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Optimization of liposomal topotecan for use in treating neuroblastoma
Lina Chernov1,2, Rebecca J Deyell3,4, Malathi Anantha1
1Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.
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 AUC0-24 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.
Insights
This study optimized liposomal topotecan for neuroblastoma, improving drug retention and tolerability in mice. While extending drug exposure, further formulation enhancements are needed for greater therapeutic impact.
Area of Science:
- Oncology
- Nanotechnology
- Pharmacology
Background:
- Neuroblastoma is a pediatric cancer with limited treatment options.
- Topotecan (Hycamtin) shows cytotoxic activity against neuroblastoma cell lines.
- Liposomal drug delivery systems offer potential for improved cancer therapy.
Purpose of the Study:
- To develop and optimize a liposomal formulation of topotecan for neuroblastoma treatment.
- To evaluate the in vitro and in vivo performance of the optimized liposomal topotecan.
Main Methods:
- Liposomes (SM/Chol and DSPC/Chol) were prepared and loaded with topotecan.
- In vitro drug retention studies were conducted.
- Dose-range finding and pharmacokinetic studies were performed in NRG mice.
Main Results:
- Sphingomyelin/cholesterol liposomes showed superior topotecan retention compared to DSPC/cholesterol liposomes.
- Optimized SM/Chol liposomes (0.025 drug-to-lipid ratio) were better tolerated in mice.
- Liposomal topotecan demonstrated a 10-fold increase in plasma half-life and a 1000-fold increase in AUC0-24h compared to Hycamtin.
Conclusions:
- The optimized liposomal topotecan formulation enhances drug exposure but shows modest improvements in lifespan for neuroblastoma-bearing mice.
- Further optimization of liposomal topotecan is warranted.
- Future studies will explore combinations with radiotherapy and immunotherapy.
