Abstract/Details

Respiratory delivery of 5-fluorouracil for the treatment of lung cancer


2005 2005

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Abstract (summary)

Lung cancer is the leading cause of cancer death in the U.S. in both men and women. While 5-fluorouracil (5-FU) is an effective chemotherapeutic agent, it is not used in lung cancer because of its high toxicity and unfavorable pharmacokinetics. Nevertheless, preliminary reports suggest inhalation of 5-FU is effective in the chemotherapy/chemoprevention of squamous cell carcinoma. In these studies, the delivery of 5-FU at a high dose/short duration is efficacious through incorporation into DNA and RNA. We postulated that 5-FU would also be effective if delivered by inhalation at a low dose/long duration through inhibition of DNA synthesis, while altering the type and severity of common side effects. To identify a delivery system to test this hypothesis, a microdialysis procedure was developed to evaluate the release of 5-FU from microcarriers that could be delivered to the lung by inhalation. Thereafter, drug release profiles were obtained from liposomes, microspheres and lipid coated nanoparticles (LNPs). The liposome systems released 5-FU in 6 hours or less, microsphere systems ranged from 6 to 30 hours, and LNPs ranged from 4 to 28 hours. Based on these results, a 600-nm diameter 5-FU/poly-(glutamic acid) core with a 200-nm thick tripalmitin/cetyl alcohol shell was chosen for further evaluation. An aerosol of LNPs was generated by ultrasonic nebulization coupled with an innovative reflux drying process, which is a time independent method that is ideal for aerosol exposure of large groups of rodents. The deposition and distribution of 5-FU from the microcarrier was determined in the Syrian Golden hamster model. The inhaled dose, 1.5 mg/kg 5-FU (30 mg LNPs/kg body weight), was delivered over an 8-minute interval. The concentration of LNPs and total 5-FU (released and LNP-associated) was determined as a function of time in the lung, trachea, larynx, esophagus, and serum. Within 24 hours, 99% of the LNPs were cleared from the respiratory tract. Total 5-FU concentrations mirrored the LNP concentration. An eight-compartment pharmacokinetic model was used to estimate the released 5-FU concentrations. From this analysis, effective local targeting as well as sustained efficacious concentrations of 5-FU in the expected tumor sites were demonstrated.

Indexing (details)


Subject
Pharmaceuticals;
Pharmacology;
Oncology
Classification
0572: Pharmaceuticals
0491: Pharmacology
0992: Oncology
Identifier / keyword
Health and environmental sciences; Pure sciences; Chemotherapy; Fluorouracil-5; Lung cancer; Respiratory delivery
Title
Respiratory delivery of 5-fluorouracil for the treatment of lung cancer
Author
Hitzman, Cory James
Number of pages
226
Publication year
2005
Degree date
2005
School code
0130
Source
DAI-B 66/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542386411, 0542386410
Advisor
Wiedmann, Timothy Scott
University/institution
University of Minnesota
University location
United States -- Minnesota
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3194324
ProQuest document ID
305482495
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305482495
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