Nanocarrier for Tumor-Specific Anticancer Thiosemicarbazones

Chemotherapy and therapy with small, targeted molecules are two major strategies to fight human cancer at the late stage. Due to high iron dependence, cancer cells are known for their sensitivity against iron deprivation. In order to target this enhanced iron dependence of malignant cells, several iron chelators have been developed for the treatment of cancer. a-N-heterocyclic thiosemicarbazones arethemost promisingcandidateswithTriapine(3-aminopyridine-2-carboxaldehyde thiosemicarbazone) as the lead compound already investigated in multiple clinical phase I and II studies. However, these evaluations showed that Triapine is largely ineffective against solid tumors. The exact reasons are widely unexplored but were topic of a recently finished FWF project from our group. These studies revealed that in vivo Triapine treatment is characterized by a distinct but unfortunately very transient response. In addition, the rapid tumor re-growth between the therapy cycles was paralleled by a very low plasma half-life of this drug. Thus, the rational aim of the here presented project is to distinctly improve the pharmacokinetic profile and tumor accumulation of Triapine by use of nanocarrier systems. Two different synthetic strategies will be followed: 1) design of albumin-binding Triapine derivatives with a cleavable linker unit for specific drug release at the tumor site and 2) thiosemicarbazone-loaded biodegradable polymeric carriers (hybrid poly glutamic acid (PGA)/polyphosphazene(PPz) polymer). These strategies have been selected, as they are already known for their potential to strongly increase drug plasma half-life together with the improved tumor targeting via the so-called EPR (enhanced permeability and retention) effect. Successful drug examples using comparable strategies are Abraxane (albumin-paclitaxel nanoparticle), which is already approved for several cancer types, aldoxorubicin (maleimide-doxorubicin) which sucsessfully finished phase III or a PGA-paclitaxel conjugate currently in clinical phase III trials. All novel synthesized derivatives and nanoformulations will be in detail characterized by analytical and spectroscopic methods. Subsequently, the anticancer activity of the novel nanocarrier systems in comparison to free Triapine will be evaluated in a range of cancer cell lines and, the most promising candidates will be evaluated in vivo using subcutaneous xenografts. Taken together, in this project nanocarriers for Triapine and related derivatives will be synthesised and preclinically developed with the rational to overcome the current problems of this compound class in clinical trials.

Chemotherapy and therapy with small targeted molecules are two major strategies to fight human cancer at the disseminated stage. Due to high iron dependence, cancer cells are known for their sensitivity against iron deprivation. In order to target this enhanced iron dependence, several iron chelators have been developed for the treatment of cancer. -N-heterocyclic thiosemicarbazones are the most promising candidates with Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) as the lead compound already investigated in multiple clinical phase I and II studies. However, several clinical phase II studies revealed that Triapine is widely ineffective as monotherapy against solid tumors. The exact reasons are currently unknown. However, this question was addressed in a recently finished FWF project from our group. The results of this project revealed that in vivo Triapine treatment is characterized by a distinct but unfortunately very transient response. In addition, the rapid tumor re-growth between the therapy cycles was paralleled by a very low plasma half-life of this drug. Thus, the aim of the FWF project P31923 was, on the one hand, to better understand the parameters responsible for thiosemicarbazone anticancer activity and resistance. On the other hand, to investigate the use of nanocarrier systems to improve their activity and tumor accumulation. We could not only reveal that paraptotic cell death is a novel mode of action for anticancer thiosemicarbazones but also characterize copper-mediated ABCC1 drug efflux as an important resistance factor against the clinically developed thiosemicarbazone COTI-2. This knowledge was used for the synthesis of improved COTI-2 derivatives and the design of novel nanocarrier systems. Here especially biodegradable polymeric carriers (hybrid poly glutamic acid (PGA)/polyphosphazene (PPz) polymers) and endogenous albumin were in the focus. In total, 14 manuscripts were published in international peer-reviewed top journals and 4 master as well as 7 PhD students participated in this research project. We also gained attention by the public e.g. in form of diverse national and international outreach activities including press releases and participation in laymen activities e.g. the Lange Nacht der Forschung. Taken together, in this project novel insights into the mode of action of anticancer thiosemicarbazones and their interaction with cellular metal ions could be gained and new polymeric drug delivery systems developed to improve the pharmacokinetic properties and increase the tumor accumulation. These results are an important contribution to enabling the development of improved thiosemicarbazone-based anticancer agents.