Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors

Ramsay, Euan; Anantha, Malathi; Zastre, Jason; Meijs, Marieke; Zonderhuis, Jet; Strutt, Dita; Webb, Murray S.; Waterhouse, Dawn; Bally, Marcel B.

doi:10.1158/1078-0432.ccr-07-0780

Cited by 40 publications

(53 citation statements)

References 42 publications

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“…Mice were administered topotecan hydrochloride hydrate (Sigma) intraperitoneally at 10 mg/kg, irinotecan hydrochloride trihydrate (Hospira Canada) at 25 or 50 mg/kg i.v., or irinophore C (gift from Marcel Bally, Department of Experimental Therapeutics, BC Cancer Agency) also dosed at 50 mg/kg irinotecan i.v. (6). To label S-phase cells and tissue hypoxia, mice were administered 1,000 mg/kg bromodeoxyuridine (BrdUrd; Sigma-Aldrich) and 60 mg/kg pimonidazole by intraperitoneal injection 2 hours before tumor excision.…”

Section: Mice and Tumorsmentioning

confidence: 99%

“…Sample quantification was carried out on an Agilent 1260 Infinity HPLC using a mobile phase of 20% acetonitrile and 80% 50 mmol/L ammonium dihydrogen orthophosphate, pH 6.4, at 2 mL/minute, 40 C, and a Halo fused-core C18 column (50 Â 4.6 mm, 2.7 mm, Advanced Materials Technology). Of note, 10 mL injections were made and detection of open-and closed-ring conformations of the camptothecins was done using fluorescence excitation 375 nm, emission 425 nm (irinotecan, SN38), and 525 nm (topotecan) modified from published methods (6,36). Samples were processes and injected as they were being produced during the experiment.…”

Section: Camptothecin Media Stability and Cellular Accumulationmentioning

confidence: 99%

“…To date, two clinically approved analogues exist, topotecan and irinotecan, while there are currently efforts being made to develop a new generation of compounds that exhibit significantly longer systemic exposures (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…Irinophore C, a lipid-based nanoparticulate formulation of irinotecan with excellent preclinical efficacy, was included as being a representative of the next generation of high-molecular weight camptothecin derivatives and nanoformulations. In the case of irinophore C, acidified liposomes in the range of 40 nm are used as a drug carrier platform that produces sustained plasma levels over a period of 24 to 72 hours in mice (6). In contrast, the plasma half-lives in mice of topotecan and irinotecan are approximately 20 and 60 minutes, respectively (6,18), see Supplementary Table S1 for a summary of relevant physicochemical properties.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of irinophore C, acidified liposomes in the range of 40 nm are used as a drug carrier platform that produces sustained plasma levels over a period of 24 to 72 hours in mice (6). In contrast, the plasma half-lives in mice of topotecan and irinotecan are approximately 20 and 60 minutes, respectively (6,18), see Supplementary Table S1 for a summary of relevant physicochemical properties. These agents are designed to produce longer systemic exposures but it is unclear how effectively they will access the tumor compartment and it has been theorized that they might benefit from an enhanced permeability and retention (EPR) effect, theoretically exploiting the greater permeability of tumor vessels for selective delivery of large agents.…”

Section: Introductionmentioning

confidence: 99%

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Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

Kyle¹,

Baker

Gandolfo³

et al. 2014

Molecular Cancer Therapeutics

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The ability of a panel of camptothecin derivatives to access the tumor compartment was evaluated to determine the mechanisms by which the architecture of solid tumors may act to limit their activity. Microregional localization and activity of members of the camptothecin class of topoisomerase I targeting agents, including topotecan, irinotecan, and irinophore C, a lipid-based nanoparticulate formulation of irinotecan, were evaluated over time in HCT116 and HT29 colorectal tumor xenografts. Using native drug fluorescence, their distributions in tissue cryosections were related to the underlying tumor vasculature, tumor cell proliferation, and apoptosis. Topotecan exhibited a relatively uniform tumor distribution; in tissue 100 mm away from vessels, it reached 94% AE 5% of levels seen around blood vessels, whereas irinotecan and irinophore C were found to reach only 41% AE 10% and 5% AE 2%, respectively. Surprisingly, all three agents were able to initially inhibit proliferation uniformly throughout the tumors, and it was their rate of washout (topotecan > irinotecan > irinophore C) that correlated with activity. To explain this discrepancy, we looked at SN38, the active metabolite of irinotecan, and found it to penetrate tissue similarly to topotecan. Hence, the poor access to the tumor compartment of irinotecan and irinophore C could be offset by their systemic conversion to SN38. It was concluded that all three agents were effective at reaching tumor cells, and that despite the poor access to the extravascular compartment of irinophore C, its extended plasma exposure and systemic conversion to the diffusible metabolite SN38 enabled it to effectively target solid tumors.

