Stefan Grudén1, Martin Sandelin2, Veera Rasanen3, Patrick Micke4, Mikael Hedeland5, Niklas Axén6, Marie Jeansson7. 1. LIDDS AB, Uppsala, Sweden. Electronic address: stefan.gruden@liddspharma.com. 2. Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden. Electronic address: martin.sandelin@medsci.uu.com. 3. Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: veera.rasanen.9072@student.uu.se. 4. Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: patrick.micke@igp.uu.se. 5. National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, Uppsala, Sweden; Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden. Electronic address: mikael.hedeland@sva.se. 6. LIDDS AB, Uppsala, Sweden. Electronic address: niklas.axen@liddspharma.com. 7. Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: marie.jeansson@igp.uu.se.
Abstract
BACKGROUND: Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed. METHODS: Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n=60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations. RESULTS: Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts. CONCLUSIONS: The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.
BACKGROUND:Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed. METHODS: Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n=60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations. RESULTS: Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts. CONCLUSIONS: The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.
Authors: Xiaoyu Lu; Min Fang; Yue Yang; Yu Dai; Jiaqiu Xu; Di Zhao; Yang Lu; Xijing Chen; Shan Lu; Ning Li Journal: Drug Deliv Transl Res Date: 2020-02 Impact factor: 4.617