New Scaffolds for the Delivery of Protease Sensitive Photosensitizer Prodrugs
To improve the selectivity of conventional photosensitizers (PS) we have developed quenched PS prodrugs based on poly (L) lysine and cyclopeptidic carriers that target up-regulated proteolytic activities related to certain diseases, including cancer. These compounds are based on energy transfer between multiple copies of PSs tethered to oligomeric carriers via protease sensitive peptide linkers, thus, silencing any photodynamic activity. Proteolytic digestion of the peptide results into the release of a PS peptidyl fragment thereby restoring photodynamic activity. These conceptually new compounds act through several complementary targeting mechanisms. They 1) accumulate preferentially in pathologic tissue, 2) target pathology-related proteases, 3) are taken-up selectively by abnormal cells, and 4) being selectively irradiated in the diseased area. Using poly(L)lysine based carriers we have designed quenched PS prodrugs that effectively image and treat prostate cancer. Unfortunately, due to their undefined chemical structure these prodrugs are not suitable for clinical use.
Therefore, we have proceeded to design defined quenched PS prodrugs based on a cyclopeptidic carrier vehicle. These novel prodrugs have a constrained secondary structure with a defined molecular weight and predefined number and positions of the PS peptide conjugates. Preliminary evaluation demonstrated that these compounds show the expected tendencies, i.e. increased quenching with increasing number PSs per carrier and digestion by recombinant target proteases including, uPA, Cathepsin B and MMPs. The influence of different design parameters has been investigated in vitro and in vivo. For instance, we have shown that high molecular weight PEGylation is unfavorable for high quenching efficiencies.
Furthermore, we have characterized quenched PS prodrugs with respect to activation and phototoxicity in human cancer cell lines with special emphasis on prostate and ovarian cancer. Furthermore, preliminary optimization of pharmacokinetics and biodistribution will be carried out in the chorioallantoic membrane model inoculated with tumor spheroids.
Finally, might be possible to translate the gained knowledge into other scientific fields such as for instance the improved drug delivery of chemotherapeutics using cyclopeptidic protease sensitive carriers or the targeted imaging of GLP-1 receptors through the multimerization of targeting moieties onto the cyclopeptidic scaffold.