Liposomal Irinotecan

Abstract

Purpose:The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas.Experimental Design: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases.Results: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively.Conclusions: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

“…The liposomal lipid elimination rate was comparable to that described previously for DSPC/Chol liposomes. 31 These results suggest that Cu(DDC) 2 prepared inside DSPC/Chol liposomes does not remain inside the liposomes following iv dosing. This result was surprising given the stability of the formulation as determined using in vitro methods ( Figure 1).…”

The Potential and Challenges of siRNA-Based Targeted Therapy for Treatment of Patients with Glioblastoma

“…An orthotopic GBM pre-clinical study showed anti-vascular activity of doxorubicin when encapsulated in LNPs, and these effects were not observed with the free form of the drug or in normal brain tissue (Zhou et al, 2002). Other pre-clinical studies showed that liposomal formulations of irinotecan are more efficacious than the unencapsulated form in brain tumors (Krauze et al, 2007;Noble et al, 2006;Verreault et al, 2011b) and in colorectal and adenocarcinoma tumors (Hattori et al, 2009;Messerer et al, 2004;Ramsay et al, 2008). More specifically, our laboratory has established that Irinophore C TM (IrC TM ), a LPN formulation of irinotecan, exhibits improved anti-cancer efficacy compared to the free drug in a GBM orthotopic model (Verreault et al, 2011b).…”

Nanomedicine developments in the treatment of metastatic pancreatic cancer: focus on nanoliposomal irinotecan

“…Despite these theoretical advantages, prior liposomal formulations of irinotecan, as well as of other camptothecins (lurtotecan and SN-38, among others), have not necessarily shown improved pharmacokinetic characteristics or toxicity profiles compared to their free drug counterparts when evaluated in the preclinical setting. [32][33][34] …”