Pharmacokinetic and pharmacodynamic evaluation of a novel in situ forming poly(ethylene glycol)-based hydrogel for the controlled delivery of the camptothecins

Inadequate drug delivery, due to problems associated with achieving constant therapeutic blood levels, has hampered the use of anticancer agents of the camptothecin (CPT) class. The objective of the current studies was to develop a depot delivery system for the water-soluble analog of CPT, topotecan...

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Bibliographic Details
Published in:Journal of controlled release 2006-05, Vol.112 (3), p.333-342
Main Authors: Lalloo, Anita, Chao, Piyun, Hu, Peidi, Stein, Stanley, Sinko, Patrick J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Camptothecin
Camptothecin - administration & dosage
Camptothecin - pharmacokinetics
Cell Line, Tumor
Cell Proliferation - drug effects
Controlled release
Delayed-Action Preparations - administration & dosage
Delayed-Action Preparations - pharmacokinetics
Drug Delivery Systems - methods
Drug Evaluation, Preclinical - methods
Female
General pharmacology
Hydrogel
Hydrogels - administration & dosage
Hydrogels - pharmacokinetics
Medical sciences
Neoplasm Transplantation
Pharmaceutical technology. Pharmaceutical industry
Pharmacokinetics
Pharmacology. Drug treatments
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - pharmacokinetics
Rats
Rats, Inbred F344
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Summary:Inadequate drug delivery, due to problems associated with achieving constant therapeutic blood levels, has hampered the use of anticancer agents of the camptothecin (CPT) class. The objective of the current studies was to develop a depot delivery system for the water-soluble analog of CPT, topotecan (TPT). In this study, a 2-phase drug depot consisting of TPT-loaded liposomes entrapped in a poly(ethylene glycol) hydrogel was designed. Physically entrapped unaltered TPT displayed a rapid release rate from the hydrogel. Controlled release was demonstrated in vitro and in vivo from the 2-phase system with constant blood levels being achieved for several days in rats. Cytotoxicity and antitumor activity were also evaluated in rats inoculated with syngeneic MAT B III breast cancer cells. Rats treated with the liposome-loaded hydrogel displayed significantly longer tumor growth suppression and did not exhibit body weight loss compared to those treated with other delivery modes. These experiments constitute a proof-of-principle of the 2-phase depot concept and its potential value for enhancing safety and efficacy in chemotherapy.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2006.03.002