Project

Back to overview

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

Applicant Vermathen Martina
Number 149438
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 01.06.2014 - 31.05.2018
Approved amount 260'124.00
Show all

All Disciplines (2)

Discipline
Physical Chemistry
Biophysics

Keywords (9)

drug delivery; NMR-spectroscopy; photosensitizers; cells; biocompatible nanoparticles; chlorin; photodynamic therapy; Magic angle spinning; photosensitizers

Lay Summary (German)

Lead
Porphyrine werden als Photosensibilisatoren in der Photodynamischen Therapie (PDT) von Krebs und anderen Erkrankungen eingesetzt. Da die Porphyrine erst im Zusammenwirken mit Licht und Sauerstoff zelltoxisch wirken, bilden sie eine selektive, vielversprechende Alternative zur herkömmlichen Krebstherapie. Aufgrund ihrer Struktur weisen viele Porphyrine jedoch nur eine verminderte Löslichkeit und damit auch eine verminderte Phototoxizität auf, und die Zahl der zugelassenen Präparate ist bis heute nur sehr gering. Daher wird zur Zeit nach Wegen gesucht, die Effektivität von Porphyrinen für die PDT zu verbessern, z.B. durch den Einsatz von Nanopartikeln als Trägermaterial.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Ziel dieses Projektes ist es, geeignete Nanopartikel zu finden, welche die Eigenschaften bestimmter Porphyrinderivate bezüglich Löslichkeit, Zellaufnahme und Phototoxizität verbessern. Dazu sollen im Detail folgende Punkte bearbeitet werden: (i) Herstellung von geeigneten biokompatiblen Nanopartikeln und Einlagerung der Porphyrine, welche sich mittels NMR-Spektroskopie sehr gut verfolgen lässt. (ii) Mit Hilfe von Fluoreszenz-technischen Methoden werden die photophysikalischen Eigenschaften sowie die Zellaufnahme des Porphyrin-Nanopartikel-Komplexes untersucht. (iii) Mit HR-MAS NMR Spektroskopie an lebenden Zellen wird die metabolische Response auf den Komplex erprobt sowie die phototoxische Reaktion nach Bestrahlung mit Licht verfolgt.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt soll dazu beitragen, effizientere Formulierungen für Porphyrin-basierte PDT Medikamente entwickeln zu können. Die Kombination von NMR- und Fluoreszenz-spektroskopischen Methoden sowie die Anwendung von HR-MAS NMR auf lebende Zellen ermöglichen es, viele verschiedene Aspekte simultan zu beleuchten, um ein besseres Verständnis zu erlangen, wie entsprechende Nanopartikel konzipiert sein sollten.

