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Rational design of combined PDT photosensitizers and chemotherapeutic agent as new approach in cancer therapy: a computational approach

Periodic Reporting for period 1 - COMBPDCHEMOTHERAPY (Rational design of combined PDT photosensitizers and chemotherapeutic agent as new approach in cancer therapy: a computational approach)

Reporting period: 2015-07-01 to 2017-06-30

To increase the effectiveness of anticancer therapy, the combination of multimodal treatment methods into a single synergistic system is a very promising approach. One of the newest and most challenging strategies, still in its infancy, is to functionalize a photosensitizer suitable for application in Photodynamic Therapy (PDT), with a cisplatin-like compound, thus combining PDT effect and cytostatic activity. These conjugates are able to promote a better distribution Pt-mediated of the PS within the tumour and to address the several drawbacks associated with the classic Pt-chemotherapy.
The search for the ideal photosensitizer is very much under way and the information that can be gained from computational studies is very useful, as it has the potential to increase the understanding of the entire photochemical pathways involved.
The overall aim of the COMBPDCHEMOTHERAPY was to
1) establish the most appropriate computational protocol investigating the crucial photophysical properties of selected combined PDT and chemotherapeutic agents, gaining information and useful guidelines;
2) Investigate members of novel and very interesting classes of bioactive molecules of interest as anti-cancer agents able to afford a dual action in killing cancer cells. Form one side we were interested in promising assemblies consisting of a light-absorber chromophore (PS) and a cisplatin-like unit. On the other hand, we were also interested in dyads characterized by a low-lying 3IL state able to afford a dual Type I/Type II action depending on the oxygen tension in the tissues.
The rationalization of the photophysical properties of existing classes of photosensitizers allowed us to gain rational guidelines to propose the design of novel photosensitizers with desired molecular properties.
The research project was developed following the implementation scheme already planned in the original proposal and in agreement to the Career Development Plan. Concerning the research program, the initial stage was devoted to the search and to the validation of an accurate quantum chemical protocol to investigate promising candidates molecules for PDT and to study antineoplastic agents displaying a dual action against cancer.

Work performed on expanded bacteriochlorins in order to assess whether some of recently synthesized dyes could be proposed as photosensitizers in PDT, was published in Molecules, 2016, 21, 288.

Another class of porphyrogenic macrocycles made of five pyrrolic rings linked by meso-like bridges, was investigated for their potential use both in photodynamic therapy and as likely photoactivated agent for water disinfection. The results of this investigation were published in Theor Chem Acc, 2016, 135:29.

The first two-component conjugate investigated during the action was a very interesting RuII-PtII assembly, in which a Ru polypyridine chromophore is functionalized by a cisplatin moiety We decided to undertake a detailed exploration of the photophysical properties of [(Ph2phen)2Ru(dpp)]2+ complex and of its assembly with cisplatin revealing that a successful synergistic effect exist between the two units. The outcomes of this exploration were published as Hot Paper in Chem. Eur. J. 2016, 22, 9162-9168 and also presented as cover picture of the journal. Moreover, they were presented as poster communication on the occasion of the ESPA2016 conference (Castellón de la Plana, Spain, June 28 - July 1, 2016) and were also included in the oral speech given by the researcher at the EuCheMS Chemistry Congress (Sevilla, Spain, September 11-15 2016).

A class of Ru polypyridine dyads was studied during the action, in view of their ability to promote Type I/Type II photoreactions depending on the length of the organic chain bound to the metal centre. The outcomes of such exploration were published as full paper in Inorg. Chem. 2016, 55, 11185–11192. Moreover, the results were presented as Oral Communication during the ACS National Meeting (April 2-6 2017, San Francisco, USA).

Porphyrinoids systems combined with cisplatin-like compounds have also been explored during the individual fellowship. In particular, we started our investigation focusing on tetraplatinated porphyrins conjugates that have been recently synthesized and studied for their anticancer properties. Moreover, to propose a further advance in this novel field and give some insights useful for the design of new PSs with improved efficiency, we have also decided to introduce structural modification into the porphyrin dye evaluating the consequent changes in the chemical and photophysical properties. Results reveal that the designed dyes better meet the criteria to be successful in the PDT application.
The outcomes of such exploration were published in Chem. Eur. J. 2017, DOI 10.1002/chem.201702876 and were also included in the invited speech given by the researcher at the Theoretical Biophysics Conference 2017 (26-30, June 2017, Invited Lecture)
The research project developed under the excellent Marie Curie Individual Fellowship action, was characterized by a high level of originality allowing us to go beyond the usual computational approach developed to study photosensitizer for PDT approach, mainly oriented toward a photochemical description of the chromophoric dyes. Our project aimed instead at providing a dual description of the investigated systems, exploring the synergy between the two units involved in the two-component conjugates. Beside the scientific records obtained during the action, published in high impact journals, this action also provided to the experienced researcher to achieve transverse competences, through an intense participation at conferences and workshops, raising awareness about the socio-economic impact of issues related to cancer treatment and through the acquisition of new skills and knowledge which are essential to increase creativity, efficacy and performance.
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