The Role of the Transition Metal Copper and the Ionophore A23187 in the Development of Irinophore C™

Patankar, Nilesh A.; Anantha, Malathi; Ramsay, Euan; Waterhouse, Dawn; Bally, Marcel B.

doi:10.1007/s11095-010-0340-2

Cited by 11 publications

(4 citation statements)

References 31 publications

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“…Previous studies suggested that drug retention can increase in formulations exhibiting higher drug‐to‐lipid ratios; an effect thought to be due to drug precipitation within the liposome core . For the loading method described here, however, it can be suggested that faster drug release rates would be associated with loss of the transmembrane pH gradient as well as loss of encapsulated copper which is known to complex topotecan and affect drug retention. Consequently, it can be suggested that increased internal copper levels and minimal dissipation of the pH gradient could result in improved drug retention.…”

Section: Resultsmentioning

confidence: 99%

Optimization of liposomal topotecan for use in treating neuroblastoma

et al. 2017

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The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-dis tearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Doserange finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/ Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. Cancer Medicine Open Access 1241

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Section: Resultsmentioning

confidence: 99%

Optimization of liposomal topotecan for use in treating neuroblastoma

et al. 2017

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“…From previous reports, it is found that metal ions, such as Cu 2+ , Pt 2+ and Ce 4+ , can mediate effective loading of doxorubicin, topotecan and irinotecan, which is based on the complexation of drugs with metal ions. [7][8][9][10] Among them, we find that (i) Cu 2+ could mediate an effective and stable encapsulation of doxorubicin; 11 (ii) Cu 2+ may form a complex with Dox at a neutral pH and separate at an acidic pH, resulting in controlled release of Dox; 4,12 (iii) Cu 2+ has strong influences on the drug release rate, toxicity and efficacy. 11,13,14 Thus, the pH-sensitive CuDox precipitates within liposomes could retain the drug stability in circulation and reduce the toxicity; their application and development, however, are vastly limited due to slow release of the encapsulated drug.…”

Section: Introductionmentioning

confidence: 99%

A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper–doxorubicin complex and gold nanorods

Liu

Pang

et al. 2015

Nanoscale

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The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability during blood circulation and trigger Dox release in the tumor site. Synergistically, we also rationally applied gold nanorods (AuNRs) coupled with near-infrared (NIR) field strength to produce a precise and localized temperature, which not only remotely controlled the drug release but also directly destroyed the tumor, to enhance the therapeutic efficacy. As expected, the in vitro release studies showed that the drug release from CuDox-TSLs (Copper ion mediated Doxorubicin loading-Temperature Sensitive Liposomes) was both pH-dependent and temperature-dependent. Furthermore, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assays showed that CuDox-TSLs combined with AuNRs exhibited a closer antiproliferative activity to free Dox in MCF-7 cells. The efficient intracellular Dox release from CuDox-TSLs toward the tumor cells further confirmed the anti-tumor effect. Moreover, the in vivo imaging and biodistribution studies revealed that CuDox-TSLs combined with AuNRs could actively target the tumor site. In addition, the therapeutic studies in MCF-7 nude mice exhibited CuDox-TSLs plus AuNRs in combination with NIR irradiation inhibited tumor growth to a great extent and possessed much lower side effects, which were further confirmed by systemic histological analyses. All detailed evidence suggested a considerable potential of CuDox-TSLs combined with AuNRs for treatment of metastatic cancer.

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“…IRI is entrapped in the acidic aqueous interior of the liposomes when a pH gradient is generated in the presence of the divalent metal ionophore A23187, which is required for the stability and maintenance of the pH gradient [21], [26]. The combination of the ionophore-generated pH gradient, together with the presence of encapsulated Cu 2+ , results in excellent drug retention properties for the formulation in vivo [26], [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Treatment of Colorectal Cancer Using a Combination of Liposomal Irinotecan (Irinophore C™) and 5-Fluorouracil

et al. 2013

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PurposeTo investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer.Experimental DesignThe effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU.ResultsThe cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg).ConclusionsSingle agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.

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The Role of the Transition Metal Copper and the Ionophore A23187 in the Development of Irinophore C™

Abstract: Results explain why irinotecan loading rates are enhanced in the presence of formulations prepared with copper, and we speculate that the Irinophore C formulation exhibits improved drug retention, due to generation of a complex between copper and irinotecan.

Cited by 11 publications

References 31 publications

Optimization of liposomal topotecan for use in treating neuroblastoma

Optimization of liposomal topotecan for use in treating neuroblastoma

A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper–doxorubicin complex and gold nanorods

Treatment of Colorectal Cancer Using a Combination of Liposomal Irinotecan (Irinophore C™) and 5-Fluorouracil

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