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Optimization of liposomal topotecan for use in treating neuroblastoma

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 neuroblast...

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Autores principales: Chernov, Lina, Deyell, Rebecca J., Anantha, Malathi, Dos Santos, Nancy, Gilabert‐Oriol, Roger, Bally, Marcel B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463073/
https://www.ncbi.nlm.nih.gov/pubmed/28544814
http://dx.doi.org/10.1002/cam4.1083
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author Chernov, Lina
Deyell, Rebecca J.
Anantha, Malathi
Dos Santos, Nancy
Gilabert‐Oriol, Roger
Bally, Marcel B.
author_facet Chernov, Lina
Deyell, Rebecca J.
Anantha, Malathi
Dos Santos, Nancy
Gilabert‐Oriol, Roger
Bally, Marcel B.
author_sort Chernov, Lina
collection PubMed
description 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‐distearoyl‐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. Dose‐range 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.
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spelling pubmed-54630732017-06-09 Optimization of liposomal topotecan for use in treating neuroblastoma Chernov, Lina Deyell, Rebecca J. Anantha, Malathi Dos Santos, Nancy Gilabert‐Oriol, Roger Bally, Marcel B. Cancer Med Clinical Cancer Research 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‐distearoyl‐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. Dose‐range 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. John Wiley and Sons Inc. 2017-05-23 /pmc/articles/PMC5463073/ /pubmed/28544814 http://dx.doi.org/10.1002/cam4.1083 Text en © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Cancer Research
Chernov, Lina
Deyell, Rebecca J.
Anantha, Malathi
Dos Santos, Nancy
Gilabert‐Oriol, Roger
Bally, Marcel B.
Optimization of liposomal topotecan for use in treating neuroblastoma
title Optimization of liposomal topotecan for use in treating neuroblastoma
title_full Optimization of liposomal topotecan for use in treating neuroblastoma
title_fullStr Optimization of liposomal topotecan for use in treating neuroblastoma
title_full_unstemmed Optimization of liposomal topotecan for use in treating neuroblastoma
title_short Optimization of liposomal topotecan for use in treating neuroblastoma
title_sort optimization of liposomal topotecan for use in treating neuroblastoma
topic Clinical Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463073/
https://www.ncbi.nlm.nih.gov/pubmed/28544814
http://dx.doi.org/10.1002/cam4.1083
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