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Nanoaerosols reduce required effective dose of liposomal levofloxacin against pulmonary murine Francisella tularensis subsp. novicida infection.

Propst CN, Nwabueze AO, Kanev IL, Pepin RE, Gutting BW, Morozov VN, van Hoek ML - J Nanobiotechnology (2016)

Bottom Line: Second, the generator was used to aerosolize the antibiotic levofloxacin to determine the effectiveness of nanoaerosolized levofloxacin as treatment against F. novicida.In addition, treatment with nanoaerosols consumes less total volume of therapeutic solutions and is gentler on sprayed material than the aerosolization by a conventional three-jet Collison nebulizer as seen by the preservation of liposomes.This could represent a significant advance for the use of expensive therapeutics and lung directed therapies.

View Article: PubMed Central - PubMed

Affiliation: School of Systems Biology and National Center for Biodefense and Infectious Diseases, George Mason University, MS1H8, Manassas, VA, 20110, USA.

ABSTRACT

Background: The Institute of Theoretical and Experimental Biophysics in Moscow recently developed a new nanoaerosol generator. This study evaluated this novel technology, which has the potential to enhance therapeutic delivery, with the goal of using the generator to treat pulmonary Francisella tularensis subsp. novicida (F. novicida) infections in BALB/c mice.

Results: First, the analysis of quantum dots distribution in cryosections of murine lungs demonstrated that nanoaerosols penetrate the alveoli and spread more homogenously in the lungs than upon intranasal delivery. Second, the generator was used to aerosolize the antibiotic levofloxacin to determine the effectiveness of nanoaerosolized levofloxacin as treatment against F. novicida. The generator was capable of delivering a sufficient dose of nanoaerosolized liposome-encapsulated levofloxacin to rescue mice against 100LD50 of F. novicida.

Conclusions: The nanoaerosol-delivered dosage of liposome-encapsulated levofloxacin required to rescue mice is approximately 94× lower than the oral required dose and approximately 8× lower than the intraperitoneal dose required for rescue. In addition, treatment with nanoaerosols consumes less total volume of therapeutic solutions and is gentler on sprayed material than the aerosolization by a conventional three-jet Collison nebulizer as seen by the preservation of liposomes. This could represent a significant advance for the use of expensive therapeutics and lung directed therapies.

No MeSH data available.


Related in: MedlinePlus

Liposome-encapsulated levofloxacin nanoaerosol and standard aerosol. a Size distribution of nanoaerosolized liposome-encapsulated levofloxacin. b Survival curve of mice treated with nanoaerosolized liposome-encapsulated levofloxacin (blue) against 100LD50 intranasal F. novicida infection. c Survival curve of mice treated with aerosolized levofloxacin (30 min—red, 1 h—green, 2 h—blue) against 100LD50 intranasal F. novicida infection
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Fig4: Liposome-encapsulated levofloxacin nanoaerosol and standard aerosol. a Size distribution of nanoaerosolized liposome-encapsulated levofloxacin. b Survival curve of mice treated with nanoaerosolized liposome-encapsulated levofloxacin (blue) against 100LD50 intranasal F. novicida infection. c Survival curve of mice treated with aerosolized levofloxacin (30 min—red, 1 h—green, 2 h—blue) against 100LD50 intranasal F. novicida infection

Mentions: In order to apply this improvement to the study, liposomes containing levofloxacin were prepared from DPPC, DPPG, and cholesterol precursors (2:1:2 molar ratio) using the well-established thin film dehydration/rehydration technique, including sonication and extrusion, to produce small unilamellar vesicles [29]. As seen in Fig. 4a, the ESN nanoaerosol generator produced nanoaerosolized particles with a geometric mean diameter of 153 nm, which is larger than the nanoaerosolized levofloxacin but still small enough to deliver material to the alveoli. The MPPD model predicts a total deposition of 30.2 % for particles of this size: 8.69 % alveolar, 4.91 % tracheobronchial, and 16.6 % nasal (Fig. 1). The nanoaerosolization of a 4 mg/mL liposome-encapsulated levofloxacin solution increased the percentage of surviving mice to 80 % (4/5 mice rescued) and decreased the estimated delivered dose of levofloxacin to the entire respiratory tract to approximately 0.35 mg/kg per day using the same exposure time of 4 h per day for 5 days (Fig. 4b). The lower delivered dose and decreased percentage delivered to the alveoli compared to the nanoaerosolized levofloxacin suggests that the liposomes themselves may assist with delivery and uptake.Fig. 4


Nanoaerosols reduce required effective dose of liposomal levofloxacin against pulmonary murine Francisella tularensis subsp. novicida infection.

