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Transporter-Targeted Drug Delivery´s Profile image

Transporter-Targeted Drug Delivery

Research group
01.09.2012 -
School of Pharmacy, Faculty of Health Sciences
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Leaders

Our research group studies how transporter proteins can be utilized in order to target drugs to their site of action, which would improve their efficacy and safety. We develop novel transporter-utilizing compounds and prodrugs that can release the active drug at their target site. More specifically we aim to:

1. Improve the drug delivery across the blood-brain barrier (BBB) and selectively into different cell types (neurons, astrocytes or microglia) within brain (intra-brain targeting)

2. Explore if dual targeting of LAT1-utilizing compounds into the brain and simultaneously into the pancreas (brain-pancreas axis) can have beneficial effects on the treatment of neurodegenerative diseases

3. Target chemotherapeutics (prodrugs or drug analogues) selectively into the cancer cells and inhibit specific transporter’s function to block nutrient delivery into the cancer cell or drug efflux out of the cancer cells (chemoresistance) to increase antiproliferative effects

We are also interested in how to modulate the expression of specific transporter’s expression or function to regulate nutrient or toxin uptake e.g., into the brain that can affect the progession of neurological diseases, or into specific cells, like cancer cells.

In our research group we focus on the journey of lifelong learning, although the scientific road can be a daily roll-a-coaster.

Read more about our scientific activities from our Word Press and Blogger pages:

https://sites.uef.fi/drug-targeting/

https://tmtdd.blogspot.com/

Our Research Projects

Methods

  • Computational drug design is used in the design of transporter-utilizing (pro)drugs and transporter inhibitors.

    The designed prodrug molecules are synthesized, purified (recrystallization, chromatography), and characterized (NMR, MS, Elemental analysis) in our state-of-the-art synthesis laboratories.

    Physicochemical and pharmaceutical properties (e.g. distribution coefficient (log D), aqueous solubility) and chemical stabilities at various pH values as well as plasma protein binding of the novel prodrugs are determined in our state-of-the-art analysis laboratories. The rate and quantity of the released parent drugs are evaluated in vitro in various enzyme-containing media (rodent and human-derived) and buffered solutions containing pure enzymes.

    Transporter- mediated uptake rate and extend of (pro)drugs into the human cells are evaluated in suitable cell lines expressing the desired transporter. The analysis are carried out in updated analytical equipment (UPLC-DAD, HPLC-F or LC-MS/MS) after suitable sample preparation.

    (Pro)drug pharmacokinetics and targeting efficacies are evaluated with more sophisticated in vivo studies in rodents. The analyses are carried as mentioned above and metabolic profiles of novel compounds are studied . Finally, in vitro-in vivo correlations of compound structure and targeting efficacy are projected.

    Pharmacological efficacy (preventative and curative) and possible toxicological properties (biocompatibility, cytotoxicity, genotoxicity, etc.) of the developed (pro)drugs are studied firstly in vitro and secondly in vivo. Reliable biomarkers (already known but also possible novel biomarkers) are identified by LC-MS/MS (targeted/global proteomics/metabolomics). Finally, in vitro-in vivo correlations are projected and translated to human situation.

Vacancies

Postdoctoral Candidates
Unfortunately, we do not have currently any open positions for postdoctoral researchers. However, our group is happy to support and help in writing any candidate with a clear vision of the proposed project that could be funded by e.g., Marie Skłodowska-Curie Individual Fellowship, Academy of Finland Postdoctoral Fellowship, UEF Postdoctoral Fellowship, or any other grants from national or international foundations.

Topics for M.Sc. Thesis or Diploma Work in Pharmacy for ERASMUS students:

