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Macrophage Hitchhiking Nanoparticles for the Treatment of Myocardial Infarction: An In Vitro and In Vivo Study |
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| Authors: | Giulia Torrieri Imran Iqbal Flavia Fontana Virpi Talman Heidi Liljenbäck Andriana Putri Wail Nammas Johan Rajander Xiang Guo-Li Philip S. Low Tambet Teesalu Anne Roivainen Jouni Hirvonen Heikki Ruskoaho Vimalkumar Balasubramanian Antti Saraste Hélder A. Santos |
| Affiliation: | 1. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00140 Helsinki, Finland;2. Turku PET Centre, University of Turku, 20521 Turku, Finland;3. Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, FI-00140 Helsinki, Finland;4. Turku PET Centre, University of Turku, 20521 Turku, Finland Turku Center for Disease Modeling, University of Turku, FI-20014 Turku, Finland;5. Accelerator Laboratory, Åbo Akademi University, Turku, FI-20500 Finland;6. Turku PET Centre, University of Turku, 20521 Turku, Finland InFLAMES Research Flagship Center, University of Turku, Turku, Finland;7. Department of Chemistry, Purdue University, West Lafayette, IN, 47907-2084 USA;8. Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, 50411 Estonia Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, 92037 USA;9. Turku PET Centre, University of Turku, 20521 Turku, Finland Turku Center for Disease Modeling, University of Turku, FI-20014 Turku, Finland InFLAMES Research Flagship Center, University of Turku, Turku, Finland Turku PET Centre, Turku University Hospital, 20521 Turku, Finland;10. Chemical and Pharmaceutical Development, Bayer Oy, FI-20210 Turku, Finland |
| Abstract: | Myocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above-mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI-selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin-TT1 peptide-mediated hitchhiking on M2-like macrophages. The system based on pH-responsive putrescine-modified acetalated dextran (Putre-AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor-dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self-renewal promoting compounds, CHIR99021 and SB203580, induces a 4-fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2-like macrophages targeting by lin-TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short-term safety of the developed system in vivo. Overall, the study results in the development of a peptide-guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart. |
| Keywords: | cardiac regeneration heart targeting nanoparticles hitchhiking effect macrophage recruitment positron emission tomography |