Direct link to Lay Summary Last update: 06.05.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Monitoring the encapsulation of chlorin e6 derivatives into polymer carriers by NMR spectroscopy
Pfister Sara, Sauser Luca, Gjuroski Ilche, Furrer Julien, Vermathen Martina (2019), Monitoring the encapsulation of chlorin e6 derivatives into polymer carriers by NMR spectroscopy, in Journal of Porphyrins and Phthalocyanines, 23(11n12), 1576-1586.
Evaluation of polyvinylpyrrolidone and block copolymer micelle encapsulation of serine chlorin e6 and chlorin e4 on their reactivity towards albumin and transferrin and their cell uptake
Gjuroski Ilche, Girousi Eleftheria, Meyer Christoph, Hertig Damian, Stojkov Darko, Fux Michaela, Schnidrig Nicolas, Bucher Jan, Pfister Sara, Sauser Luca, Simon Hans-Uwe, Vermathen Peter, Furrer Julien, Vermathen Martina (2019), Evaluation of polyvinylpyrrolidone and block copolymer micelle encapsulation of serine chlorin e6 and chlorin e4 on their reactivity towards albumin and transferrin and their cell uptake, in Journal of Controlled Release, 316, 150-167.
1 H HR-MAS NMR spectroscopy to study the metabolome of the protozoan parasite Giardia lamblia
Vermathen Martina, Müller Joachim, Furrer Julien, Müller Norbert, Vermathen Peter (2018), 1 H HR-MAS NMR spectroscopy to study the metabolome of the protozoan parasite Giardia lamblia, in Talanta, 188, 429-441.
How Does the Encapsulation of Porphyrinic Photosensitizers into Polymer Matrices Affect Their Self-Association and Dynamic Properties?
Gjuroski Ilche, Furrer Julien, Vermathen Martina (2018), How Does the Encapsulation of Porphyrinic Photosensitizers into Polymer Matrices Affect Their Self-Association and Dynamic Properties?, in ChemPhysChem, 19(9), 1089-1102.
Metabolic Profiling of Cells in Response to Drug Treatment using 1 H High-resolution Magic Angle Spinning (HR-MAS) NMR Spectroscopy
Vermathen Martina, Diserens Gaëlle, Vermathen Peter, Furrer Julien (2017), Metabolic Profiling of Cells in Response to Drug Treatment using 1 H High-resolution Magic Angle Spinning (HR-MAS) NMR Spectroscopy, in CHIMIA International Journal for Chemistry, 71(3), 124-129.
Metabolic stability of cells for extended metabolomical measurements using NMR. A comparison between lysed and additionally heat inactivated cells
Diserens G., Hertig D., Vermathen M., Legeza B., Flück C. E., Nuoffer J.M., Vermathen P. (2017), Metabolic stability of cells for extended metabolomical measurements using NMR. A comparison between lysed and additionally heat inactivated cells, in The Analyst, 142(3), 465-471.
Direct determination of phosphate sugars in biological material by 1H high-resolution magic-angle-spinning NMR spectroscopy
Diserens Gaëlle, Vermathen Martina, Gjuroski Ilche, Eggimann Sandra, Precht Christina, Boesch Chris, Vermathen Peter (2016), Direct determination of phosphate sugars in biological material by 1H high-resolution magic-angle-spinning NMR spectroscopy, in Analytical and Bioanalytical Chemistry, 408(20), 5651-5656.
Interactions of Polyvinylpyrrolidone with Chlorin e6-Based Photosensitizers Studied by NMR and Electronic Absorption Spectroscopy
Hädener Marianne, Gjuroski Ilche, Furrer Julien, Vermathen Martina (2015), Interactions of Polyvinylpyrrolidone with Chlorin e6-Based Photosensitizers Studied by NMR and Electronic Absorption Spectroscopy, in The Journal of Physical Chemistry B, 119(36), 12117-12128.
1H HR-MAS NMR Based Metabolic Profiling of Cells in Response to Treatment with a Hexacationic Ruthenium Metallaprism as Potential Anticancer Drug
Vermathen Martina, Paul Lydia E. H., Diserens Gaëlle, Vermathen Peter, Furrer Julien (2015), 1H HR-MAS NMR Based Metabolic Profiling of Cells in Response to Treatment with a Hexacationic Ruthenium Metallaprism as Potential Anticancer Drug, in PLOS ONE, 10(5), e0128478-e0128478.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Oliver Mühlemann, Department of Biochemistry, University of Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Dr. Jaro Ricka, Department of Applied Physics, University of Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Dr. Peter Vermathen, Dept. BioMedical Research & Metabolomics Facility, Inselspital and Univer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Jean-Christophe Leroux, Drug Formulation & Delivery group, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Dr. Jean-Louis Reymond, Dept. Chemsitry and Biochemsitry, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Dr. Martin Frenz, Div. of Biomedical Photonics, Dept. Applied Physics, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCS Fall Meeting 2018 Poster Impact of drug delivery systems on cell-uptake and photo-physical properties of chlorin e6-based photosensitizers 07.09.2018 EPFL Lausanne, Switzerland, Switzerland Furrer Julien; Gjuroski Ilche; Vermathen Martina;
