Non-invasive pulmonary aerosol delivery in mice by the endotracheal route

Bivas-Benita, Maytal; Zwier, Raphaël; Junginger, Hans E.; Borchard, Gerrit

doi:10.1016/j.ejpb.2005.04.009

Cited by 184 publications

(111 citation statements)

References 16 publications

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“…We used the MicoSprayer Aerolizer, which has been previously used for drug delivery to the smaller airways. 46 Whereas only low luciferase activity was observed in mice that were treated with PEI gene vectors, a strong signal for lucifrease activity was evident in mice treated with P[DMAEMA 80 -co-OEGMA (9) 40 ] (EG units ) 9 and F OEGMA ) 33.3%) gene vectors ( Figure 6A,B). After 24 h, 7-fold higher transfection efficiency could be observed for P(DMAEMA-co-OEGMA) gene vectors in lung homogenates compared to the control group brPEI in vivo.…”

Section: Resultsmentioning

confidence: 98%

“…Subsequently, gene transfer complexes were incubated for 20 min at room temperature prior to further use. The complexes were applied to Balb/C mice (n ) 5) via an intratracheal administration route as described by Bivas-Benita et al 46 Mice were anesthesized with a mixture of medetomdiine (11.5 µg/kg), midazolam (115 µg/kg), and fentanyl (1.15 µg/kg) and suspended on a plate system (Hallowell EMC) at a 45°a ngle by the upper teeth. A modified cold-light otoscope Beta 200 (Heine Optotechnik) was used to provide optimal illumination of the trachea, while a small spatula helped to open the lower jaw of the mouse and blunted forceps were used to displace the tongue for maximal oropharyngeal exposure.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

et al. 2009

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Oligo(ethylene glycol) methyl ether methacrylates (OEGMA) of various chain lengths (i.e., 9, 23, or 45 EG units) and N,N-dimethylaminoethyl methacrylate (DMAEMA) were copolymerized by atom transfer radical polymerization (ATRP), yielding well-defined P(DMAEMA-co-OEGMA) copolymers with increasing OEGMA molar fractions (F OEGMA) but a comparable degree of polymerization (DP ∼ 120). Increase of both F OEGMA and OEGMA chain lengths correlated inversely with gene vector size, morphology, and zeta potential. P(DMAEMA-co-OEGMA) copolymers prevented gene vector aggregation at high plasmid DNA (pDNA) concentrations in isotonic solution and did not induce cytotoxicity even at high concentrations. Transfection efficiency of the most efficient P(DMAEMA-co-OEGMA) copolymers was found to be >10-fold lower compared with branched polyethylenimine (PEI) 25 kDa. Although OEGMA copolymerization largely reduced gene vector binding with the cell surface, cellular internalization of the bound complexes was less affected. These observations suggest that inefficient endolysosomal escape limits transfection efficiency of P(DMAEMA-co-OEGMA) copolymer gene vectors. Despite this observation, optimized p(DMAEMA-co-OEGMA) gene vectors remained stable under conditions for in vivo application leading to 7-fold greater gene expression in the lungs compared with PEI. Tailor-made P(DMAEMA-co-OEGMA) copolymers are promising nonviral gene transfer agents that fulfill the requirements for successful in vivo gene delivery.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

et al. 2009

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“…Fifty microliters of saline solution alone or saline solution containing 1 U of porcine pancreatic elastase (Sigma) was sprayed into the trachea (36,51). Mice were killed at day 1, 7, or 21 after elastase injection.…”

Section: Methodsmentioning

confidence: 99%

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

172

166

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Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O 2 • ─ . ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m 3 ) to 6 mo (100 mg/m 3 total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.antioxidants | cigarette smoke | chronic obstructive pulmonary disease | oxidants | glutathione E xtracellular superoxide dismutase (ECSOD or SOD3) is one of the three SOD antioxidant enzyme isoforms, and is highly expressed in lungs and vessels (1, 2). It is located in the ECM, the junctions of airway epithelial cells, the surface of airway smooth muscle, and the lining of vessels of the lung. SOD3 functions as a superoxide anion scavenger, thereby attenuating oxidative stress, which may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Acute loss of SOD3 in adult mice causes death, whereas low mortality rates are seen in SOD3-overexpressing animals exposed to hyperoxia, suggesting an essential role of SOD3 for survival (3,4). Accumulating evidence shows that SOD3 polymorphism is associated with a decline in lung function in rodents and humans, and susceptibility to COPD, which may be a result of alteration of its encoding protein structure, function, and level (5-14). However, it is unclear whether endogenous SOD3 participates in the development/ progression of the inflammatory response, leading to COPD/ emphysema.Cigarette smoke (CS) is the major etiological factor in the pathogenesis of COPD, which is characterized by chronic lung inflammation, parenchymal destruction (i.e., emphysema), and accelerated decline in lung function....

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“…22,24 Briefly, mice were anesthetized and given 25 mg/ mouse of RB6-8C5 MAb using a Microsprayer Aerosolizer Model IA-1C connected to a FMJ-250 high-pressure syringe (Penn-Century, Philadelphia, PA, USA) introduced just before the first trachea bifurcation. 32 In all experiments, mice were weighed twice weekly, euthanized at the end of experiments and macroscopic lung metastases counted. All in vivo experiments were repeated at least twice.…”

Section: Mice and Experimental Protocolsmentioning

confidence: 99%

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

et al. 2016

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Due to their constant exposure to inhaled antigens, lungs represent a particularly immunosuppressive environment that limits excessive immune responses; however, cancer cells can exploit this unique environment for their growth. We previously described the ability of aerosolized CpG-ODN combined with Poly(I:C) (TLR9 and TLR3 agonists, respectively) to promote antitumor immunity in a B16 melanoma lung metastasis model. Here, we explored the possibility of improving the therapeutic efficacy of TLR9/TLR3 agonist combinations by including in the inhalant either an antibody directed to both Ly6G and Ly6C markers to locally deplete myeloid-derived suppressive cells (MDSCs) or IFNa to directly activate the natural killer (NK) and macrophage innate immune cells in the lung. Addition of nebulized anti-MDSC antibody RB6-8C5 to aerosolized CpG-ODN/Poly(I:C) resulted in reduced mRNA levels of immunsuppressive molecules (IL10, Arg-1, and Nos2), increased activation of resident NK cells and improved treatment outcome, with a significant reduction in established B16 melanoma lung metastases compared to treatment with CpG-ODN/ Poly(I:C) alone. Likewise, addition of aerosolized IFNa led to increased mRNA levels of proinflammatory cytokines (IL15 and IFNg) in the lung and recruitment of highly activated NK cells, with no evident signs of toxicity and with a significantly improved antitumor effect as compared with aerosolized CpG-ODN/Poly(I:C). Combining both IFNa and RB6-8C5 with CpG-ODN/Poly(I:C) did not produce an additive effect compared to IFNa C CpG-ODN/Poly(I:C) or RB6-8C5 C CpG-ODN/Poly(I:C). Our results indicate that the inhalation therapy is a feasible and non-invasive strategy to deliver immunodulatory molecules, including antibodies and cytokines that reprogram the lung tumor microenvironment to foster immune destruction of tumors.

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Non-invasive pulmonary aerosol delivery in mice by the endotracheal route

Cited by 184 publications

References 16 publications

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

Characterization of Tailor-Made Copolymers of Oligo(ethylene glycol) Methyl Ether Methacrylate and N,N-Dimethylaminoethyl Methacrylate as Nonviral Gene Transfer Agents: Influence of Macromolecular Structure on Gene Vector Particle Properties and Transfection Efficiency

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

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