Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel.
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.
LIDDS AB, Uppsala, Sweden. Electronic address: stefan.gruden@liddspharma.com.
Stefan
S
Grudén
Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden. Electronic address: martin.sandelin@medsci.uu.com.
Martin
M
Sandelin
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: veera.rasanen.9072@student.uu.se.
Veera
V
Rasanen
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: patrick.micke@igp.uu.se.
Patrick
P
Micke
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.
Mikael
M
Hedeland
LIDDS AB, Uppsala, Sweden. Electronic address: niklas.axen@liddspharma.com.
Niklas
N
Axén
Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: marie.jeansson@igp.uu.se.
Marie
M
Jeansson
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology* / Q000633:toxicity; D002133:Calcium Sulfate / Q000737:chemistry*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D000077143:Docetaxel; D004339:Drug Compounding; D005079:Excipients; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology* / Q000633:toxicity
D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D043823:Taxoids; D000077143:Docetaxel; D002133:Calcium Sulfate
Bioresorbable; Calcium sulfate; Docetaxel; Intratumoral; Lewis lung carcinoma; Non-small cell lung cancer; Slow release formulation