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

Končič, Marijana; Zorc, Branka; Novak, Predrag

doi:10.2478/v10007-011-0039-x

Abstract

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[α,β-(N-2-hydroxyethyl-DL-aspartamide)]-poly[α,β-(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-17β-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.

References

F. M. Veronese and M. Morpurgo, Bioconjugation in pharmaceutical chemistry, Farmaco 54 (1999) 497-516; DOI: 10.1016/S0014-827X(99)00066-X.10.1016/S0014-827X(99)00066-X
Search in Google Scholar
F. Greco and M. J. Vicent, Combination therapy: Opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines, Adv. Drug Deliver. Rev. 61 (2009) 1203-1213; DOI: 10.1016/j.addr.2009.05.006.10.1016/j.addr.2009.05.006
Search in Google Scholar
G. Pitarresi, F. Saiano, G. Cavallaro, D. Mandracchia and F. S. Palumbo, A new biodegradable and biocompatible hydrogel with polyaminoacid structure, Int. J. Pharm. 335 (2007) 130-137; DOI: 10.1016/j.ijpharm.2006.11.012.10.1016/j.ijpharm.2006.11.012
Search in Google Scholar
B. Zorc, M. Ljubić, S. Antolić, J. Filipović-Grčić, D. Maysinger, T. Alebić-Kolbah and I. Jalšenjak, Macromolecular prodrugs. II. Esters of L-dopa and α-methyldopa, Int. J. Pharm. 99 (1993) 135-143.10.1016/0378-5173(93)90355-J
Search in Google Scholar
M. Lovrek, B. Zorc, B. Boneschans and I. Butula, Macromolecular prodrugs. VIII. Polymer-gemfibrozil conjugates, Int. J. Pharm. 200 (2000) 59-66.10.1016/S0378-5173(00)00340-9
Search in Google Scholar
M. Zovko, B. Zorc, M. Lovrek and B. Boneschans, Macromolecular prodrugs. IX. Synthesis of polymer-fenoprofen conjugates, Int. J. Pharm. 228 (2001) 129-138.10.1016/S0378-5173(01)00822-5
Search in Google Scholar
G. Cavallaro, L. Maniscalco, M. Campisi, D. Schillaci and G. Giammona, Synthesis, characterization and in vitro cytotoxicity studies of a macromolecular conjugate of paclitaxel bearing oxytocin as targeting moiety, Eur. J. Pharm. Biopharm. 66 (2007) 182-192; DOI: 10.1016/j.ejpb.2006.10.013.10.1016/j.ejpb.2006.10.01317182230
Search in Google Scholar
G. Cavallaro, S. Scirè, M. Licciardi, M. Ogris, E. Wagner and G. Giammona, Polyhydroxyethyl-aspartamide-spermine copolymers: Efficient vectors for gene delivery, J. Control. Release 131 (2008) 54-63; DOI: 10.1016/j.jconrel.2008.07.001.10.1016/j.jconrel.2008.07.00118675862
Search in Google Scholar
M. Zovko, B. Zorc, P. Novak, P. Tepeš, B. Cetina-Čižmek and M. Horvat, Macromolecular prodrugs. XI. Synthesis and characterization of polymer-estradiol conjugate, Int. J. Pharm. 285 (2004) 35-41; DOI: 10.1016/j.ijpharm.2004.07.013.10.1016/j.ijpharm.2004.07.01315488677
Search in Google Scholar
M. Barbarić, M. Kralj, M. Marjanović, I. Husnjak, K. Pavelić, J. Filipović-Grčić, D. Zorc and B. Zorc, Synthesis and in vitro antitumor effect of diclofenac and fenoprofen thiolated and non-thiolated polyaspartamide-drug conjugates, Eur. J. Med. Chem. 42 (2007) 20-29; DOI: 10.1016/j.ejmech.2006.08.009.10.1016/j.ejmech.2006.08.00917010482
Search in Google Scholar
B. Zorc, D. Maysinger, I. Kalčić and I. Butula, Macromolecular prodrugs. V. Polymer-broxuridine conjugates, Int. J. Pharm. 123 (1995) 65-70; DOI: 10.1016/0378-5173(95)00040-P.10.1016/0378-5173(95)00040-P
Search in Google Scholar
A. Agarwal, S. Saraf, A. Asthana, U. Gupta, V. Gajbhiye and N. K. Jain, Ligand based dendritic systems for tumor targeting, Int. J. Pharm. 350 (2008) 3-13; DOI: 10.1016/j.ijpharm.2007.09.024.10.1016/j.ijpharm.2007.09.024
Search in Google Scholar
G. M. Dubowchik and M. A. Walker, Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer, Pharmacol. Therapeut. 83 (1999) 67-123; DOI: 10.1016/S0163-7258(99)00018-2.10.1016/S0163-7258(99)00018-2
Search in Google Scholar
I. Kalčić, M. Zovko, M. Jadrijević-Mladar Takač, B. Zorc and I. Butula, Synthesis and reactions of some azole carboxylic acid derivatives, Croat. Chem. Acta 76 (2003) 217-228.
Search in Google Scholar
T. O. Yellin, Estradiol 17β-hemisuccinate: an improved procedure, J. Lipid Res. 13 (1972) 554-555.10.1016/S0022-2275(20)39390-1
Search in Google Scholar

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

Abstract

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