Tumor targeting of oxaliplatin and cisplatin by an albumin-affine prodrug design

Based on its very strong anticancer activity, cisplatin and its successors carbo- and oxaliplatin are nowadays inherent part of most clinically relevant chemotherapy schemes. However, therapy with platinum compounds is limited by strong side effects, resistance development and insufficient tumor accumulation. To overcome these drawbacks we have aimed to enhance tumor-targeting of oxaliplatin via binding to albumin in course of a project funded by Vienna Fund for Innovative Interdisciplinary Cancer Research. In this recently published study, the first maleimide-containing platinum(IV) derivative of oxaliplatin was synthesized and characterized for its tolerability and anticancer activity. The new oxaliplatin-derivative was well tolerated with no significant loss of body weight and had potent anticancer potential resulting in distinctly reduced tumor growth of a colon cancer xenograft. Aim of the here presented project is to gain more insights into the mode of action underlying the enhanced activity of the novel albumin-directed platinum drug. Thus, the following questions will be addressed: 1) Is the enhanced anticancer activity of the new drug based on enhanced tumor accumulation or on a prolonged plasma half life? 2) Does the new drug exert its potent anticancer activity in vivo based on apoptosis induction and/or inhibition of cell proliferation? 3) Is this based on specific oxaliplatin release in the malignant tissue? 4) Does the tumor-targeting of the new drug result in reduced side-effects? and 5) Does this albumin-targeting approach also work with a cisplatin-releasing prodrug? To answer these questions an interdisciplinary team of synthetic and analytical chemists together with cell/molecular biologists and experts for preclinical drug development will closely cooperate to integrate their knowledge and experience on platinum drugs. Thus, this project unites groups with high expertise in all the fields necessary to translate research results on novel anticancer drugs from bench to bedside. This strong and well established scientific cooperation will be used in this project to generate and preclinically develop new derivatives of classical anticancer drugs (oxaliplatin and cisplatin) which are selectively targeted to and activated in the malignant tissue. To this end, we will combine histological and toxicological analyses of tissue and blood samples together with high end analytical methodology (ICP-MS, SEC-ICP-MS, LC-ICP-MS) of the already available maleimide-containing platinum(IV) derivative of oxaliplatin as well as a newly synthesized cisplatin analogues. Overall, this project will help not only to preclinically develop novel, better tolerable derivatives of cisplatin and oxaliplatin but also to gain more in vivo knowledge on other albumin-directed chemotherapeutics, such as abraxane or INNO-206/aldoxorubicin and platinum(VI) drugs in general.

Based on its very strong anticancer activity, cisplatin and its successors carbo- and oxaliplatin are nowadays inherent part of most clinically relevant chemotherapy schemes. However, therapy with platinum compounds is limited by strong side effects, resistance development and insufficient tumor accumulation. To overcome these drawbacks, the first maleimide-containing platinum(IV) derivative of oxaliplatin was synthesized and characterized for its tolerability and anticancer activity. The new oxaliplatin derivative was well tolerated with no significant loss of body weight and had potent anticancer potential resulting in distinctly reduced tumor growth of a colon cancer xenograft. Aim of the here presented project was to gain more insights into the mode of action underlying the enhanced activity of the novel albumin-directed platinum drug. Subsequently, we were able to show that the enhanced anticancer activity of the new drug is based on a prolonged plasma half- life together with an enhanced accumulation of the drug in the malignant tissue. This results in a depot effect characterized by continuous release of the active platinum(II) species in the tumor, which kills the cells by massive induction of programmed cell death (apoptosis). In addition, to these biological investigations, a large panel of new derivatives was synthesized and evaluated for their anticancer activity. This resulted in the identification of a new lead compound, which is now intensively preclinically investigated towards clinical phase I evaluation.