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Liposome-based targeting of dopamine to the brain: a novel approach for the treatment of Parkinson’s disease

Molecular Psychiatry volume 26, pages 2626–2632 (2021)Cite this article

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Abstract

Delivery of drugs into the brain is poor due to the blood brain barrier (BBB). This study describes the development of a novel liposome-based brain-targeting drug delivery system. The liposomes incorporate a diacylglycerol moiety coupled through a linker to a peptide of 5 amino acids selected from amyloid precursor protein (APP), which is recognized by specific transporter(s)/receptor(s) in the BBB. This liposomal system enables the delivery of drugs across the BBB into the brain. The brain-directed liposomal system was used in a mouse model of Parkinson’s disease (PD). Intra-peritoneal (IP) administration of liposomes loaded with dopamine (DA) demonstrated a good correlation between liposomal DA dose and the behavioral effects in hemiparkinsonian amphetamine-treated mice, with an optimal DA dose of 60 µg/kg. This is significantly lower dose than commonly used doses of the DA precursor levodopa (in the mg/kg range). IP injection of the APP-targeted liposomes loaded with a DA dose of 800 µg/kg, resulted in a significant increase in striatal DA within 5 min (6.9-fold, p < 0.05), in amphetamine-treated mice. The increase in striatal DA content persisted for at least 3 h after administration, which indicates a slow DA release from the delivery system. No elevation in DA content was detected in the heart or the liver. Similar increases in striatal DA were observed also in rats and mini-pigs. The liposomal delivery system enables penetration of compounds through the BBB and may be a candidate for the treatment of PD and other brain diseases.

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Fig. 1: Whole brain (upper panels) and coronal brain sections (lower panels) of mice.
Fig. 2: The impact of administration of free DA (600 µg/kg) and APP-targeted liposomes loaded with DA (40 and 60 µg/kg) on turns of hemiparkinsonian amphetamine-treated mice (mean ± SEM) for 15 min.
Fig. 3: The effect of IP administration of APP-targeted liposomes loaded with DA on striatal DA content (picomoles of DA/striatum) in amphetamine-treated mice, expressed by relative increases.
Fig. 4: Changes in striatal DA content 30 min after IP injection of APP-targeted liposomes loaded with DA (400 µg/kg) to naïve rats compared with non-targeted liposomes loaded with DA (400 µg/kg) and vehicle (50 mM ascorbic acid).
Fig. 5: The impact of APP-targeted liposomes loaded with DA compared with vehicle on striatal DA content in mini-pigs.

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Acknowledgements

This work was partially supported by the KAMIN project (Technion in collaboration with Tel Aviv University) of the Israel Innovation Authority [IIA] in the Ministry of Economy and Industry. The grant was given to MG and AW.

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Author notes

  1. Deceased: Nahum Allon.

Authors and Affiliations

  1. The Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, 31096, Haifa, Israel

    Meygal Kahana, Martin Gabay, Yelena Loboda, John Finberg, Nahum Allon & Moshe Gavish

  2. Research Unit at Geha Mental Health Center and the Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, 4910002, Petah Tikva, Israel

    Abraham Weizman

  3. Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Abraham Weizman, Hadar Segal-Gavish, Avishai Gavish & Dani Offen

  4. Sagol School of Neuroscience, Tel-Aviv University, 6997801, Tel Aviv, Israel

    Abraham Weizman & Dani Offen

  5. Laboratory of Neuroscience, Felsenstein Medical Research Center, 4910002, Petah Tikva, Israel

    Hadar Segal-Gavish, Yael Barhum & Dani Offen

  6. The Child Psychiatry Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, 5262000, Israel

    Hadar Segal-Gavish

  7. Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, 5262000, Israel

    Avishai Gavish

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  1. Meygal Kahana
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Correspondence to Moshe Gavish.

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None of the authors report any conflict of interest. They would like to note, however, that the present technology directed at liposome-based targeting of dopamine to the brain was described and patented by some of them.

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The study was approved by the Tel Aviv University and the Technion Institute of Technology Animal Care Committees and maintenance according to the guidelines of these committees

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Kahana, M., Weizman, A., Gabay, M. et al. Liposome-based targeting of dopamine to the brain: a novel approach for the treatment of Parkinson’s disease. Mol Psychiatry 26, 2626–2632 (2021). https://doi.org/10.1038/s41380-020-0742-4

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