Development of a Highly Active Nanoliposomal Irinotecan Using a Novel Intraliposomal Stabilization Strategy

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. (Cancer Res 2006; 66(6): 3271-7)

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…Nanoliposomal irinotecan (nal-IRI; Onivyde, irinotecan liposome injection, MM-398, PEP02, BAX2398) comprises irinotecan encapsulated in a nanoparticle drug delivery system in the form of the irinotecan sucrose octasulfate salt with an average particle size of 110 nm (10,11). Nal-IRI in combination with 5-fluorouracil/ leucovorin (5-FU/LV) is approved for use in the United States, European Union, and Taiwan Health Authorities for the treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy (11,12).…”

High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile

“…Interestingly, the normal brain has been found to have a low concentration which may be beneficial, assuming that liposomes accumulate in brain tumors via leakage from malformed tumor microvasculature, as demonstrated by Munson et al 51 We explored a gradient-based method owing to its simplicity and efficient loading. 52,53 Earlier gradient loading studies reported that liposomal uptake of drugs was driven by neutral external pH and low internal pH. We tested this and other pH profiles in an effort to optimize loading and, for the first time, describe enhancement of loading by reversing the gradient profile, so that external pH was low while internal pH was neutral (Figure 1).…”

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

“…Additional therapeutic advances are expected from studies evaluating strategies for depletion stromal, inhibition pathways of cancer (i.e., Hedgehog, RAS-RAF-MAPK and PI3K-AKT), new chemotherapeutic drugs (i.e., MM-398 irinotecan encapsulated into liposomal-based nano particles) [65,66] , or the new era of immunotherapy. The identification of biomarkers continues to be clinically challenging but essential in order to tailor therapy to specific patients' subgroups in which the maximal antitumour effect from novel agents can be obtained.…”