Polymeric nanocarriers for the treatment of systemic iron overload

Abstract

Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload. Although iron chelators have been utilized since the 1960s and there has been much improvement in available therapy, there is still the need for new drug candidates due to limited long-term efficacy and drug toxicity. Moreover, all currently approved iron chelators are of low molecular weight (MW) (<600 Da) and the objectives reported for the “ideal” chelator of low MW, including possessing the ability to promote iron excretion without causing toxic side effects, has proven difficult to realize in practice. With prolonged iron chelator use, patients may develop toxicities or become insensitive. In contrast, the limited research that has been geared towards developing higher MW, polymeric, long circulating iron chelators has shown promise. The inherent potential of polymeric iron chelators toward longer plasma half-lives and reduction in toxicity provides optimism and may be a significant addition to the currently available low MW iron chelators. This article reviews knowledge pertaining to this theme, highlights some unique advantages that these nanomedicines have in treating systemic iron overload as well as their potential utility in the treatment of other disease states.

In vivo efficacy, toxicity and biodistribution of ultra-long circulating desferrioxamine based polymeric iron chelator

“…Although the properties offered by polymerconjugated forms of DFO are desirable, there is currently limited information available in the literature on the use of ULC drug conjugates for ICT [6]. Therefore, the information obtained by paying special attention to toxicity, effect of extended half-life on organ accumulation, and the lowest effective doses for ICT are highly valuable in enabling optimization of ULC chelators.…”

“…This has been well demonstrated in the field of iron chelation therapy (ICT) [6]. ICT is used to treat transfusion dependent patients with sickle-cell anemia (SC), β-thalassemia (β-TM) and the myelodysplastic syndromes (MDS) [7][8][9].…”

“…This was achieved using high MW biocompatible polymers [5,6,[18][19][20][21]. Different studies have shown that the properties of DFO can be tuned and enhanced to generate more suitable safety profiles, metal chelating efficacy and slower elimination.…”

Klinik Olarak Faydalı Demir Bağlayıcı Ligandların Tasarım Özellikleri

“…Şelat kelimesi Yunancada pençe anlamına gelen "chele" kelimesinden gelmektedir, bunu yengecin avını pençelemesine benzetilebilir. Bu durum bir metal iyonunun şelat yapıcı ajan tarafından hapsedilmesinin moleküller işlevini anlamamıza yardımcı olur (Şekil.1) 1,2,3,4 . 4 Ligandlar her bir moleküldeki verici atomların sayısına göre yapısal olarak sınıflandırılabilirler.…”

“…Bu durum bir metal iyonunun şelat yapıcı ajan tarafından hapsedilmesinin moleküller işlevini anlamamıza yardımcı olur (Şekil.1) 1,2,3,4 . 4 Ligandlar her bir moleküldeki verici atomların sayısına göre yapısal olarak sınıflandırılabilirler. Ligandtaki metal iyonu tutan bağların sayısına değinmek için dişlilik terimi kullanılır.…”