Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy

• Published in: Journal of controlled release Vol. 183; pp. 18 - 26
• Main Authors: Kaminskas, Lisa M., McLeod, Victoria M., Ryan, Gemma M., Kelly, Brian D., Haynes, John M., Williamson, Mark, Thienthong, Neeranat, Owen, David J., Porter, Christopher J.H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.06.2014
• Subjects: Administration, Inhalation; Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Delayed-Action Preparations; Dendrimer; Dendrimers - administration & dosage; Dendrimers - pharmacokinetics; Dendrimers - therapeutic use; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Delivery Systems; Drug Liberation; Female; Inhalation; Injections, Intravenous; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung metastases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Molecular Structure; Pharmacokinetics; Pulmonary; Rats, Inbred F344; Rats, Sprague-Dawley; Tissue Distribution; Lung metastases; Dendrimer; Pharmacokinetics; Pulmonary; Inhalation
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2014.03.012

Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10–13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30–50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity. [Display omitted]