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  • Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy.

Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy.

Cancer research (2006-03-17)
Daryl C Drummond, Charles O Noble, Zexiong Guo, Keelung Hong, John W Park, Dmitri B Kirpotin
ABSTRACT

Liposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with unprecedented drug loading efficiency and in vivo drug retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, either polymeric (polyphosphate) or nonpolymeric (sucrose octasulfate), liposomes were capable of entrapping CPT-11 at extremely high drug-to-lipid ratios (>800 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release in the circulation of 56.8 hours. CPT-11 was also protected from hydrolysis to the inactive carboxylate form and from metabolic conversion to SN-38 while circulating. The maximum tolerated dose in normal mice was determined to be 80 mg/kg for free CPT-11 and >320 mg/kg for nanoliposomal CPT-11. Nanoliposomal CPT-11 showed markedly superior efficacy when compared with free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models. This study shows that intraliposomal stabilization of CPT-11 using a polymeric or highly charged, nonpolymeric polyanionic trapping agent results in a markedly active antitumor agent with low toxicity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
NanoFabTX-DOTAP Lipid Mix, for synthesis of cationic (DOTAP) liposomes
Sigma-Aldrich
NanoFabTx- COOH Lipid Mix, for synthesis of carboxyl functionalized liposomes
Sigma-Aldrich
NanoFabTX- NH2 Lipid Mix, for synthesis of amine functionalized liposomes
Sigma-Aldrich
NanoFabTx-DC-Chol Lipid Mix, for synthesis of cationic (DC-cholesterol) liposomes
Sigma-Aldrich
NanoFabTx - PEG Lipid Mix, for synthesis of PEGylated liposomes