Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy
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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 56 kDa 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 24 h) 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 7 days, 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 2 weeks 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 within several 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.