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Development of an optimized liposomal formulation of a camptothecin to improve treatment of neuroblastoma

University of British Columbia

Purpose: To develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Experimental design: Cytotoxic activity of both camptothecins (topotecan (Hycamtin) and irinotecan (Camptosar)) was determined against SK-N-SH; IMR-32 and LAN-1 neuroblastoma 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 using a method that relies on copper-drug complexation in combination with a transmembrane pH gradient. The influence of lipid composition and encapsulated drug-to-lipid ratio was assessed in-vitro in the presence and absence of serum. Dose-range finding studies were used to define maximum tolerated dose of the optimized liposomal formulation. Pharmacokinetic studies were completed to compare plasma elimination of topotecan following intravenous administration of the liposomal formulation or the currently used clinical product (Hycamtin). Studies were done in NRG mice bearing established subcutaneous tumours. The anti-tumour activity of the liposomal formulation was compared to Hycamtin when administered to NRG mice with established neuroblastoma tumours. Results: Topotecan was significantly more effective than irinotecan when used to treat neuroblastoma cell lines (as determined by IC50). Increased exposure time to topotecan further increased the drug potency against all neuroblastoma cell lines. In vitro studies showed that SM/Chol liposomes retained topotecan better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio from 0.1 to 0.025(mol: mol) engendered significant increase in drug retention. The optimized SM/Chol liposomal topotecan formulation exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC0-24h when compared to Hycamtin administered at equivalent doses. When administered at 5mg/kg, SM/Chol liposomal topotecan was significantly more effective than Hycamtin administered at 2-times the dose. The liposomal formulation increased the life span of mice by 50% for the systemic tumour model and by 87% for the subcutaneous models. Conclusion: Increased systemic drug exposure following administration of the optimized SM/Chol liposomal topotecan formulation produced superior response in subcutaneous and systemic models of neuroblastoma. In the future, this formulation will be assessed in combination with radiotherapy and immunotherapy treatment modalities currently used in neuroblastoma therapy.

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2016-07-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58465

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/