Drug delivery liposomes and extracellular vesicles

A key focus of our research is the development of liposome based drug delivery systems (LDS). The LDS represents the most developed and promising form of nanovector, representing more than half of all approved nanomedicine based therapies approved so far. The liposome, from which the LDS is formed, is a phospholipid bilayer formed into an enclosed sack. The LDS is a versatile drug delivery vector: it can both carry lipophilic drugs in the phospholipid membrane, or hydrophilic drugs in the internal cavity. The properties of the phospholipid bilayer can be controlled through formulation. A protective polymer corona and even targeting ligands can be added to the LDS exterior through functionalization of the phospholipid headgroups. The current gold standard for protective polymer corona is poly(ethylene glycol) (PEG); an LDS with such a polymer corona is said to be “PEGylated”. The relationship between formulation and the structure and function of the LDS is not immediately apparent. We have, over the course of several years and through several publications listed below, developed a combined computational-experimental framework for the study of the relationship between LDS formulation and structure and function. In many cases we have been able to provide guidance to experimental researchers developing LDS based therapies. Extracellular vesicles (EVs), the lipid bilayer structured vesicles secreted by cells that can be found in most body fluids, share common characteristics with the LDS e.g., size, morphology and surface charge; EVs encapsulate various genes, proteins, and other molecules from their cells of origin. EVs can deliver their cargo to recipient cells over long distances, and are therefore considered as promising biomarkers for many diseases as well as drug carriers. In the context of their use as a drug delivery agent, the EV can be seen as the next step in complexity beyond the LDS. We are aiming to build a better mechanistic understanding of EVs in respect to drug targeting and delivery by further utilizing the combined computational-experimental framework developed to study LDS based formulations. Our publications in this area of research are linked below.

Drug delivery liposomes and extracellular vesicles

 

Publications in this area:

 

M. Dzieciuch-Rojek, C. Poojari, J. Bednar, A. Bunker, B. Kozik, M. Nowakowska, I. Vattulainen, P. Wydro, M. Kepczynski, and T. Rog: Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications. Molecular Pharmaceutics. 14, 4, p. 1057-1070 (2017).

N. Wilkosz, S. Rissanen, M. Cyza, R. Szybka, M. Nowakowska, A. Bunker, T. Rog and M. Kepczynski: Effect of piroxicam on lipid membranes: Drug encapsulation and gastric toxicity aspects. Eur. J. Pharm. Sci. 100, p. 116-125 (2017).

A. Magarkar, A., T. Róg and A. Bunker: A computational study suggests that replacing PEG with PMOZ may increase exposure of hydrophobic targeting moiety Eur. J. Pharm. Sci. 103, p. 128-135 (2017).

V. Dhawan, A. Magarkar, G. Joshi, D. Makhija, A. Jain, J. Shah, B. V. Reddy, M. Krishnapriya, T. Róg, A. Bunker, A. Jagtap, and M. Nagarsenker: Stearylated cycloarginine nanosystems for intracellular delivery - simulations, formulation and proof of concept. RSC Adv. 6, 114, pp. 113538-113550 (2016).

Alex Bunker: Computational Modeling Using the Multiscale Modeling Paradigm: The Key to Achieving Rational Design in Nanomedicine; Liposome-Based Drug Delivery Systems as a Case Study. CRS Newsletter 33(5), pp. 13-15 (2016).

Lauri Viitala, Adam M. Maley, H. W. Millie Fung, Robert M. Corn, Tapani Viitala and Lasse Murtomäki: Surface Plasmon Resonance Imaging Microscopy of Liposomes and Liposome-Encapsulated Gold Nanoparticles. J. Phys. Chem. C 120(45), pp. 25958–25966 (2016).

Otto K. Kari, Tatu Rojalin, Stefano Salmaso, Michela Barattin, Hanna Jarva, Seppo Meri, Marjo Yliperttula, Tapani Viitala and Arto Urtti: Multi-parametric surface plasmon resonance platform for studying liposome-serum interactions and protein corona formation. Drug Deliv. Transl. Res. 7(2), pp 1-13 (2017).

A. Bunker, A. Magarkar and T. Viitala: Rational design of liposomal drug delivery systems, a review: combining insight from experimental and computational study of lipid membranes, liposomes and their PEGylation. BBA – Biomembranes 1858(10), pp. 2334 – 2352 (2016).

P. Pathak, V. Dhawan, A. Magarkar, R. Danne, S. Govindarajan, S. Ghosh, F. Steiniger, P. Chaudhari, V. Gopal, A. Bunker, T. Róg, A. Fahr and M. Nagarsenker: Design of cholesterol arabinogalactan anchored liposomes for asialoglycoprotein receptor mediated targeting to hepatocellular carcinoma: in silico modelling, in vitro and in vivo evaluation. Int. J. Pharm. 509 (1-2), pp. 149 – 158 (2016).

