Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model

Beck-Broichsitter, Moritz; Gauss, Julia; Packhaeuser, Claudia B.; Lahnstein, Kerstin; Schmehl, Thomas; Seeger, Werner; Kissel, Thomas; Gessler, Tobias

doi:10.1016/j.ijpharm.2008.09.017

Cited by 104 publications

(57 citation statements)

References 36 publications

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“…The chemical structures of polymers for polymeric nanoparticles used in pulmonary delivery systems are shown Figure 2. 26,29,38,39,[54][55][56][57]59,61,69,70,74,75,[79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] Due to their biocompatibility, surface modification capability, and sustained-release properties, polymeric nanoparticles are intensively studied using various important pulmonary drugs. These pulmonary drug include antiasthmatic drugs, 22,26 antituberculosis drugs, 38,39 pulmonary hypertension drugs, 29 and anticancer drugs.…”

Section: Drugs For Inhalationmentioning

confidence: 99%

Nanomedicine in pulmonary delivery

Mansour¹,

Rhee²,

Wu³

2009

IJN

403

269

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Section: Drugs For Inhalationmentioning

confidence: 99%

Nanomedicine in pulmonary delivery

Mansour¹,

Rhee²,

Wu³

2009

IJN

403

269

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“…We focus on the inhaled route because inhalational drug delivery would generate high pulmonary drug levels relative to systemic delivery, thereby minimizing systemic side effects (19,20), which is important considering the ubiquitous nature of TRPV4 (21). In addition, the initiation of mechanical ventilation in humans at risk of or with ARDS is universally preceded by a period during which oxygen is delivered via facemask, so inhaled nanotherapy could be given to all patients during this time to prevent VILI.…”

mentioning

confidence: 99%

Prevention of Ventilator-Induced Lung Edema by Inhalation of Nanoparticles Releasing Ruthenium Red

Jurek

Hirano-Kobayashi

Chiang

et al. 2014

Am J Respir Cell Mol Biol

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The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.

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“…Recently, several different DDS have been developed for inhalation delivery of different drugs. Liposomes (10-13), lipid-and polymerbased nanoparticles (14)(15)(16)(17), are the most frequently used carriers for local pulmonary delivery of different drugs, antisense oligonucleotides (ASO), and short-interfering RNA (siRNA).…”

mentioning

confidence: 99%

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

Garbuzenko¹,

Saad²,

Pozharov³

et al. 2010

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

167

149

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Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.inhalation | antisense oligonucleotides | liposomes | orthotopic lung cancer model | pump and nonpump resistance L ung cancer is the leading cause of cancer-related death worldwide (1). Because of the size and distribution of lung cancer, cytoreductive surgery is not very effective for this disease, and therefore chemotherapy and/or radiation are the treatments of choice. However, despite the advances in cancer treatment and improvements in lifestyle and health care, death rates from lung cancer have not changed significantly over the last 50 years. In contrast, mortality from heart disease, the leading cause of death, declined almost 2.5-fold over the same period (2). The patient survival has been in a plateau for three decades (3), with a 5-year relative survival rate of less than 18% in most countries (4). The efficacy of chemotherapy in lung cancer is limited by the rapid development of cancer cell resistance during treatment. To overcome this resistance, higher doses of toxic anticancer drug(s) are administered, often producing adverse side effects in healthy organs. We hypothesize that a substantial enhancement in the efficiency of lung cancer treatment is possible by (i) local delivery of chemotherapeutic agent(s) by inhalation and (ii) simultaneous suppression of at least major mechanisms of lung cancer cell resistance. Local delivery of anticancer drugs directly into the lungs will increase their accumulation in tumor cells and will reduce adverse side effects on healthy organs by limiting drug concentration in the blood. Simultaneous suppression of cellular resistance in tumors will increase the intracellular concentration of the drug in cancer cells and enhance its cytolethality for cancerous cells.Patients with asthma and chronic obstructive pulmonary disease commonly use inhaled drugs (5). Although some chemotherapeutic agents can be delivered through the pulmonary or intratracheal route (6-9), most anticancer drugs cannot be inhaled in t...

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Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model

Cited by 104 publications

References 36 publications

Nanomedicine in pulmonary delivery

Nanomedicine in pulmonary delivery

Prevention of Ventilator-Induced Lung Edema by Inhalation of Nanoparticles Releasing Ruthenium Red

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

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