    • Methods: Computer-aided Drug Design of Novel Molecules
    • Main supervisor: A. Prof. Kristiina Huttunen, Ph.D., Dr. Maija Lahtela-Kakkonen, Ph.D., and Ville Kuorikoski, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this project, the student will study the target protein (crystal structure or homology model) and design novel compounds (screening substructures and/or docking final compounds) against the target protein (activators, inhibitors, or substrates). If the student is interested to continue, you can participate in synthesizing these compounds. The compounds are studied further against neurodegenerative diseases or cancer in our in vitro and in vivo laboratories. The prepared compounds depends on the current state of the research and selected target protein. In this project, the student will learn the basics of computer-aided drug design. PROMM course is mandatory for modelling.
    • Methods: Design (database), Synthesis (organic chemistry) and Structural Characterization (NMR, MS) of Novel (Pro)Drug Molecules
    • Main supervisor: A. Prof. Kristiina Huttunen, Ph.D., Dr. Santosh Adla, Ph.D., (Seyed)Hamed Maljaei, M.Sc., and Landry Amamea, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this study, novel designed (prodrugs of) neuroprotective agents are synthesized by conventional organic chemistry methods, purified by chromatographic or crystallographic methods and finally characterized by NMR (nuclear magnetic resonance) and mass spectroscopy . In this project, the student will learn to design multistep reaction routes by using several databases and published literature as well as to perform essential methods in organic chemistry. Prepared prodrugs are then studied further against neurodegenerative diseases in our in vitro and in vivo laboratories. The project requires basic knowledge of organic/synthetic chemistry. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students. The prepared compounds depend on the current state of the research.
    • Methods: Chemical and Enzymatic Stability, Solubility, Unspecific Protein Binding, HPLC (UV/MS), Targeted/Global Proteomics/Lipidomics/Metabolomics
    • Supervisors: A. Prof. Kristiina Huttunen, Ph.D., Janne Tampio, M.Sc., and Adela Kralova, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this project, physicochemical and pharmaceutical properties, such as aqueous solubility, chemical stability, unspecific plasma/tissue protein binding, enzymatic bioconversion in various biological matrices (plasma, microsomes, liver/brain homogenate) and/or with pure enzymes of novel prodrugs of selected neuroprotective agents synthesized in our laboratories are evaluated. For each prodrug a simple HPLC (High Performance Liquid Chromatography)  or LC-MS (Mass Spectrometry) method are developed, by which the samples are analyzed. Selected biomarkers for each neuroprotective parent drugs and their prodrugs are evaluated by MS with targeted or untargeted (global) proteomic/lipidomic methods. In this study, the student will learn basic pharmaceutical techniques and learn to analyze properties of compounds from various sample matrices. The project requires basic knowledge of analytical chemistry. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students. The prepared compounds depend on the current state of the research.
    • Methods: Cell Culturing, Cytotoxicity, HPLC (UV/MS)
    • Supervisors: A. Prof. Kristiina Huttunen, Ph.D., and Janne Tampio, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this project, cellular uptake of transporter inhibitors and their effects on chemo-resistance mediated by efflux transporters are evaluated in human breast cancer cell lines. Transporter inhibitors and their cancer-cell targeted prodrugs are studied together with selected anti-cancer agent to evaluate the increase of combination therapy in anti-proliferative efficacy. In this study, the student will learn to handle the cell line, to perform the uptake and cell viability studies as well as analyze the results by a feasible HPLC (High Performance Liquid Chromatography) methods, which will be developed for each prodrug. The project requires basic knowledge of analytical chemistry and cell culturing. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students. The prepared compounds depend on the current state of the research.
    • Methods: Cell Culturing, Working with Radiolabeled Materials, HPLC (UV/MS)
    • Supervisors: A. Prof. Kristiina Huttune, Ph.D., Janne Tampio, M.Sc., and Adela Kralova, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In these studies, in-house prepared (pro)drugs are evaluated as substrates for selected transporter(s). This includes cis- and trans-inhibition studies of radiolabeled amino acids as well as concentration-dependent cellular uptake of studied compounds in human cancer cells or brain cells (e.g., microglia or astrocytes) over-expressing the selected transporter. The student will learn to handle the cell line as well as to perform the uptake studies and analyze the results by a feasible UV- or MS- HPLC (High Performance Liquid Chromatography) method, which will be developed for each prodrug. Several sub-projects are available and the studied compounds depend on the current state of the research. The project requires basic knowledge of analytical chemistry and cell culturing. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students.
    • Methods: In vivo, Mass Spectrometry (LC-MS)
    • Supervisors: A. Prof. Kristiina Huttunen, Ph.D. and Dr. Aaro Jalkanen, Ph.D.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this project, pharmacokinetic properties and brain-targeting efficacy of novel in-house synthesized prodrugs of neuroprotective agents are evaluated from the samples collected after in vivo studies from mice. The student will learn essential sample preparation techniques (extraction, protein precipitation) of plasma and tissue samples (brain, liver, kidney, pancreas, etc.) and to analyze compounds and biomarkers from biological matrices by feasible LC-MS methods. If wanted, student can also participate in in vivo studies. The project requires basic knowledge of analytical chemistry and possibly animal experiments. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students. The studied compounds depend on the current state of the research.
    • Methods: Mass Spectrometry, Targeted/Untargeted Proteomics/Lipidomics/Metabolomics, (Pathway) Data Analysis
    • Supervisors: A. Prof. Kristiina Huttunen, Ph.D., Janne Tampio, M.Sc., and Ahmed Montaser, M.Sc.
    • Contact: kristiina.huttunen (at) uef.fi
    • Other information: In this project, targeted proteomic/lipidomic/metabolomic approach is used to evaluate protein, lipid and metabolite differences in healthy, disease and drug-treated stages analyzed from the prepared in vitro and/or in vivo samples with mass spectrometry (MS). In addition, global proteomic/lipidomic/metabolomic approach (untargeted) and pathway analysis will be used to understand detailed mechanisms behind different diseases. In this study, the student will learn essential sample preparation techniques and how to analyze a massive amounts of data. The project requires basic knowledge of analytical chemistry and proteomic/lipidomic/metabolomic approach. However, the subprojects are scalable to both to Master Thesis level as well as to ERASMUS students. The exact topic depend on the current state of the research. The exact topic depend on the current state of the research.

Funding

  • Academy of Finland

    Sigrid Juselius Foundation

    Päivikki and Sakari Sohlberg’s Foundation

    Jane and Aatos Erkko Foundation

    Magnus Ehrnrooth Foundation

    UEF Strategic Funding (Doctoral Programme and Infrastructure Investments)

    Finnish Cultural Foundation

    Emil Aaltonen Foundation

    Alfred Kordelin Foundation

    Orion Research Foundation

    Finnish Pharmaceutical Society

    Paavo Koistinen Foundation

Keywords

drug analysis drug delivery drug synthesis drug targeting intrabrain drug delivery and targeting medicinal chemistry pharmaceutical chemistry pharmacokinetics pharmacy prodrug solute carriers transporter-mediated targeted drug delivery transporters

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    Publications

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