title: Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy.
abstract: 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.
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC 3052, Australia. Electronic address: lisa.kaminskas@monash.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kaminskas
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC 3052, Australia.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: McLeod
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC 3052, Australia.
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Ryan
authors.affiliation: Starpharma Pty Ltd, 75 Commercial Rd, Melbourne VIC 3004, Australia.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kelly
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville VIC 3052, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Haynes
authors.affiliation: Gribbles Veterinary Pathology, 1868 Dandenong Rd, Clayton VIC 3168, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Williamson
authors.affiliation: Starpharma Pty Ltd, 75 Commercial Rd, Melbourne VIC 3004, Australia.
authors.forename: Neeranat
authors.initials: N
authors.lastname: Thienthong
authors.affiliation: Starpharma Pty Ltd, 75 Commercial Rd, Melbourne VIC 3004, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Owen
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Pde, Parkville, VIC 3052, Australia. Electronic address: chris.porter@monash.edu.
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D050091:Dendrimers / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D050091:Dendrimers; D004317:Doxorubicin
keywords: Dendrimer; Inhalation; Lung metastases; Pharmacokinetics; Pulmonary