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  • Final Report Summary - LEEP-NANO-ASTRO-RAD (Investigation of condensed-phase low-energy (0-30 eV) electron induced processes for application to nanolithography, astrochemistry and radiotherapy.)

Final Report Summary - LEEP-NANO-ASTRO-RAD (Investigation of condensed-phase low-energy (0-30 eV) electron induced processes for application to nanolithography, astrochemistry and radiotherapy.)

The purpose of the award was to develop, research programs within the European Union (EU), to investigate systems of relevance to three important applications of low-energy electron (LEE) induced processes, namely nanolithography, astrochemistry and radiotherapy. In the case of nanolithography, our main objective was to investigate in greater detail condensed phase reaction mechanisms and find the suitable molecules and pathways to control unique reactions on a nanometer scale with LEE. In the field of astrochemistry, our goal was to develop a program to probe the physical-chemistry of ice surfaces under astronomical conditions. Another objective of the program was based on our comprehension of the major fundamental processes induced by LEE in cellular biomolecules. We proposed to study the effect of secondary LEE generated by high-energy radiation in Radiotherapy.
While residing in Europe, L. Sanche developed strong links and ties with the researchers of the host laboratory and those of the RADAM networks (www.isa.au.dk/radam) and an EU training Network (www.isa.au.dk/epic) which involved researchers from fifteen European institutions. Mutual scientific exchanges were established within present research programs on LEE-induced surface chemistry, in systems related to the research goals. State-of-the-art European knowledge and technology for understanding LEE induced processes were combined to the experience, knowledge and state-of-the-art techniques developed in Sanche's group to induce chemistry in condensed-phase model systems. These latter emulated the conditions found in the practical applications mentioned above. Some of the unique techniques in the applicant's laboratory were implanted in Europe. Professor Sanche provided valuable leadership to the research assistants, postdoctoral fellows and research students involved in the European projects he developed at The Open University and in France at the Université de Paris (Orsay) and at the Université Franche-Conté in Besançon.
More specifically, we investigated LEE-induced damage to DNA, the most important cellular target in radiotherapy. By incorporating chemotherapeutic agents within DNA, we were able to improve and suggest protocols for radiotherapy. Considerable information both theoretical and experimental was obtained on the interaction of LEE with DNA alone and in the presence of water, organic cations, gold nanoparticles (GNP) and chemotherapeutic agents. Data was also obtained on such interactions on smaller biomolecules including amino acids-nucleotide pairs and basic subunits of DNA. The effect of the coating of GNP on their radiosensitization efficiency (i.e., ability to kill cancer cells) was investigated as well as key parameters governing radiosensitization of DNA with GNP. The results suggested that efficient radiosensitization in cancer patients, undergoing radiotherapy with GNP injections, should be achieved when GNP reach the DNA of cancer cells.
Other experiments with DNA and the chemotherapeutic agent cisplatin established the role of LEE in the production of additional harmful radicals near the DNA of cancer cells of irradiated patients concomitantly treated with this chemotherapeutic agent. With cisplatin bound to DNA, damage to the molecule by electrons of low (1-100 eV) and high (60 keV) energies increased by factors varying from 4.4 to 1.3. The enhancement in DNA damage was triggered by modifications of the interaction of LEE with DNA, caused by cisplatin. These results suggested that the superadditive effect observed in tumor regression in concomitant chemoradiation therapy (CRT) is related to modification in the LEE-DNA interaction. The enhancement of bond dissociation in DNA arose from the formation of transient anions, which may therefore lie at the basis of the efficiency of concomitant CRT. Since these experiments were performed with a ratio of cisplatin to DNA molecules below the range utilized in most chemotherapy treatments, the proposed mechanism was expected to be applicable in the clinic and be most efficient for cancer cells having a high DNA uptake of cisplatin (and possibly other platinum drugs), and when the concentration of the chemotherapeutic agent is maximum in cancer cells. Thus, additional research with cells and animals was performed. We investigated the cytotoxicity, pharmacokinetics, cellular uptake, DNA binding and synergy with radiation of GNP and the 5 Pt chemotherapeutic agents: cisplatin, carboplatin, oxaliplatin, Lipoplatin and Lipoxal. The latter two consist of cisplatin and oxaliplatin encapsulated in a liposome, respectively. The results are the following: (1) the concomitant treatment with carboplatin and radiation produces the highest sensitizing effect (a 30-fold increase with respect to carboplatin alone); (2) Lipoplatin improved the cell uptake of cisplatin by 3-fold, and its sensitizing potential was enhanced by 14-fold; (3) attaching a peptide (derived from the HIV virus) to GNP, increased its retention in the tumor by at least an order of magnitude. We conclude that (1) the liposomal formulation could become much more powerful agents in CRT, if their content was completely released in the cancer cells, entered the nucleus and bound to DNA; and (2) vectorized GNP could become highly potent radiosensitizers. From these results, a new clinical protocol was established for the administration of carboplatin in the CRT treatment of brain tumor. This new protocol has been approved and we started treating patients in February 2010.

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THE OPEN UNIVERSITY
United Kingdom
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