Novel injectable calcium sulfate depot formulations for local cancer treatment

Sammanfattning: In the present thesis, a novel drug delivery technology named NanoZolid® based on hydrating inorganic calcium sulfate, is investigated. NanoZolid is injected as a liquid suspension of calcium sulfate, which solidifies in vivo by hydration forming a biocompatible and bioresorbable depot that slowly dissolves and releases the active substance. In order to optimize the formulation and preparation procedure of NanoZolid, we have characterized the material properties of calcium sulfate and its influence on drug release. In paper I, the in vitro release of the antiandrogen, 2-hydroxyflutamide (2-HOF) was investigated using formulations containing porous and densified drug-loaded powder fractions. The formulations were produced for the local long-term treatment of prostate cancer. The densified powder fractions were prepared utilizing cold isostatic pressing (CIP), a new process introduced into the pharmaceutical industry. Reproducible in vitro release profiles were achieved from solidified depots with a drug release time of at least five months. Calcium sulfate-based drug product candidates were evaluated in both preclinical and clinical settings. A xenograft mouse model of Lewis lung carcinoma (LLC) was used in paper II for evaluating intratumorally injected depots loaded with docetaxel. The study showed similar antitumor effects from the local depots, as from the systemic administration of docetaxel. Adverse effects including decreased levels of blood cells and weight loss were observed in mice treated with intraperitoneal administration, while not in mice that received intratumor depots. In addition, no adverse tissue reactions were observed from the depot. In Paper III, we evaluated the possibility of encapsulating a biomolecule in the NanoZolid as a drug delivery system. Both in vivo solidification process to a depot and in vivo slow release of the biomolecule, epidermal growth factor (EGF), were studied using a mouse xenograft model inoculated subcutaneously with A549 human lung cancer cells. A fluorescence-labelled EGF was encapsulated into the NanoZolid depot that was injected subcutaneously in the neck. Results showed that the EGF released in vivo targeted the corresponding tumor receptors on the hind leg with a slow-release pattern and maintained its bioactivity. To better understand the potential of intraprostatic depot injections with the antiandrogen 2- HOF, the effects of the new formulations on prostate specific antigen (PSA), prostate volume, testosterone levels and local tissue reactions, were investigated in a multicenter clinical trial (paper IV). The study included sixty-one men with localized prostate cancer who received intraprostatic depot injections (Liproca® Depot). The treatment was well tolerated and showed potential for long-term suppression of the tumor – as indicated by a decrease in PSA value, lower prostate volume and unchanged or improved MRI results in the majority of the patients. In conclusion, the present results show that the calcium sulfate-based drug delivery system, NanoZolid, is a promising approach for local cancer treatment, and may benefit both individual patients and society as a whole

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.