T. Lajunen, L.-S. Kontturi, L. Viitala, M. Manna, O. Cramariuc, T. Róg, A. Bunker, T. Laaksonen, T. Viitala, L. Murtomäki and A. Urtti: Indocyanine green loaded liposomes for light triggered drug release. Mol. Pharm 13(6), pp. 2095 – 2107 (2016).

Lauri Viitala, Saija Pajari, Tatu Lajunen , Leena-Stiina Kontturi, Timo Laaksonen, Päivi Kuosmanen, Tapani Viitala, Arto Urtti and Lasse Murtomäki: Photothermally Triggered Lipid Bilayer Phase Transition and Drug Release from Gold Nanorod and Indocyanine Green Encapsulated Liposomes. Langmuir 32, pp. 4554-4563 (2016).

Zachary J. Smith, Changwon Lee, Tatu Rojalin, Randy  P. Carney, Sidhartha Hazari, Alisha Knudson, Kit Lam, Heikki Saari, Elisa Lazaro Ibañez, Tapani Viitala, Timo Laaksonen, Marjo Yliperttula, and Sebastian Wachsmann-Hogiu: Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J. Extracell. Vesicles 4, 28533 (2015).

Heikki Saari, Elisa Lázaro-Ibáñez, Tapani Viitala, Elina Vuorimaa-Laukkanen, Pia Siljander and Marjo Yliperttula: Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of paclitaxel in autologous prostate cancer cells. J. Control. Release 220, pp. 727-737 (2015).

Lauri Viitala, Tatu Lajunen, Arto Urtti, Tapani Viitala and Lasse Murtomäki: Detection of bilayer phase transition in photosensitive liposomes for advanced QCM. J. Phys. Chem. C 119, pp. 21395–21403 (2015).

Tatu Lajunen, Lauri Viitala, Timo Laaksonen, Huamin Liang, Elina Vuorimaa-Laukkanen, Tapani Viitala, Xavier Le Guével, Marjo Yliperttula, Lasse Murtomäki and Arto Urtti: Light induced cytoplasmic drug delivery from liposomes with gold nanoparticles. J. Control. Release 203, pp. 85-98 (2015) .

Monika Dziechiuch, Sami Rissanen, Natalia Szydlowska, Alex Bunker, Marta Kumorek, Dorota Jamróz, Ilpo Vattulainen, Maria Nowalkowska, Tomasz Róg and Mariusz Kepczynski: PEGylated liposomes as carriers of hydrophobic porphyrins. J. Phys. Chem. B. 119(22), pp. 6646 – 6657 (2015).

Aniket Magarkar, Tomasz Róg and Alex Bunker: Molecular dynamics simulation of inverse-phosphocholine lipids.  J. Phys. Chem. C 118(33), pp. 19444-19449 (2014).

Aniket Magarkar, Tomasz Róg and Alex Bunker: Molecular dynamics simulation of PEGylated membranes with cholesterol: building toward the DOXIL formulation. J. Phys. Chem. C 118(28), pp. 15541-15549 (2014).

Mohammed Elmowafy, Tapani Viitala, Hany Mahmoud, Sherief Khalifa, Ahmed Samy, Alaa Kassem and Marjo Yliperttula: Silymarin loaded hepatic targeting liposomes: In vitro evaluation and HepG2 drug uptake. Eur. J. Pharm. Sci. 50, pp. 161-171 (2013).

Huamin Liang, Jussi-Pekka Tuppurainen, Julia Lehtinen, Tapani Viitala and Marjo Yliperttula: Non-labelled monitoring of targeted liposome interactions with a model receptor surface: effect of flow rate and water content. Eur. J. Pharm. Sci. 50, pp. 492-501 (2013).

Julia Lehtinen, Aniket Magarkar, Michał Stepniewski, Satu Hakola, Mathias Bergmann, Tomasz Róg, Marjo Yliperttula, Arto Urtti and Alex Bunker: Analysis of cause of failure of new targeting peptide in PEGylated liposome: molecular modeling as rational design tool for nanomedicine. Eur. J. Pharm. Sci. 46(3), pp. 121-130 (2012).

 Aniket Magarkar, Esra Karakas, Michał Stepniewski, Tomasz Róg and Alex Bunker: Molecular dynamics simulation of PEGylated bilayer interacting with salt ions: a model of the liposome surface in the bloodstream. J. Phys. Chem. B 116(14), pp. 4212-4219 (2012).

Michał Stepniewski, Marta Paswnkiewicz-Gierula, Tomasz Róg, Reinis Danne, Adam Orłowski, Mikko Karttunen, Arto Urtti, Marjo Yliperttula, Elina Vuorimaa and Alex Bunker: Study of PEGylated lipid layers as a model for PEGylated liposome surfaces: molecular dynamics simulation and Langmuir monolayer studies. Langmuir 27(12):7788-7798 (2011).