Improving the Delivery of Camptothecin through the Blood-Brain Barrier via Modulation of Paracellular Pathway using E-Cadherin Peptide
Issue Date
2014-12-31Author
Tabanor, Kayann
Publisher
University of Kansas
Format
31 pages
Type
Thesis
Degree Level
M.S.
Discipline
Chemistry
Rights
Copyright held by the author.
Metadata
Show full item recordAbstract
The successful treatments of brain tumors and many other brain disorders have been limited due to the presence of barricade from microvascular endothelium called the blood-brain barrier (BBB). It was estimated that over 98% of newly developed pharmaceutical drugs do not cross the BBB; therefore, it is necessary to develop methods to improve the delivery of drugs to the brain. In this investigation, we evaluated the ability of HAV6 peptide (Ac-SHAVSS-NH2) to improve the paracellular transport of Camptothecin-glutamate (CPT-Glu) across the BBB using an in-situ rat brain perfusion model. CPT-Glu was synthesized through conjugation between an anti-cancer drug camptothecin (CPT) and L-glutamic acid via an ester bond to improve its solubility. A perfusate containing CPT-Glu (10 mg/kg) and 1.0 mM HAV6 peptide was delivered to the brain of anesthetized Sprague Dawley rats using the in-situ brain perfusion technique. Accumulation in the brain was determined through acidic extraction of CPT-Glu and its hydrolyzed product CPT from harvested brain, followed by detection using LC-MS/MS. The extraction and LC-MS/MS detection methods have been successfully developed to detect 0.25 and 17 ng/mL CPT and CPT-Glu respectively. Both CPT-Glu and CPT were successfully detected in the rat brains after in-situ brain perfusion in the absence and presence of HAV6 peptide. Rats perfused with CPT-Glu in combination with HAV6 had higher deposition of drug in the brain compared to CPT-Glu alone. The HAV6 treated rats had 650.85 ng of CPT equivalent delivered per gram of brain (1.30-fold) compared to 498.40 ng/g in control. The results also showed that CPT-Glu conjugate was hydrolyzed to CPT in the brain after delivery. In future studies, HAV6 peptide perfusion time will be extended for receptor saturation to promote effective BBB opening. The concentration of CPT-Glu will be increased to enhance delivery and improve detection in the brain.
Collections
- Chemistry Dissertations and Theses [335]
- Theses [3906]
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.