Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 549, Issue 1-2, Pages 352-362Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2018.08.010
Keywords
Solid lipid nanoparticles; Oral administration; Reduction-response; Lipid-drug conjugate; Camptothecin
Categories
Funding
- Major National Science and Technology Program of China for Innovative Drug [2017ZX09101002-001-004]
- National Natural Science Foundation of China, China [51373034]
- Special Fund for Transformation of Scientific and Technological Achievements by the Department of Science & Technology of Jiangsu Province, China [BA2017089]
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Camptothecin (CPT) is an important topoisomerase I enzyme (Topo I) targeting anti-cancer drug, but its oral administration is limited by poor bioavailability and severe side effects. In this study, a redox sensitive CPT prodrug loaded solid lipid nanoparticles (SLN) system for oral delivery was developed. First of all, CPT-palmitic acid conjugate via a cleavable disulfide bond linker (CPT-SS-PA) was synthesized and encapsulated into SLN. The drug release of SLN was evaluated in neutral environment, simulated gastrointestinal fluid and reductive solution. The results indicated that CPT-SS-PA SLN maintained chemical structural stability in simulated physiological environment but exhibited quick reduction-response release of CPT in the presence of dithiothreitol. Furthermore, in vitro cytotoxicity of CPT-SS-PA SLN was tested against cancer cell lines, and the cellular uptake behavior for oral delivery was checked by confocal laser scanning microscopy (CLSM) using Caco-2 cells model. From the data, CPT-SS-PA SLN revealed high anti-cancer activity and enhanced Caco-2 cell absorption. Finally, the oral bioavailability and intestinal safety of CPT-SS-PA SLN were preliminary evaluated by in vivo pharmacokinetic and histopathological study, respectively. This study demonstrated that CPT-SS-PA SLN could be developed as an effective CPT oral delivery system due to its enhanced oral bioavailability and reduced intestinal side effect.
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