Abstract:
The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that mainly results from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Hence, drug delivery in oncology is of particular interest, and research in drug targeting is currently one of the major sources of innovation in cancer therapy. During the past 15 years we have witnessed a renaissance of antibody drug conjugates with highly potent drugs and the dawning era of polymer therapeutics and nanomedicine (1,2).
Differences in the biochemical and physiological characteristics of healthy and malignant tissue are responsible for the passive tumor accumulation of macromolecules. This seemingly universal strategy exploits anomalies of malignant tissue on a vasculolymphatic level that directly result from the tumor's pathophysiology characterized by a leaky vasculature combined with an absent of defective lymphatic drainage system. Following this approach, classified as passive tumor targeting, an accumulation of drugs in tumor tissue is achieved by employing large molecules such as synthetic or biopolymers. Consequently, several promising macomolecular prodrug approaches have been followed in the last decades with the aim of improving chemotherapy.
The molecular weight, three-dimensional structure, immunogenic potential and drug loading ratio influence the distribution of the drug carrier and dictate the amounts of drug that reach the target site. Optimizing the physicochemical properties of the respective carrier is the first critical aspect of carrier-linked prodrug design.
The second aspect that is relevant for the design of carrier-linked prodrugs is the modification of the carrier with the drug that should preserve the targeting properties of the carrier and ensure a controlled release of the drug inside or outside of tumor cells. The pre-determined breaking point introduced in the prodrugs should have sufficient stability in the blood stream but allow the drug to be released effectively at the tumor site by enzymatic cleavage, by reduction, or in a pH-dependent manner.
In this lecture the fundamental principles of passive drug targeting and drug release are described with a focus on representative examples of prodrugs that illustrate the salient features of the respective targeting strategy and that have reached an advanced stage of preclinical testing or are being evaluated in clinical trials (3).

1. R. Haag, F. Kratz (2006): Polymer Therapeutics: Concepts and Applications, Angewandte Chemie, Int. Ed., 45, 1198-1215.
2. F. Kratz, F. Kratz, Y. Muller, C. Ryppa, A. Warnecke (2008): Prodrug strategies in cancer chemotherapy, ChemMedChem, 3, 20-53.
3. K. Abu Ajaj, A. Warnecke (2007): Anticancer carrier-linked prodrugs in clinical trials, Expert Opin. Investig. Drugs, 16, 1037-1058.

Brief Biography of the Speaker:
Felix Kratz, PhD., Head of the Division of Macromolecular Prodrugs; Clinical Research, Tumor Biology Center at the Albert-Ludwigs-University of Freiburg, Breisacher Stra?e 117, 79106 Freiburg i.Br. Tel.: 0049-761-2062930, Telefax: 0049-761-2062905; E-Mail: kratz@tumorbio.uni-freiburg.de
The Division Macromolecular Prodrugs was founded in 1994 by Dr. Felix Kratz in the Clinical Research Department at the Tumor Biology Center, Freiburg, Germany. The Tumor Biology Center at the University of Freiburg is a leading private cancer clinic and research institution focusing on the development of novel approaches for the effective treatment of cancer patients (http://www.tumorbio.uni-freiburg.de).
Felix Kratz graduated in Chemistry from the University of Heidelberg in 1991. The primary goal of his research team is the development of novel drug delivery concepts for improving the efficacy and toxicity of anticancer agents. He has 20 years of experience in the preclinical development of anticancer drugs and profound knowledge of translational research from the laboratory to the clinic and has successfully transferred a first albumin-binding prodrug (INNO-206) into the clinic. His research areas are drug targeting, drug delivery systems, prodrugs, receptor targeting, bioconjugate chemistry, polymer therapeutics and nanocarriers.
He serves on the Editorial Board for Bioconjugate Chemistry, Current Medicinal Chemistry and Current Bioactive Compounds. He has authored approximately 200 scientific publications and proceedings and is the inventor of 24 patents and patent applications.