SCS Fall Meeting 2018 Poster Bicelles – Combining the Advantages of Micelles and Liposomes for Photosensitizer Delivery? 07.09.2018 EPFL Lausanne, Switzerland, Switzerland Gjuroski Ilche; Furrer Julien; Vermathen Martina;
SCS Fall Meeting 2018 Poster Protective Role of Polymeric Carriers in Chlorin Delivery Against Protein Binding 07.09.2018 EPFL Lausanne, Switzerland, Switzerland Gjuroski Ilche; Furrer Julien; Vermathen Martina;
10th International Conference on Porphyrins and Phthalocyanines (ICPP-10) Talk given at a conference Impact of Polymer encapsulation on the Properties of Chlorin e6-based Photosensitizers and their Cell Uptake 01.07.2018 Munich, Germany Furrer Julien; Gjuroski Ilche; Diserens Gaëlle; Vermathen Martina;
10th International Conference on Porphyrins and Phthalocyanines (ICPP-10) Poster Conjugation of Porphyrinic Photosensitizers to Peptide Dendrimers 01.07.2018 Munich, Germany Gjuroski Ilche; Furrer Julien; Vermathen Martina;
ISMRM - ESMRMB Joint 27th Annual Meeting 23rd Poster Determination of the metabolome of Giardia lamblia by 1H Magic Angle Spinning NMR 16.06.2018 Paris, France Furrer Julien; Vermathen Martina;
SCS Fall Meeting 2017 Poster Probing Cellular Uptake of Different Delivery Approaches for Porphyrinic Photosensitizers on HeLa cells 21.08.2017 Bern, University of Bern, Switzerland Furrer Julien; Gjuroski Ilche; Vermathen Martina;
SCS Fall Meeting 2017 Poster Enhancing the Properties of Chlorin e4 as Porphyrinic Photosensitizer by Polymer Encapsulation 21.08.2017 Bern, University of Bern, Switzerland Vermathen Martina; Furrer Julien; Gjuroski Ilche;
SCS Fall Meeting 2017 Poster Can Polymeric Nanoparticles protect Porphyrinic Compounds from reacting with Proteins? – An NMR Spectroscopic Investigation 21.08.2017 Bern, University of Bern, Switzerland Vermathen Martina; Gjuroski Ilche; Furrer Julien;
SCS Fall Meeting 2017 Poster Binding Properties of Polymer Nanoparticles Encapsulating Porphyrinic Photosensitizers 21.08.2017 Bern, University of Bern, Switzerland Gjuroski Ilche; Furrer Julien; Vermathen Martina;
ISMRM (International Society for Magnetic Resonance in Medicine) 24th Annual Meeting and Exhibition 2017 Poster NMR measurements of cell cultures: Increasing the metabolic stability of lysed cells by additional heating due to enzymatic inactivation 22.04.2017 Honolulu, United States of America Vermathen Martina; Diserens Gaëlle;
SCS Fall Meeting 2016 Poster Can Nanoparticle Carrier Systems decrease the Reactivity of Porphyrinic Photosensitizers towards Serum and Cytosolic Proteins? 15.09.2016 Zürich, University of Zürich, Switzerland Furrer Julien; Gjuroski Ilche; Vermathen Martina;
SCS Fall Meeting 2016 Poster Probing the cellular uptake and response of porphyrinic photosensitizers in polymeric nanoparticles by fluorescence measurements and 1H HR-MAS NMR based metabolic profiling of HeLa cells 15.09.2016 Zürich, University of Zürich, Switzerland Vermathen Martina; Diserens Gaëlle; Gjuroski Ilche; Furrer Julien;
SCS Fall Meeting 2016 Poster Polymer Delivery Systems of Porphyrin Photosensitizers Monitored by NMR Spectroscopy 15.09.2016 Zürich, University of Zürich, Switzerland Furrer Julien; Gjuroski Ilche; Vermathen Martina;
SCS Fall Meeting 2016 Poster Efficacy of Block Copolymers to Disaggregate and Encapsulate Porphyrins monitored by NMR Spectroscopy 15.09.2016 Zürich, University of Zürich, Switzerland Furrer Julien; Vermathen Martina; Gjuroski Ilche;
9th International Conference on Porphyrins and Phthalocyanines (ICPP-9) Talk given at a conference Encapsulation of Porphyrinic Photosensitizers into Polymers monitored by NMR Spectroscopy 03.07.2016 Nanjing, China Gjuroski Ilche; Furrer Julien; Vermathen Martina;
9th International Conference on Porphyrins and Phthalocyanines (ICPP-9) Poster 1H HR-MAS NMR Based Metabolic Profiling of Cells in Response to Treatment with Chlorin-Polymer Systems 03.07.2016 Nanjing, China Furrer Julien; Gjuroski Ilche; Diserens Gaëlle; Vermathen Martina;
12th Annual Conference of the Metabolomics Society Talk given at a conference Improving the metabolic stability of cultured cells during extended HR-MAS NMR measurements by prior heating 27.06.2016 Dublin, Ireland Diserens Gaëlle; Vermathen Martina; Furrer Julien;
SCS (Swiss Chemical Society) Fall Meeting 2015 Poster Preventing aggregation of porphyrinic photosensitizers using a biodegradable triblock copolymer 04.09.2015 Lausanne, EPFL, Switzerland Vermathen Martina; Furrer Julien; Gjuroski Ilche;
ISMRM (International Society for Magnetic Resonance in Medicine) 23rd Annual Meeting Poster Direct determination of phosphate sugars in biological material by 1H High Resolution-Magic Angle Spinning (HR-MAS) NMR spectroscopy. 30.05.2015 Toronto, Canada Vermathen Martina; Gjuroski Ilche; Diserens Gaëlle;
8th International Conference on Porphyrins and Phthalocyanines (ICPP-8) Poster Polyvinylpyrrolidone as Carrier System for Amino Acid Derivatives of Chlorin e6 studied by NMR Spectroscopy 22.06.2014 Istanbul, Turkey Vermathen Martina; Furrer Julien;


