Irinophore C™, a lipid-based nanoparticulate formulation of irinotecan, is more effective than free irinotecan when used to treat an orthotopic glioblastoma model

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

“…Verreault et al showed that using a liposomal formulation of CPT-11 provided a 25% increase in CPT-11 in the brain and led to a significant increase in average survival (63.1 vs 58.3 days, after liposomal and normal formulation administration, respectively). 32 It has also been demonstrated that TMZ and CPT-11 are drug efflux transporter ABCB1 (P-glycoprotein) substrates that have been associated with higher TMZ and CPT-11 brain distribution in ABCB1-deficient mice. 9 Interestingly, the amount of increase in brain-toblood ratios obtained after BBB opening (1.37-fold and 2.70-fold higher after ultrasound for TMZ and CPT-11, respectively) were close to those obtained in ABCB1-deficient mice (1.1 and 2.1 for TMZ and CPT-11, respectively), suggesting that BBB opening reverses the effects of ABCB1 on drug brain distribution, which is of great interest in brain tumor treatment.…”

Irinophore C™, a lipid nanoparticulate formulation of irinotecan, improves vascular function, increases the delivery of sequentially administered 5-FU in HT-29 tumors, and controls tumor growth in patient derived xenografts of colon cancer

“…IrC™ therefore has immediate advantages over the free drug since the formulation reduces toxicity in the gut, while prolongation of the active lactone forms in liposomes helps increase exposure of the active drug to the tumor. Further studies in colorectal cancer and glioma tumor models further suggest that tumor perfusion and accumulation of a second drug is improved following treatment with IrC™ treatment [19][20][21]. Vascular changes in the glioma model also indicate that IrC™ treatment is associated with blood vessel normalization [21] .…”

“…This formulation makes more of the active lactone forms of irinotecan and SN-38 available over extended time periods in the blood, and the change in pharmacokinetics is associated with lower irinotecan toxicity and a significant increase in anti-tumor efficacy [16,17]. IrC™ is more efficacious than the free drug in several tumor models including colorectal cancer models [15,[18][19][20][21]. Irinotecan associated toxicities are markedly reduced in mice; doses equivalent to 350 mg/kg irinotecan in the liposomal form can be administered to immune competent mice without side-effects in contrast to a maximum tolerated dose (MTD) of only 80 mg/kg for free irinotecan [18].…”

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

“…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). We demonstrated that the presence in the brain of irinotecan and its active metabolite SN-38 is extended following administration of IrC™ compared to irinotecan.…”

“…Thus, IrC™ exerts a dual mechanism of action in GBM tumors. As described in section 8, the therapeutic activity of irinotecan is improved by the extended exposure of tumor cells to the drug provided by the drug carrier (Verreault et al, 2011b). Moreover, the effects of the formulation on the tumor micro-environment may increase the delivery and efficacy of a second agent (Verreault et al, 2011c).…”