Targeted Delivery to the Central Nervous System utilizing Magnetically Guided Immunomagnetoliposomes
Author
Linemann, Thomas
Term
4. term
Publication year
2012
Submitted on
2012-06-01
Pages
43
Abstract
Behandling af hjernesygdomme er vanskelig, fordi blod-hjerne-barrieren (BBB) fungerer som et sikkerhedsfilter, der kun lader få, små fedtopløselige stoffer passere. Det begrænser mulighederne for at levere større og mere målrettede lægemidler. I dette projekt udviklede vi et magnetisk responsivt lægemiddelbæresystem: små magnetiske nanopartikler belagt med stivelse blev indkapslet i fosfolipider til magnetoliposomer. Dernæst koblede vi OX26-antistoffer på overfladen. OX26 binder til transferrinreceptoren, som findes i høj grad på endothelcellerne i hjernens kapillærer, og kan dermed hjælpe partiklerne med at blive genkendt og optaget. Vi testede først, hvor godt celler optog de forskellige partikler i dyrkede rotte-hjerneendothelceller. Derefter injicerede vi magnetoliposomer med og uden OX26 i unge rotter og undersøgte, hvor i kroppen partiklerne endte (hjerne, lever, milt, lunger og nyrer). Til sidst undersøgte vi i en kontrolleret hjerneperfusion, om partiklerne kunne passere BBB, både med og uden et eksternt magnetfelt. Resultaterne viste, at magnetoliposomer blev optaget markant bedre af celler end de oprindelige nanopartikler, og at OX26 yderligere øgede optaget. Efter injektion ophobede partiklerne sig især i lever og milt, mens der var meget lidt i hjernens blodkar. I perfusionsforsøgene blev OX26-magnetoliposomer optaget effektivt af kapillærernes endothelceller selv uden magnetfelt, hvilket passer med receptor-medieret optag. Med et magnetfelt sås en lille mængde partikler uden for blod-hjerne-barrieren, hvilket antyder, at transcytose (transport gennem cellerne) kan forekomme, men evidensen var ikke stærk eller konsekvent. Samlet set kan OX26-magnetoliposomer målrette hjernens kapillærceller og kan være nyttige til at levere lægemidler til disse celler. Om de også kan transportere lægemidler sikkert og effektivt ind i selve hjernevævet er derimod uklart. Derudover bør partiklernes stabilitet i blod forbedres for at gøre intravenøs behandling realistisk.
Treating brain disorders is difficult because the blood–brain barrier (BBB) acts like a security gate, allowing only a few small, fat-loving molecules to pass. This limits how we can deliver larger, more targeted medicines. In this project, we built a magnetically responsive drug carrier: starch-coated magnetic nanoparticles were packaged in a lipid shell to form magnetoliposomes. We then attached OX26 antibodies, which bind the transferrin receptor abundant on brain capillary endothelial cells, to help the particles be recognized and taken up. We first tested how well different particles were taken up by cultured rat brain endothelial cells. We then injected magnetoliposomes with and without OX26 into young rats and checked where the particles went in the body (brain, liver, spleen, lungs, and kidneys). Finally, we used a controlled brain perfusion setup to see whether the particles could cross the BBB, with and without an external magnetic field. We found that magnetoliposomes were taken up by cells much better than the original nanoparticles, and that OX26 further increased uptake. After injection, most particles accumulated in the liver and spleen, with very little in brain blood vessels. In perfusion experiments, OX26-magnetoliposomes were efficiently taken up by capillary endothelial cells even without a magnet, consistent with receptor-mediated uptake. With a magnetic field, a small amount appeared beyond the BBB, suggesting that transcytosis (transport through the cells) may occur, but the evidence was not strong or consistent. Overall, OX26-magnetoliposomes can target brain capillary cells and may be useful for delivering medicines to these cells. However, their ability to carry drugs across the BBB into brain tissue remains uncertain. The particles also need improved stability in blood to make intravenous use feasible.
[This abstract was generated with the help of AI]
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