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 131I‐metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy.
Highlights
Neuroblastoma is the third leading cause of childhood cancer-related mortality and is the most common and the deadliest pediatric extracranial solid tumor [1]
The activity of topotecan is highly dependent on exposure time and this is illustrated by the data summarized in Figure 1B and 1C
The antitumor activity of topotecan administered (i.v., Q7D × 3) as the SM/Chol liposomal formulation or Hycamtin was evaluated and the results, summarized in Figure 5, indicated in both models that the therapeutic activity of the SM/Chol liposomal topotecan was greater than Hycamtin when given at two-times the dose
Summary
Neuroblastoma is the third leading cause of childhood cancer-related mortality and is the most common and the deadliest pediatric extracranial solid tumor [1]. It is a cancer of the sympathetic nervous system, and arises from the sympathoadrenal lineage of the neuronal crest [1, 2]. Neuroblastoma is primarily sporadic with less than 2% of cases having a familial origin [1, 3]. Recent genome-wide association studies suggest that common, low-penetrance germline polymorphisms may predispose children to developing neuroblastoma, even in sporadic cases [4]. 500–700 new patients are diagnosed every year in North America; more than 50% have a high-risk disease who present with widespread metastases and have poor survival outcomes despite intensive, multi-modality approaches to therapy
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