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Section: Mice and Tumorsmentioning

confidence: 99%

Section: Camptothecin Media Stability and Cellular Accumulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

Kyle¹,

Baker

Gandolfo³

et al. 2014

Molecular Cancer Therapeutics

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Topophore C: a liposomal nanoparticle formulation of topotecan for treatment of ovarian cancer

et al. 2012

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We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein as Topophore C) and test its activity in pre-clinical model of ovarian carcinoma. Topotecan was encapsulated into preformed liposomes containing 300 mM copper sulfate and the divalent metal ionophore A23187. Formulation optimization studies included assessments of loading efficiency, influence of temperature on drug loading and in vitro stability of the resulting formulation. In vivo assessments included drug and liposome pharmacokinetics, drug levels within plasma and the peritoneal cavity following intravenous (i.v.) administration in mice and efficacy studies on ES2 ovarian cancer model. Topotecan loading into liposomes was optimized with encapsulation efficiency of >98 % at a final drug-to-lipid (D/L) mole ratio of 0.1. Higher D/L ratios could be achieved, but the resulting formulations were less stable as judged by in vitro drug release studies. Following Topophore C administration in mice the topotecan plasma half-life and AUC were increased compared to free topotecan by 10-and 22-fold, respectively. Topophore C was 2-to 3-fold more toxic than free topotecan, however showed significantly better anti-tumor activity than free topotecan administered at doses with no observable toxic effects. Topophore C is a therapeutically interesting drug candidate and we are particularly interested in developing its use in combination with liposomal doxorubicin for treatment of platinum refractory ovarian cancer.

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Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities

et al. 2014

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SummaryIrinotecan is a water-soluble camptothecin derivative with clinical activity against colorectal and small cell lung cancers and is currently a standard of care therapeutic in the treatment of colorectal cancer in combination with 5-fluorouracil. One of the major clinical issues limiting the use of irinotecan is gastrointestinal toxicity manifested as life-threatening diarrhea which is reported in up to 45 % of treated patients. The studies summarized here tested, in a rat model of irinotecan-associated gastro-intestinal toxicity, whether a lipid nanoparticle formulation of irinotecan, Irinophore C™, mitigated early-onset or late-onset diarrhea when given at doses equivalent to unformulated irinotecan that engenders both early- and late-onset diarrhea. Specifically, rats administered intravenously on two consecutive days with unformulated irinotecan at 170 mg/kg then 160 mg/kg experienced transient early-onset diarrhea after each administration and then experienced significant late-onset diarrhea peaking 4 days after treatment. Irinophore C™ given at the identical dose and schedule did not elicit either early- or late-onset diarrhea in any animals. When Irinophore C™ was combined with 5-fluorouracil there was also no early- or late-onset diarrhea observed. Histopathological analysis of the gastro-intestinal tract confirmed that the effects associated with irinotecan treatment were absent in rats given Irinophore C™ at the identical dose. Pharmacokinetic analysis demonstrated significantly higher systemic concentrations of irinotecan in rats given the nanoparticle formulation compared to those given unformulated irinotecan. These results demonstrate that the Irinophore C™ formulation is significantly less toxic than irinotecan, used either as a single agent or in combination with 5-fluorouracil, in a rat model of irinotecan-induced gastrointestinal toxicity.

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Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors

Abstract: Purpose: To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of

Cited by 40 publications

References 42 publications

Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

Tissue Penetration and Activity of Camptothecins in Solid Tumor Xenografts

Topophore C: a liposomal nanoparticle formulation of topotecan for treatment of ovarian cancer

Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities

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