Novel polypyrrole scaffolds for therapy and imaging of lung cancer

Overview

Project Summary

Lung cancer (LC) is the leading cause of death by cancer worldwide, with increasing incidence and high mortality. Photodynamic therapy (PDT), which relies on photosensitizers that accumulate selectively in tumors and induce cytotoxicity upon irradiation via the generation of reactive oxygen species, is used as an endobronchial therapy, to definitively treat early-stage lung cancer and multifocal primary tumors. PDT of lung cancer is also particularly useful for patients with advanced disease used as a palliation strategy and as an effective surgical adjuvant in patients with non-small cell lung cancer with pleural spread. 

The development of more efficient photosensitizers as well as more efficient diagnostic tools will certainly have a huge impact on the therapeutic outcome and applications of PDT. Therefore, the focus of the current project is to explore innovative chemistry for the synthesis of new pyrrolic compounds to be used on PDT and imaging of lung cancer.

The chemistry of nitrosoalkenes and azoalkenes is one of our research topics, applied to the alkylation of five-membered heterocycles and on the development of new routes to bis(heterocycle)methanes. Particularly relevant to this project, are the novel synthetic strategies to dipyrromethanes and to meso-substituted corroles, based on the chemistry of these building blocks, recently described by our research group.

In this project, novel contracted porphyrins, namely triphyrins and corroles, and expanded porphyrins (hexaphyrins) as well as BODIPYs will be prepared by exploring nitroso- and azoalkene chemistry. Compounds with new substitution patterns will be accessible which will always include oxime or hydrazone functionalities. This will be a strategy to tune the solubility of these heterocycles in biological media as well as their photophysical properties in order to have the required features for their application as efficient therapeutic or luminescence imaging agents of lung cancer.

The synthesis of novel subporphyrins, namely triphyrins(1.1.1) and triphyrins(2.1.1) will be carried out, a type of compounds with unique spectral and electronic features. Corroles with one oxime or hydrazone substituent at a meso-position will be obtained through oxidative macrocyclization of bilanes and explored as photosensitizers for in vitro PDT of lung cancer (A549 and H1299 human lung cancer cell lines). In vivo PDT of lung cancer, using corroles as photosensitizers, will also be studied. Biodistribution studies will be carried out using BALB/c nude mice and PDT outcome will be evaluated in xenograft and in orthotopic animal models of LC (RNU rats). 

Hypoxia is known to occur in tumors and is an important clinical factor in cancer-treatment planning and efficacy. Luminescence sensing and imaging enable the direct measurement and quantification of oxygen concentrations within tissues. Therefore, considering the importance of understanding tumor oxygenation, new gold corroles with oxime substituents will be developed as luminescent oxygen sensors.

The synthesis of hexaphyrins will be carried out following two strategies, cyclization of linear hexapyrroles via condensation with aldehydes and [3+3] cyclization of tripyrroles. The photophysical properties of these hexaphyrins will be determined and their capability as PDT agents against lung cancer will be evaluated.

Novel BODIPYs as fluorescence imaging agents will be studied. Dipyrromethanes (DPs) with an oxime substituent at 5-position obtained by our approach as well as DPs with one or two additional oxime moieties at 2 and 9 position will be used as starting materials for the synthesis of BODIPYs. Additionally, similar strategies will be explored starting from 5-alkyl or 5-aryl-dipyrromethanes. Overall, the relationship between imaging properties/amphiphilicity with the number and position of oxime groups should be uncovered. Interestingly, the feasibility of obtaining BODIPYs bearing oxime functionalities has already been demonstrated.

The cytotoxicity of all these compounds in lung cancer cells will be studied. Fluorescence confocal microscopy experiments will be conducted to investigate the ability of the noncytotoxic BODIPYs for in vitro detection and visualization of multiple subcellular entities.

The characteristic difference in extra/intratumoral pH of lung cancer, the acidic pH of the endo/lysosomal compartments of lung tumor cells, and the reactivity of glutathione with the oxime group open the possibility of using fluorescent BODIPYs with oxime substituents, as fluorescence imaging agents, with the potential to identify tumors and different intracellular environments.

Exciting preliminary results regarding the evaluation of novel corroles, bearing an oxime or hydrazone functionality, as PDT agents, showing high photocytotoxicity against lung cancer cells and absence of cytotoxicity per se, are an indication that the novel compounds hold great promise in the fight against lung cancer.

Main Goals

The strategy outlined to achieve these goals involves implementing the following objectives:

1. Synthesis of novel cyclic tripyrrole derivatives (Task 1)

2. Corroles as photosensitizers for in vitro PDT of lung cancer (Task 2)

3. Corroles for in vivo PDT of lung cancer and in vivo Imaging (Task 3)

4. Hexaphyrins for in vitro PDT of lung cancer (Task 4)

5. BODIPYs as fluorescence imaging agents (Task 5)

Project Details