Propst CN, Nwabueze AO, Kanev IL, Pepin RE, Gutting BW, Morozov VN, van Hoek ML - J Nanobiotechnology (2016)

Liposome-encapsulated levofloxacin nanoaerosol and standard aerosol. a Size distribution of nanoaerosolized liposome-encapsulated levofloxacin. b Survival curve of mice treated with nanoaerosolized liposome-encapsulated levofloxacin (blue) against 100LD50 intranasal F. novicida infection. c Survival curve of mice treated with aerosolized levofloxacin (30 min—red, 1 h—green, 2 h—blue) against 100LD50 intranasal F. novicida infection
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835885&req=5

Fig4: Liposome-encapsulated levofloxacin nanoaerosol and standard aerosol. a Size distribution of nanoaerosolized liposome-encapsulated levofloxacin. b Survival curve of mice treated with nanoaerosolized liposome-encapsulated levofloxacin (blue) against 100LD50 intranasal F. novicida infection. c Survival curve of mice treated with aerosolized levofloxacin (30 min—red, 1 h—green, 2 h—blue) against 100LD50 intranasal F. novicida infection
Mentions: In order to apply this improvement to the study, liposomes containing levofloxacin were prepared from DPPC, DPPG, and cholesterol precursors (2:1:2 molar ratio) using the well-established thin film dehydration/rehydration technique, including sonication and extrusion, to produce small unilamellar vesicles [29]. As seen in Fig. 4a, the ESN nanoaerosol generator produced nanoaerosolized particles with a geometric mean diameter of 153 nm, which is larger than the nanoaerosolized levofloxacin but still small enough to deliver material to the alveoli. The MPPD model predicts a total deposition of 30.2 % for particles of this size: 8.69 % alveolar, 4.91 % tracheobronchial, and 16.6 % nasal (Fig. 1). The nanoaerosolization of a 4 mg/mL liposome-encapsulated levofloxacin solution increased the percentage of surviving mice to 80 % (4/5 mice rescued) and decreased the estimated delivered dose of levofloxacin to the entire respiratory tract to approximately 0.35 mg/kg per day using the same exposure time of 4 h per day for 5 days (Fig. 4b). The lower delivered dose and decreased percentage delivered to the alveoli compared to the nanoaerosolized levofloxacin suggests that the liposomes themselves may assist with delivery and uptake.Fig. 4

Bottom Line: Second, the generator was used to aerosolize the antibiotic levofloxacin to determine the effectiveness of nanoaerosolized levofloxacin as treatment against F. novicida.In addition, treatment with nanoaerosols consumes less total volume of therapeutic solutions and is gentler on sprayed material than the aerosolization by a conventional three-jet Collison nebulizer as seen by the preservation of liposomes.This could represent a significant advance for the use of expensive therapeutics and lung directed therapies.

View Article: PubMed Central - PubMed

Affiliation: School of Systems Biology and National Center for Biodefense and Infectious Diseases, George Mason University, MS1H8, Manassas, VA, 20110, USA.

ABSTRACT

Background: The Institute of Theoretical and Experimental Biophysics in Moscow recently developed a new nanoaerosol generator. This study evaluated this novel technology, which has the potential to enhance therapeutic delivery, with the goal of using the generator to treat pulmonary Francisella tularensis subsp. novicida (F. novicida) infections in BALB/c mice.

Results: First, the analysis of quantum dots distribution in cryosections of murine lungs demonstrated that nanoaerosols penetrate the alveoli and spread more homogenously in the lungs than upon intranasal delivery. Second, the generator was used to aerosolize the antibiotic levofloxacin to determine the effectiveness of nanoaerosolized levofloxacin as treatment against F. novicida. The generator was capable of delivering a sufficient dose of nanoaerosolized liposome-encapsulated levofloxacin to rescue mice against 100LD50 of F. novicida.

Conclusions: The nanoaerosol-delivered dosage of liposome-encapsulated levofloxacin required to rescue mice is approximately 94× lower than the oral required dose and approximately 8× lower than the intraperitoneal dose required for rescue. In addition, treatment with nanoaerosols consumes less total volume of therapeutic solutions and is gentler on sprayed material than the aerosolization by a conventional three-jet Collison nebulizer as seen by the preservation of liposomes. This could represent a significant advance for the use of expensive therapeutics and lung directed therapies.

No MeSH data available.


Related in: MedlinePlus