Liposomes are poorly absorbed via lung lymph after inhaled administration in sheep
- Ibrahim, Jibriil, Haque, Shadabul, Bischof, Robert, Whittaker, Andrew, Whittaker, Michael, Kaminskas, Lisa
- Authors: Ibrahim, Jibriil , Haque, Shadabul , Bischof, Robert , Whittaker, Andrew , Whittaker, Michael , Kaminskas, Lisa
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in pharmacology Vol. 13, no. (2022), p. 880448-880448
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- Description: Enhancing the delivery of therapeutic agents to the lung lymph, including drugs, transfection agents, vaccine antigens and vectors, has the potential to significantly improve the treatment and prevention of a range of lung-related illnesses. One way in which lymphatic delivery can be optimized is via the use of nanomaterial-based carriers, such as liposomes. After inhaled delivery however, there is conflicting information in the literature regarding whether nanomaterials can sufficiently access the lung lymphatics to have a therapeutic benefit, in large part due to a lack of reliable quantitative pharmacokinetic data. The aim of this work was to quantitatively evaluate the pulmonary lymphatic pharmacokinetics of a model nanomaterial-based drug delivery system (HSPC liposomes) in caudal mediastinal lymph duct cannulated sheep after nebulized administration to the lungs. Liposomes were labelled with 3 H-phosphatidylcholine to facilitate evaluation of pharmacokinetics and biodistribution in biological samples. While nanomaterials administered to the lungs may access the lymphatics via direct absorption from the airways or after initial uptake by alveolar macrophages, only 0.3 and 0.001% of the 3 H-lipid dose was recovered in lung lymph fluid and lymph cell pellets (containing immune cells) respectively over 5 days. This suggests limited lymphatic access of liposomes, despite apparent pulmonary bioavailability of the 3 H-lipid being approximately 17%, likely a result of absorption of liberated 3 H-lipid after breakdown of the liposome in the presence of lung surfactant. Similarly, biodistribution of 3 H in the mediastinal lymph node was insignificant after 5 days. These data suggest that liposomes, that are normally absorbed via the lymphatics after interstitial administration, do not access the lung lymphatics after inhaled administration. Alternate approaches to maximize the lung lymphatic delivery of drugs and other therapeutics need to be identified.
- Authors: Ibrahim, Jibriil , Haque, Shadabul , Bischof, Robert , Whittaker, Andrew , Whittaker, Michael , Kaminskas, Lisa
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in pharmacology Vol. 13, no. (2022), p. 880448-880448
- Full Text:
- Reviewed:
- Description: Enhancing the delivery of therapeutic agents to the lung lymph, including drugs, transfection agents, vaccine antigens and vectors, has the potential to significantly improve the treatment and prevention of a range of lung-related illnesses. One way in which lymphatic delivery can be optimized is via the use of nanomaterial-based carriers, such as liposomes. After inhaled delivery however, there is conflicting information in the literature regarding whether nanomaterials can sufficiently access the lung lymphatics to have a therapeutic benefit, in large part due to a lack of reliable quantitative pharmacokinetic data. The aim of this work was to quantitatively evaluate the pulmonary lymphatic pharmacokinetics of a model nanomaterial-based drug delivery system (HSPC liposomes) in caudal mediastinal lymph duct cannulated sheep after nebulized administration to the lungs. Liposomes were labelled with 3 H-phosphatidylcholine to facilitate evaluation of pharmacokinetics and biodistribution in biological samples. While nanomaterials administered to the lungs may access the lymphatics via direct absorption from the airways or after initial uptake by alveolar macrophages, only 0.3 and 0.001% of the 3 H-lipid dose was recovered in lung lymph fluid and lymph cell pellets (containing immune cells) respectively over 5 days. This suggests limited lymphatic access of liposomes, despite apparent pulmonary bioavailability of the 3 H-lipid being approximately 17%, likely a result of absorption of liberated 3 H-lipid after breakdown of the liposome in the presence of lung surfactant. Similarly, biodistribution of 3 H in the mediastinal lymph node was insignificant after 5 days. These data suggest that liposomes, that are normally absorbed via the lymphatics after interstitial administration, do not access the lung lymphatics after inhaled administration. Alternate approaches to maximize the lung lymphatic delivery of drugs and other therapeutics need to be identified.
- Haque, Shadabul, Feeney, Orlagh, Meeusen, Els, Boyd, Ben, McIntosh, Michelle, Pouton, Colin, Whittaker, Michael, Kaminskas, Lisa
- Authors: Haque, Shadabul , Feeney, Orlagh , Meeusen, Els , Boyd, Ben , McIntosh, Michelle , Pouton, Colin , Whittaker, Michael , Kaminskas, Lisa
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Controlled Release Vol. 307, no. (2019), p. 32-43
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- Description: The development of inhalable ‘nanomedicines’ based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1β were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats. Pulmonary inflammation has a significant impact on the short term disposition, and longer term clearance kinetics and response of the lungs to inhaled drug-loaded PEGylated liposomes after a single pulmonary dose. [Display omitted] •Pulmonary inflammation had a significant impact on the lung disposition of liposome.•Systemic absorption of lipids, but not of drug, was increased in the inflamed lungs.•Lung inflammation reduced the mucociliary clearance of the liposome dose.•A single liposome dose was not found to exacerbate pre-existing lung inflammation.
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