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Systematic Biomimetic Studies on Porphyrins interacting with Membranes probed by NMR Spectroscopy

Applicant Vermathen Martina
Number 119691
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physical Chemistry
Start/End 01.07.2008 - 30.06.2011
Approved amount 170'451.00
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Keywords (8)

NMR-spectroscopy; porphyrins; vesicles; model membranes; phospholipid bilayers; photodynamic therapy; membrane interactions; membrane kinetics

Lay Summary (English)

Lead
Lay summary
Background
Porphyrinic compounds selectively accumulate in proliferating tissue and exhibit special light absorbing properties. Therefore, these compounds have emerged as promising photosensitizers for Photodynamic Therapy (PDT) which has evolved as highly selective, minimally invasive treatment modality for various cancers as well as non-cancerous diseases. However, the reasons for porphyrin accumulation in tumour tissue are not yet clear. Moreover, the determinants of subcellular localization patterns of porphyrinic compounds are still uncertain. I t is generally accepted that membranes are the primary targets of porphyrin based sensitizers and solubility and retention of the porphyrinic drug in membranes are of vital importance for their photosensitizing efficiency.

Goals
The goal of this research project is to perform systematic studies on biomimetic systems for defining the principles of porphyrin membrane interactions.
NMR spectroscopy applied to unilamellar phospholipid vesicles will be used to probe the porphyrin membrane interactions. A series of selected porphyrin compounds including metalloporphyrins will be studied in the absence and presence of model membranes by established NMR spectroscopic methods. The anticipated results will provide a comprehensive library of porphyrin structures with their corresponding parameters relevant for membrane interactions, such as aggregation behaviour, membrane affinity, preferred localization sites, orientation, and membrane transition rate. For metalloporphyrins, the role of the metal ion and the axial ligands for membrane interaction will be defined thus adding new important insights into the scarcely explored field of metalloporphyrin membrane interactions. In addition, methodological studies will be performed which are aimed at resolution improvements to add complementary site specific information on binding interfaces.

Potential relevance of the proposed project The projected systematic study of porphyrin membrane interactions is expected to contribute substantial progress to the current state of knowledge:
(i) The resulting data will identify the molecular constraints for optimal membrane incorporation and penetration which in turn promotes improved rational design of efficient PDT drugs.
(ii) Knowing the relationship between porphyrin structure and membrane location allows predicting the subcellular localization sites and thus the pathways of cell damage.
(iii) The knowledge of membrane partitioning allows drawing conclusions for cell uptake mechanisms and potential reasons for porphyrin accumulation.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
68576 MHV 2002:NMR-spectroscopic investigations on porphyrin-model membrane system 01.01.2003 Marie Heim-Voegtlin grants
149438 Amino acid conjugated Photosensitizers in biocompatible nanoparticles and their interactions with Cellular Environments studied by High Resolution Liquid and Magic Angle Spinning (HR-MAS) NMR Spectroscopy 01.06.2014 Project funding (Div. I-III)
128736 High Resolution Magic Angle Spinning (HR-MAS) probe for NMR Spectroscopic Investigations of semi-solid liquid-like materials 01.12.2009 R'EQUIP

Abstract

1. BackgroundPorphyrinic compounds selectively accumulate in proliferating tissue and exhibit special light absorbing properties. Therefore, these compounds have emerged as promising photosensitizers for Photodynamic Therapy (PDT) which has evolved as highly selective, minimally invasive treatment modality for various cancers as well as non-cancerous diseases. Due to this great potential, in recent years, a huge amount of novel porphyrinic photosensitizers has been created covering an enormous variety of structural modifications of the basic porphyrin macrocycle. However, the number of approved PDT drugs is still very little, and effective photosensitizers are usually discovered by “trial and error”. This is mainly due to the fact that the reasons for porphyrin accumulation in tumour tissue are not yet clear. Moreover, the determinants of subcellular localization patterns of porphyrinic compounds are still uncertain. However, it is generally accepted that membranes are the primary targets of porphyrin based sensitizers and PDT efficiency has been shown to correlate with membrane affinity of the porphyrinic drug. Membrane penetration of the porphyrin is crucial since singlet oxygen, the actual cytotoxic species, acts in the immediate environment where it is generated by the sensitizer. Thus, solubility and retention of the porphyrinic drug in membranes are of vital importance for their photosensitizing efficiency. Therefore, exact knowledge of the principles underlying porphyrin membrane interactions is fundamental to improve rational efficient PDT drug design.2. GoalsAs has been often stated in recent reviews related to PDT, systematic studies are highly desirable to gain more insight into the principles underlying PDT and to provide rational criteria for improved and efficient PDT drug design. Therefore, the goal of this research project is to perform systematic studies on biomimetic systems for defining the principles of porphyrin membrane interactions which are of fundamental importance for PDT efficiency. NMR spectroscopy applied to unilamellar phospholipid vesicles will be used to probe the porphyrin membrane interactions. Own previous as well as other studies reported in the literature have demonstrated that NMR spectroscopy is a powerful tool for pursuing the goal of this project, since both, structural properties and dynamic processes can be studied by this technique. A series of carefully selected porphyrin compounds including metalloporphyrins will be studied in the absence and presence of model membranes by established NMR spectroscopic methods. The anticipated results will provide a comprehensive library of porphyrin structures with their corresponding parameters relevant for membrane interactions, such as aggregation behaviour, membrane affinity, preferred localization sites, orientation, and membrane transition rate. For metalloporphyrins, the role of the metal ion and the axial ligands for membrane interaction will be defined thus adding new important insights into the scarcely explored field of metalloporphyrin membrane interactions. In addition, methodological studies will be performed by including NMR techniques and different model membranes. These will be adapted and optimized for their application to porphyrin membrane systems. The anticipated studies are aimed at resolution improvements to add complementary site specific information on binding interfaces.3. Potential relevance of the proposed projectThe projected systematic study of porphyrin membrane interactions is expected to contribute substantial progress to the current state of knowledge:(i) The resulting data will identify the molecular constraints for optimal membrane incorporation and penetration which in turn promotes improved rational design of efficient PDT drugs.(ii) Knowing the relationship between porphyrin structure and membrane location allows predicting the subcellular localization sites and thus the pathways of cell damage.(iii) The knowledge of membrane partitioning allows drawing conclusions for cell uptake mechanisms and potential reasons for porphyrin accumulation.
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