Associated projects

Number Title Start Funding scheme
128736 High Resolution Magic Angle Spinning (HR-MAS) probe for NMR Spectroscopic Investigations of semi-solid liquid-like materials 01.12.2009 R'EQUIP
119691 Systematic Biomimetic Studies on Porphyrins interacting with Membranes probed by NMR Spectroscopy 01.07.2008 Project funding (Div. I-III)

Abstract

BackgroundPhotodynamic Therapy (PDT) is based on the light triggered toxicity of photosensitizers (PSs), mainly porphyrinic compounds, accumulating in diseased tissue. PDT is thus a highly selective, minimally invasive treatment modality and as such recognized as promising alternative to conventional cancer therapy. Following the early success of Hematoporphyrin and Photofrin® numerous differently structured 2nd generation porphyrinic PSs have been designed. However, poor water solubility and self-association of porphyrinic PSs under physiologic conditions are still the main limitations of PDT and the reason for the yet small number of clinically approved PDT drugs. Therefore, the development of suitable carrier systems for the most promising PSs like amino acid conjugates of chlorin e6 will allow overcoming these problems thereby making a big step towards successful PDT applications. In particular, the use of biocompatible nanoparticles (NPs) has become a focus of current research in the field of PDT. To date, the number of such 3rd generation PSs associated with NPs is still very limited as is the understanding of NP uptake and interactions with cells. Nevertheless, the entry of PDT into nanomedicine is currently considered the most promising approach towards clinical approval of PDT drugs. Objective The proposed research project is designed as continuation of our previous NMR spectroscopic studies characterizing aggregation behavior and membrane interactions of porphyrinic compounds including amino acid conjugates of chlorin e6. The main goals of this proposal are: A) Preparation of nanoparticles composed of biocompatible block copolymers as carrier systems tailored for encapsulation of amino acid derivatives of chlorin e6. The NP formulation is aimed at preventing self-association of the chlorin compounds, enhancing their stability, cell uptake and intracellular phototoxicity which ultimately will lead to increased PDT efficacy and prospect of clinical approval. Liquid state NMR spectroscopy will be applied as powerful tool providing both, structural and dynamic information, to monitor the encapsulation process and determine the most relevant properties like payload or release rate of the chlorin-carrier systems.B) Application of fluorescence techniques as complementary tool to monitor cell uptake, intracellular localization and photophysical properties of internalized PSs which will help to estimate the synergic effect of the carrier system.C) As new approach in the field of PDT research, High Resolution Magic angle spinning (HR-MAS) NMR spectroscopy will be employed to study the cellular metabolic response to the treatment with pure and NP-encapsulated PS. Moreover, HR-MAS will be applied to monitor the phototoxic reaction following light irradiation.Importance and impactThe design of optimized biocompatible NPs for amino acid conjugates of chlorin e6 will leverage the prospect of clinical approval of these promising PDT drugs. The systems will likewise be transferrable to structurally related PSs thus contributing to improved drug design and better prediction of the treatment outcome. Combining NMR spectroscopy which provides insights into submolecular structural and dynamic properties with fluorescence techniques for photophysical characterization will provide a comprehensive picture of the newly developed PS-NP systems. In particular, the novel approach of HR-MAS NMR applied to living cells will contribute to a better understanding of the mechanisms involved in NP assisted PDT including interactions with cells and cellular uptake.
-