Innovative cancer therapeutics based on polymers or biogenic drugs evaluated in murine tumor models

Schreiner, Laura (2013): Innovative cancer therapeutics based on polymers or biogenic drugs evaluated in murine tumor models. Dissertation, LMU München: Faculty of Veterinary Medicine

Abstract

Cancer is a leading cause of death worldwide. Although several common treatment options exist, there is an urgent need for improved tumor therapeutics. Therefore, we evaluated three innovative anticancer approaches in vivo. These were newly synthesized siRNA polyplexes, novel myxobacterial anticancer compounds, and innovative polymeric melphalan formulations. We evaluated the in vivo characteristics of polymeric bound siRNA. We could demonstrate that the polymer FolA-PEG24-K(Stp4-C)2 is an efficient carrier for targeting siRNA to the folate receptor expressing tumor tissue of mice. Moreover, the siRNA was able to enter tumor cells and led to specific gene silencing. After systemic injection, the polyplexes did neither cause any toxic side effects nor accumulate in any healthy organ. With only 6 nm average diameter, polyplexes were very small, resulting in fast removal from blood circulation by renal clearance. Addition of larger PEG spacers to the initial polyplex led to an increased polyplex size. As a result, the renal clearance was decreased, and polyplex distribution in the body was optimized. These results show that the in vivo hurdles of siRNA delivery can be overcome by binding siRNA to the precise and multifunctional polymers. Natural compounds have broad therapeutic effects, and are basis for the production of various anticancer drugs. Myxobacterial products often target cell structures which are rarely targeted by other metabolites, and they exert novel modes of action. Therefore, they are of particular importance for the development of new anticancer drugs. In this thesis, we evaluated three novel myxobacterial compounds in vivo. Within our experimental settings, we could demonstrate for the first time that archazolid, pretubulysin and chondramide can impair the migration and colonization of breast cancer cells in mice. Concerning their impact on tumor growth reduction, the compounds have promising characteristics, but the experimental setups need further improvement. Cytostatic drugs, like melphalan play an important role in cancer therapy, but bear problems, such as a low therapeutic efficacy and strong toxic side effects. Immobilization of chemotherapeutics on polymers is an interesting option to reduce their toxicity and enhance their efficacy, mainly by passive tumor targeting. We evaluated three innovative polymer-melphalan formulations in cell viability and proliferation assays. The covalent conjugate of poly(oxyethylene H-phosphonate) with melphalan was additionally investigated in vivo. This polymeric immobilization of melphalan led to an improved therapeutic effect compared to the pure cytostatic drug, as the growth and regrowth of HuH7 tumors could be hampered effectively. In conclusion, this thesis deals with the in vivo evaluation of innovative cancer therapeutics, which were successfully investigated in murine tumor models. The results with the experimental agents, based on siRNA, polymers or biogenic drugs, are encouraging starting points for further anticancer research.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: cancer therapeutics, siRNA therapy, myxobacterial compounds, polymer-melphalan conjugates
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 590 Zoological sciences
• Faculties: Faculty of Veterinary Medicine
• Language: English
• Date of oral examination: 9. February 2013
• 1. Referee: Wolf, Eckhard
• Signature of the printed copy: 0001/UMC 21183