Faculty Opinions recommendation of Optimization of liposomal topotecan for use in treating neuroblastoma.
Year: 2019
Type: peer-review
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-dis tearoyl-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.Doserange 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.
Author: Scott Kaufmann
Institution: Mayo Clinic
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4236079333