Oral delivery of camptothecin using cyclodextrin/poly(anhydride) nanoparticles.
Camptothecin (CPT), a molecule that shows powerful anticancer activity, is still not used in clinic due to its high hydrophobicity and poor active form's stability. In order to solve these drawbacks, the combination between poly(anhydride) nanoparticles and cyclodextrins was evaluated. CPT-loaded nanoparticles, prepared in the presence of 2-hydroxypropyl-β-cyclodextrin, (HPCD-NP) displayed a mean size close to 170nm and a payload of 50μg per mg (25 times higher than the one of the control nanoparticles). CPT was not released from nanoparticles under gastric conditions. However, under intestinal conditions, about 50% of the drug content was released as a burst, whereas the remained drug was released following a zero-order kinetic. Pharmacokinetic studies revealed that the CPT plasma levels, from orally administered nanoparticles, were high and sustained up to 48h. The CPT oral bioavailability was 7-fold higher than the value obtained with the control, whereas its clearance was significantly lower than for the aqueous suspension. These observations may be directly related to a prolonged residence time of nanoparticles in close contact with the intestinal epithelium, the presence of the cyclodextrin that decreases the CPT transformation into its inactive form and the generation of an acidic microenvironment during the degradation of the poly(anhydride) that would prevent the transformation of the active lactone into the inactive carboxylate conformation.
Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain.
Judit
J
Huarte
Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain.
Socorro
S
Espuelas
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
Yusi
Y
Lai
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
Bin
B
He
School of Pharmacy, University of Wolverhampton, Wolverhampton, UK.
James
J
Tang
Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain. Electronic address: jmirache@unav.es.
Juan M
JM
Irache
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage* / Q000378:metabolism; D003505:Cyclodextrins / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D049388:Polyanhydrides / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
D003505:Cyclodextrins; D004337:Drug Carriers; D049388:Polyanhydrides; D002166:Camptothecin
2-Hydroxypropyl-β-cyclodextrin (PubChem CID: 44134771); Camptothecin; Camptothecin (PubChem CID: 24360); Cyclodextrins; Gantrez AN (PubChem CID: 62708); Methyl-β-cyclodextrin (PubChem CID: 51051622); Nanoparticles; Oral delivery; β-Cyclodextrin (PubChem CID: 444041)