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Optimization of liposomal topotecan for use in treating neuroblastoma.

ABSTRACT: 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.

SUBMITTER: Chernov L

PROVIDER: S-EPMC5463073 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Optimization of liposomal topotecan for use in treating neuroblastoma.

Chernov Lina L Deyell Rebecca J RJ Anantha Malathi M Dos Santos Nancy N Gilabert-Oriol Roger R Bally Marcel B MB

Cancer medicine 20170523 6

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 ...[more]

PMID: 28544814

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Project description:The use of liposomal delivery systems for the treatment of cancer has been extensively researched because of their passive targeting to the vasculature of solid tumors. While their potential to provide prolonged retention and high drug encapsulation is desirable for anticancer agents, a mechanistic understanding is required to optimize and design liposomal drug delivery systems capable of controllable release tailored to tumor type and patient. Topotecan (TPT) is a topoisomerase I inhibitor that undergoes reversible, pH-sensitive ring-opening hydrolysis. TPT may benefit from liposomal formulation using active loading strategies to generate low intravesicular pH to prolong drug retention and increase drug encapsulation. This paper develops a mathematical model to describe TPT's permeability as a function of pH by accounting for the drug's ionization state, membrane binding, and ring-opening interconversion kinetics. Studies were conducted to determine the acid dissociation constant of TPT's phenolic -OH and interconversion kinetics between TPT's lactone and carboxylate forms. Using the constants determined from these studies and release studies conducted at varying pH, permeability coefficients and membrane binding constants for each species of TPT were determined. Based on this model, three permeable species were observed. Interestingly, the two most permeable species were zwitterionic forms of TPT, and the permeability of the lactone zwitterion was comparable to that of the neutral form of another camptothecin analogue. Furthermore, release was affected by based-catalyzed interconversion kinetics between TPT's lactone and carboxylate forms. At neutral pH, release was rate-limited by formation of the TPT lactone from the ring-opened carboxylate form. Based on these findings, the developed model describing liposomal release of TPT may be used in the future to evaluate and optimize loading and subsequent release of liposomal TPT formulations utilizing active loading strategies.

Dataset Information

Optimization of liposomal topotecan for use in treating neuroblastoma.

Publications

Optimization of liposomal topotecan for use in treating neuroblastoma.

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