Application of Reconstituted High-Density Lipoproteins for Cancer Immunotherapy
Author
Pedersbæk, Dennis
Term
4. term
Education
Publication year
2017
Submitted on
2017-08-10
Abstract
Lægemiddelleveringssystemer er bærere, der pakker og transporterer medicin til de rette celler for at forbedre effekten. Mange er rettet mod kræft, herunder immunterapi, som aktiverer kroppens eget forsvar. Dette studie undersøger højdensitetslipoprotein (HDL) – en naturlig partikel i blodet – som lægemiddelbærer. HDL er meget lille (omkring 10 nanometer), cirkulerer længe i blodet, tåles godt af mennesker og genkendes af kroppens egne receptorer. Laboratoriefremstillet HDL, kaldet rekonstitueret HDL (rHDL), kan bygges af apolipoprotein A‑I (apoA‑I) og lipider med forskellige sammensætninger og med indkapslede stoffer. Vi fremstillede skiveformede rHDL med apoA‑I oprenset fra humant plasma og varierede lipidsammensætningen. Disse rHDL‑partikler kunne indstilles til at binde sig fortrinsvist til monocytter, en type hvide blodlegemer, i helt menneskeblod. Det gør dem lovende til immunterapi, fordi de kan levere adjuvanser – immunstimulerende molekyler – der aktiverer monocytter mod kræftceller. Bemærkelsesværdigt opnåede vi denne målretning med rHDL med neutral lipidsammensætning. Til sammenligning kræver liposomer typisk positivt ladede (kationiske) lipider, som kan være toksiske, for at opnå en tilsvarende effekt. Når vi indlæssede en toll‑lignende receptor 7 (TLR7)‑agonist som adjuvans i rHDL og inkuberede dem i helt blod, udskilte blodceller cytokiner, der understøtter en antikræft immunrespons. Vi viste også, at rHDL kan levere antigen til isolerede dendritiske celler, så det kan præsenteres for cytotoksiske T‑celler, der kan dræbe kræftceller. Da levering af både adjuvans og antigen er vigtig for effektiv kræftimmunterapi, peger resultaterne på rHDL som alsidige leveringskøretøjer. Selvom nogle fund skal bekræftes ved gentagelse, indikerer studiet et stærkt potentiale for rHDL‑baserede leveringssystemer i kræftimmunterapi.
Drug delivery systems are carriers that package and transport medicines to the right cells to improve how well they work. Many are aimed at cancer, including immunotherapy that stimulates the body’s own defenses. This study explores high‑density lipoprotein (HDL)—a natural particle in blood—as a drug carrier. HDL is very small (about 10 nanometers), stays in circulation for a long time, is well tolerated in humans, and is recognized by the body’s own receptors. Laboratory‑made HDL, called reconstituted HDL (rHDL), can be built from apolipoprotein A‑I (apoA‑I) and lipids with different compositions and with drugs inside. We produced disc‑shaped rHDL using apoA‑I purified from human plasma and varied the lipid mix. These rHDL particles were tuned to associate preferentially with monocytes, a type of white blood cell, in whole human blood. This makes them promising carriers for immunotherapy because they can deliver adjuvants—immune‑stimulating molecules—to activate monocytes against cancer cells. Notably, we achieved monocyte targeting with rHDL that had a neutral lipid composition. In contrast, liposomes typically need positively charged (cationic) lipids, which can be toxic, to obtain a similar effect. When we loaded a toll‑like receptor 7 (TLR7) agonist as the adjuvant into rHDL and incubated them in whole human blood, the blood cells secreted cytokines that support anti‑cancer immune responses. We also showed that rHDL can deliver antigen to isolated dendritic cells so that it is presented to cytotoxic T cells, which can kill cancer cells. Since delivering both an adjuvant and an antigen is important for effective cancer immunotherapy, these results highlight the potential of rHDL as versatile delivery vehicles. Although some findings need to be confirmed by repeat experiments, the study indicates strong promise for rHDL‑based drug delivery in cancer immunotherapy.
[This abstract was generated with the help of AI]
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