Pulmonary targeting microparticulate camptothecin delivery system: anticancer evaluation in a rat orthotopic lung cancer model.

Abstract:

:Large (>6 microm) rigid microparticles (MPs) become passively entrapped within the lungs after intravenous (i.v.) injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In this study, PEGylated 6 microm polystyrene MPs with multiple copies of the norvaline (Nva) alpha-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope. CPT was released from the CPT-Nva-MPs over 24 h in rat plasma at 37 degrees C. In-vivo CPT plasma concentrations were low (approximately 1 ng/ml or less) and constant over a period of 4 days after a single i.v. injection of CPT-Nva-MPs as compared with high but short-lived systemic exposures after an i.v. injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anticancer efficacy was evaluated in an orthotopic lung cancer animal model and compared with a bolus injection of CPT. Animals receiving free CPT (2 mg/kg) and CPT-Nva-MPs (0.22 mg/kg CPT and 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05 and 0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was 10 times lower than after i.v. injection of free CPT, but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was 10 times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Chao P,Deshmukh M,Kutscher HL,Gao D,Rajan SS,Hu P,Laskin DL,Stein S,Sinko PJ

doi

10.1097/CAD.0b013e328332a322

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

65-76

issue

1

eissn

0959-4973

issn

1473-5741

pii

00001813-201001000-00007

journal_volume

21

pub_type

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