Macromolecular prodrugs. XIII. Hydrosoluble conjugates of 17β-estradiol and estradiol-17β-valerate with polyaspartamide polymer

Abstract

Polymer-drug conjugates are macromolecular drug carrier systems with active agents attached as side substituents to a polymer backbone using an appropriate spacer. They could be an effective way to prolong drug activity, minimize unfavorable side effects and toxicity, decrease the required dose and increase the solubility of drugs (1). In addition, polymer-drug conjugates have the ability to overpass some mechanisms of drug resistance and the potential to elicit immunostimulatory effects. They can also alter the body distribution of drugs and ensure adequate drug delivery to target cells or tissues. This is Two hydrosoluble conjugates of 17b-estradiol (ED) and estradiol-17b-valerate (EV) with polyaspartamide polymer were prepared and characterized. ED and EV were first chemically modified and bound to poly[a,b-(N-2-hydroxyethyl-DL-aspartamide)]-poly[a,b-(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-17b-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.

Feasibility of polymer-drug conjugates for non-cancer applications

“…In the context of endocrine diseases PDCs have been suggested for hormone replacement therapy and diabetes ( Table 2). With regards of hormonal replacement therapy, the purpose was to improve the water solubility of estradiol, which was obtained by the same mechanism that was described in previous sections [160,161].…”