SYNTHESIS OF ANTICANCER PRODRUGS FOR ENHANCED COMPLEXATION WITH CYCLODEXTRIN
Translated title
Syntese af anticancer prodrugs for forbedret kompleksdannelse med cyclodextrin
Author
Berentzen, Maria Fritz
Term
4. term
Education
Publication year
2017
Submitted on
2017-06-09
Pages
215
Abstract
Kræft stod i 2012 for cirka 13% af alle dødsfald globalt. Standardbehandlingen er ofte kemoterapi, men den er ikke særlig målrettet og kan give betydelige bivirkninger i hele kroppen. En mulig forbedring er at bruge nanobærere som cyklodextriner, ringformede sukkerbaserede molekyler, der kan indkapsle lægemidler. I dette projekt fremstillede vi prolægemidler (kemisk ændrede forstadier, der omdannes til det aktive lægemiddel i kroppen) af Doxorubicin og Gemcitabin for at forbedre deres kompleksdannelse med cyklodextriner. Målet var at opnå bedre binding til bærerne og dermed potentielt begrænse bivirkninger. Vi vurderede mulige ændringer og designede og syntetiserede i alt fire prolægemidler (to af hver), som blev isoleret i små mængder (~10-20 mg). Vi undersøgte derefter kompleksdannelsen med fem forskellige beta-cyklodextrin-derivater ved hjælp af isoterm titreringskalorimetri (ITC), som måler små varmeændringer for at bestemme, hvor stærkt molekyler binder. De opnåede associationskonstanter (KA) blev sammenlignet.
In 2012, cancer accounted for about 13% of all deaths worldwide. Chemotherapy remains a mainstay treatment, but it is not very specific and can cause whole-body side effects. One way to improve delivery is to use nanocarriers such as cyclodextrins, ring-shaped sugar-based molecules that can host drugs. This project created prodrugs (chemically modified precursors that convert to the active drug in the body) of Doxorubicin and Gemcitabine to improve their complexation with cyclodextrins. The aim was to achieve stronger binding to the carriers and potentially reduce side effects. We evaluated modification options and designed and synthesized four prodrugs in total (two of each), which were isolated in small amounts (~10-20 mg). We then studied complex formation with five different beta-cyclodextrin derivatives using isothermal titration calorimetry (ITC), a method that measures tiny heat changes to determine how tightly molecules bind. The resulting association constants (KA) were compared.
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