title: Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy.
abstract: We hypothesized that combining convection-enhanced delivery (CED) with a novel, highly stable nanoparticle/liposome containing CPT-11 (nanoliposomal CPT-11) would provide a dual drug delivery strategy for brain tumor treatment. Following CED in rat brains, tissue retention of nanoliposomal CPT-11 was greatly prolonged, with >20% injected dose remaining at 12 days for all doses. Tissue residence was dose dependent, with doses of 60 microg (3 mg/mL), 0.8 mg (40 mg/mL), and 1.6 mg (80 mg/mL) resulting in tissue half-life (t(1/2)) of 6.7, 10.7, and 19.7 days, respectively. In contrast, CED of free CPT-11 resulted in rapid drug clearance (tissue t(1/2) = 0.3 day). At equivalent CED doses, nanoliposomal CPT-11 increased area under the time-concentration curve by 25-fold and tissue t(1/2) by 22-fold over free CPT-11; CED in intracranial U87 glioma xenografts showed even longer tumor retention (tissue t(1/2) = 43 days). Plasma levels were undetectable following CED of nanoliposomal CPT-11. Importantly, prolonged exposure to nanoliposomal CPT-11 resulted in no measurable central nervous system (CNS) toxicity at any dose tested (0.06-1.6 mg/rat), whereas CED of free CPT-11 induced severe CNS toxicity at 0.4 mg/rat. In the intracranial U87 glioma xenograft model, a single CED infusion of nanoliposomal CPT-11 at 1.6 mg resulted in significantly improved median survival (>100 days) compared with CED of control liposomes (19.5 days; P = 4.9 x 10(-5)) or free drug (28.5 days; P = 0.011). We conclude that CED of nanoliposomal CPT-11 greatly prolonged tissue residence while also substantially reducing toxicity, resulting in a highly effective treatment strategy in preclinical brain tumor models.
authors.affiliation: Division of Hematology/Oncology, University of California at San Francisco, California 94115, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Michal T
authors.initials: MT
authors.lastname: Krauze
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Drummond
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: John W
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D049329:Nanostructures / Q000737:chemistry / Q000633:toxicity; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D010743:Phospholipids; D000077146:Irinotecan; D002166:Camptothecin