Project

Discipline

Polymer; Tumor Targeting; Radionuclide; Molecular Imaging; Peptide; biologically active synthetic polymers; pharmacology

Lead
Lay summary
Lead: Biologically active synthetic polymers (BASP) decorated with small, tumor targeting peptides could be inexpensive alternatives for monoclonal antibodies. However, little is known about the pharmacokinetic profile of BASPs. This project will investigate the targeting capacity and pharmacokinetics of BASPs. Background: Targeted delivery of effector functions and moieties to diseased sites in the human body for diagnostic or therapeutic purposes is a hallmark of modern drug development. This is particularly true for cancerous diseases since cancer accounts still for more than 20 % of deaths in developed countries (www.cancer.org). Monoclonal antibodies (MAb) have become indispensable tools in this respect. However, the development and production of such macromolecules is extremely expensive and as a consequence such drugs are growing burden for the health system. Hence, less costly alternatives have to be developed and investigated which combine the positive biological and pharmacological features of antibodies with the lower costs of development of small molecules. Toward this goal the presented project aims to investigate the possibilty to use biologically active synthetic polymers (BASP) as an alternative to MAbs. The most sensitive and reliable way to investigate and characterize the pharmacokinetics of such BASPs in vitro and in vivo is to label them with a diagnostic radionuclide useful for positron emission tomography (PET) or single photon emission tomography (SPET). PET and SPET are used in the drug development process as well as for pre-clinical research.Specific Aims: In this project we propose to design tumor specific, radioactive BASP conjugates based on various polymer back-bones. We will chemically modify these polymers in order to decorate them with tumor targeting peptide derivative of bombesin. This G-protein coupled receptor is known to be overexpressed in a wide variety of human tumors such as prostate cancer and breast cancer among the most common cancers in men and women. We will label the BASPs with various diagnostic and therapeutic radionuclides such as Cu-64/67, Ga-67/68, Tc-99m and Lu-177 and characterize these compounds chemically as well as in vitro and in vivo.Expected Value of the Proposed Project: This proposal will provide an additional dynamic impulse towards the development and characterization of synthetic polymer for use in drug delivery and specifically for tumor targeting to improve the management of cancerous diseases in the future. If this project is successful we expect significant resonance from different areas of (targeted cancer-) research as well as from the pharmaceutical industry.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Number	Title	Start	Funding scheme

Background: Targeted delivery of effector functions and moieties to diseased sites in the human body for diagnostic or therapeutic purposes is a hallmark of modern drug development. This is particularly true for cancerous diseases since cancer accounts still for more than 20 % of deaths in developed countries (www.cancer.org). Monoclonal antibodies (MAb) has become an indispensable tools in this respect. However, the development and production of such macromolecules is extremely expensive and as a consequence such drugs are growing burden for the health system. Hence, less costly alternatives have to be developed and investigated which combine the positive biological and pharmacological features of antibodies with the lower costs of development of small molecules. Possible alternatives could be biologically active synthetic polymers (BASP). Polymers are generally inexpensive, can be readily functionalized or decorated with targeting entities. However, very little is known about the pharmacokinetic profile of such constructs. Working Hypothesis: Toward this goal the presented project aims to investigate the possibilty to use BASP as an alternative to macromolecules such as MAbs. Among the most sensitive and reliable way to investigate and characterize the pharmacokinetics of molecules in vitro but particularly in vivo is to label them (additionally) with a diagnostic radionuclide. Like no other imaging methodology, nuclear imaging (positron emission tomography, PET, or single photon emission tomography, SPET) posses a very high sensitivity and can be readily quantified (or at least semi-quantified). PET and SPET are used in the drug development process as well as for pre-clinical research. Apart from the diagnostic application of such conjugates, they can also be used for therapy when labeled with particle emitting radionuclides (beta- or alpha-particle emitters). Radioconjugate of antibodies and peptides but also of small molecules are currently used in diagnostic and also therapeutic nuclear medicine. Specific Aims: In this project we propose to design tumor specific, radioactive BASP conjugates based on various polymer back-bones. We will chemically modify these polymers in order to decorate them with tumor targeting molecules. We propose to use peptide derivative of bombesin, a peptide, which binds with high affinity to the bombesin receptor. This G-protein coupled receptor is known to be overexpressed in a wide variety of human tumors such as prostate cancer and breast cancer among the most common cancers in men and women. We will furthermore functionalize these BASP with various so called bifunctional metal chelating systems, which enable the in vivo stable labeling with various diagnostic and therapeutic radionuclides such as Copper-64/67, Gallium-67/68, Technetium-99m, Lutetium-177 or Re-188. We will characterize these compounds chemically as well as in vitro and in vivo in xenografted mouse models. Modern small animal PET and SPET imaging devices will be employed to prove the tumor targeting capacity of BASP in vivo.Expected Value of the Proposed Project: This proposal will provide an additional dynamic impulse towards the development and characterization of synthetic polymer for use in drug delivery and specifically for tumor targeting to improve the management of cancerous diseases in the future. If this project is successful we expect significant resonance from different areas of (targeted cancer-) research as well as from the pharmaceutical industry.