Makromolekulski prolijekovi. XIII. Vodotopljivi konjugati 17β-estradiola i estradiol-17β-valerata s poliaspartamidnim polimerom

Two hydrosoluble conjugates of 17β-estradiol (ED) and estradiol-17β-valerate (EV) with polyaspartamide polymer were prepared and characterized. ED and EV were first chemically modified and bound to poly,-(N-2-hydroxyethyl-DL-aspartamide)-poly,-(N-2-aminoethyl-DL-aspartamide) (PAHA), a hydrosoluble polyaspartamide-type copolymer bearing both hydroxyl and amino groups. ED was first converted to 17-hemisuccinate (EDS) and then bound to PAHA. In the resulting conjugate PAHA-EDS, the estradiol moiety was linked to the polymer through a 2-aminoethylhemisuccinamide spacer. On the other hand, EV was first converted to estradiol-17-valerate-3-(benzotriazole-1-carboxylate), which readily reacted with amino groups in PAHA affording the polymer-drug conjugate PAHA-EV. In the prepared conjugate PAHA-EV, the estradiol moiety was covalently bound to the polyaspartamide backbone by carbamate linkage, through an ethylenediamine spacer. The polymer-drug conjugates were designed and prepared with the aim to increase water-solubility, bioavailability and to improve drug delivery of the lipophilic estrogen hormone.U radu je opisana priprava i karakterizacija dvaju vodotopljivih polimer-lijek konjugata 17β-estradiola (ED) i estradiol-17β-valerata (EV) s poliaspartamidnim polimerom. ED i EV su prvo kemijski modificirani i vezani na poli,-(N-2-hidroksietil-DL-aspartamid)-poli,-(N-2-aminoetil-DL-aspartamid) (PAHA), vodotopljivi poliaspartamidni kopolimer s hidroksi i amino skupinama. ED je prvo preveden u 17-hemisukcinat (EDS), a zatim vezan na PAHA. U nastalom konjugatu PAHA-EDS estradiolska komponenta vezana je na polimer preko 2-aminoetilhemisukcinatne razmaknice. S druge strane, EV je prvo preveden u estradiol-17-valerat-3-(benzotriazol-1-karboksilat), koji reagira s amino skupinama u PAHA dajući polimer-lijek konjugat PAHA-EV. U tom je konjugatu estradiolska komponenta kovalentno vezana na poliaspartamidnu okosnicu karbamatnom vezom, preko etilenediaminske razmaknice. Polimer-lijek konjugati estradiola dizajnirani su i pripravljeni sa ciljem da se poveća topljivost i bioraspoloživost te isporuka tog lipofilnog estrogenog hormona