Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung

Dailey, Lea Ann; Jekel, Norman; Fink, Ludger; Gessler, Tobias; Schmehl, Thomas; Wittmar, Matthias; Kissel, Thomas; Seeger, Werner

doi:10.1016/j.taap.2006.01.016

Cited by 198 publications

(116 citation statements)

References 29 publications

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“…A popular polymer used today is poly(D,L-lactic-co-glycolic acid) (PLGA), highly regarded for its safe biodegradability in the body and approval by the FDA. Preliminary evaluations of PLGA toxicology in the lung are promising, but work remains to prove this material for sustained pulmonary drug delivery [10,11].…”

Section: Introductionmentioning

confidence: 99%

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

Arnold

Gorman

Schieber

et al. 2007

Journal of Controlled Release

114

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Pulmonary drug delivery of controlled release formulations may provide an effective adjunct approach to orally delivered antibiotics for clearing persistent lung infections. Dry powder formulations for this indication should possess characteristics including; effective deposition to infected lung compartments, persistence at the infection site, and steady release of antibiotic. Large porous particles (∼10-15 μm) have demonstrated effective lung deposition and enhanced lung residence as a result of their large diameter and reduced clearance by macrophages in comparison to small microparticles (∼1-5 μm). In this report, Precision Particle Fabrication technology was used to create monodisperse large porous particles of poly(D,L-lactic-co-glycolic acid) (PLGA) utilizing oils as extractable porogens. After extraction, the resulting large porous PLGA particles exhibited a low density and a web-like or hollow interior depending on porogen concentration and type, respectively. Ciprofloxacin nanoparticles (nanoCipro) created by homogenization in dichloromethane, possessed a polymorph with a decreased melting temperature. Encapsulating nanoCipro in large porous PLGA particles resulted in a steady release of ciprofloxacin that was extended for larger particle diameters and for the solid particle morphology in comparison to large porous particles. The encapsulation efficiency of nanoCipro was quite low and factors impacting the entrapment of nanoparticles during particle formation were elucidated. A dry powder formulation with the potential to control particle deposition and sustain release to the lung was developed and insight to improve nanoparticle encapsulation is discussed.

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Section: Introductionmentioning

confidence: 99%

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

Arnold

Gorman

Schieber

et al. 2007

Journal of Controlled Release

114

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“…Polymeric microparticles, based on PLGA and polycaprolactone, are also being investigated for the delivery of SOD (10)(11)(12). Although polyester-based microparticles have an excellent shelf life and well-characterized degradation products, their application for the treatment of inflammatory diseases is potentially problematic because their acidic degradation products can cause inflammation (13).…”

mentioning

confidence: 99%

Polyketal Microparticles: A New Delivery Vehicle for Superoxide Dismutase

et al. 2006

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There is currently great interest in developing microparticles that can enhance the delivery of proteins to macrophages. In this communication, we present a new acid-sensitive polymer for drug delivery, poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK). PCADK is designed to hydrolyze, after phagocytosis by macrophages, in the acidic environment of the phagosome and enhance the intracellular delivery of phagocytosed therapeutics. Other key attributes of PCADK for drug delivery are its well-characterized degradation products and straightforward synthesis. PCADK hydrolyzes into 1,4-cyclohexanedimethanol, a compound used in food packaging, and acetone, a compound on the FDA GRAS list. PCADK was synthesized using the acetal exchange reaction between 1,4-cyclohexanedimethanol and 2,2-dimethoxypropane, and could be obtained on a multigram scale in one step. The hydrolysis kinetics of the ketal linkages in PCADK were measured by 1 H NMR and were determined to be pH-sensitive, having a half-life of 24.1 days at pH 4.5 and over 4 years at pH 7.4. The therapeutic enzyme superoxide dismutase (SOD), which scavenges reactive oxygen species, was encapsulated into PCADKbased microparticles using a double emulsion procedure. Cell culture experiments demonstrated that PCADKbased microparticles dramatically improved the ability of SOD to scavenge reactive oxygen species produced by macrophages. We anticipate numerous applications of PCADK in drug delivery, based on its acid sensitivity, well-characterized degradation products, and straightforward synthesis.

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“…Many studies that investigate size alone do not consider the specific impact of surface chemistry on inspirability and mucociliary clearance. Dailey et al, (35) for instance, demonstrates that larger PS particles caused greater infiltration of peripheral mononuclear cells, and Lauweryns et al (36) reports that particles smaller than 260 nm are capable of evading uptake by macrophages. Meanwhile, Henning et al (37,38) demonstrates that PS particles ranging from 50 to 6000 nm have no effect on clearance, that a physicochemical property other than particle size and total number of particles delivered affects MCC.…”

Section: Discussionmentioning

confidence: 99%

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

Navarrette¹,

Sisson²,

Nance

et al. 2012

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. Methods: We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size-and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO 4 )-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40 nm to 500 nm. Results: CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF ( p < 0.05 vs. baseline control). Filtering CSE through a 0.2-lm filter attenuated this effect. Introduction of sulphate-modified PS beads *300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200 nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300 nm increased CBF significantly and increased the number of motile points. Conclusions: These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size-and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles.

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Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung

Cited by 198 publications

References 29 publications

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

NanoCipro encapsulation in monodisperse large porous PLGA microparticles

Polyketal Microparticles: A New Delivery Vehicle for Superoxide Dismutase

Particulate Matter in Cigarette Smoke Increases Ciliary Axoneme Beating Through Mechanical Stimulation

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