAL and lung tissue. In-vivo, B[a]P-feeding increased BAL MDA, lung VEGF mRNA, lung c-myc mRNA, BAL total protein, and BAL VEGF levels by 60, 112, 71, 154, and 78%, respectively, and decreased BAL GSH by 62%. Interestingly, intratracheally administered budesonide-PLGA particles inhibited these biochemical changes. Thus, biodegradable budesonide microparticles sustained budesonide release and reduced MDA accumulation, GSH depletion, vascular leakage, and VEGF and c-myc expression in B[a]P-fed mice, indicating the potential of locally delivered sustained-release particles for inhibiting angiogenic factors in lung cancer.