Bisphosphonatliganden für die zielgerichtete Applikation liposomaler Trägersysteme an den Knochen: eine Machbarkeitsstudie

The bone is a common site of metastases for a number of different types of cancer, especially prostate and breast cancer. Today, standard options for the treatment of bone metastases include chemotherapy, hormone therapy, and radiation therapy. However, the major drawbacks of these treatments are severe side effects in non affected tissues. Therefore, special attention should be directed to developing new treatment strategies. Several attempts to develop bone-specific drug delivery systems using bisphosphonates as targeting moiety due to their known high affinity to hydroxyapatite, the mineral phase of bone have already been reported. The approach presented in the doctorial thesis describes the combination of a new tailor-made bisphosphonate ligand and pegylated liposomes as drug delivery system. The purpose is to reduce systemic side effects, to enhance therapeutic efficacy, and to improve the localisation of the active payload to the desired site of action. The ligand is composed of a cholesteryl residue to be incorporated into the liposomal membrane, a trisoxyethylene chain as spacer molecule and a bisphosphonic acid as targeting device. The research project particularly focussed on the feasibility of incorporating this ligand into liposome membranes including its evaluation as bone targeting device. The characterization of bisphosphonate-targeted liposomes comprised the determination of their physicochemical properties, in-vitro-binding studies to hydroxyapatite, pharmacokinetic studies and the verification of the bone binding capability in vivo. The bisphosphonate ligand turned out to play a key role in the performed studies. Higher ligand concentrations led to increased negative liposome surface charges, higher binding affinity to hydroxyapatite in vitro and faster blood clearances. Pilot experiments using a well-established nude mouse model for bone metastases clearly demonstrated the bone targeting capability of bisphosphonate-targeted liposomes. In summary, this thesis can be considered to have provided the proof of concept. The successful demonstration of the feasibility of combining bisphosphonate ligands and liposomes as a drug carrier system to metastatic bone tissue strongly recommends further investigation as a new therapy option for the treatment of bone metastases.