European Journal of Pharmaceutics and Biopharmaceutics
Research paperInulin–iron complexes: A potential treatment of iron deficiency anaemia
Introduction
Iron deficiency anaemia (IDA) is an extremely disseminate trouble involving about 1/3 of the global population. World Health Organization estimates that 46% of the world’s 5- to 14-year-old children are anaemic, the great majority resident in developing country [1]. In the Third World, 56% of pregnant women are anaemic. Even in developed country such as USA, about 7.8 million of women and about 700,000 of growing children have problems of iron deficiency [2], [3]. Iron is a component of proteins required for crucial cellular processes being iron-containing proteins involved in oxygen transport, ATP production, DNA synthesis, and other physiological processes [4], [5], [6]. The major processes responsible for modulating mammalian iron homeostasis are: intestinal absorption, interorgan transport and uptake, and cellular utilization [2]. Ferric iron is absorbed in the intestinal tract via a β3 integrin and mobilferrin pathway (IMP) which is unshared with other nutritional metals. Ferrous iron uptake in the intestinal tract is facilitated by a DMT-1 (divalent metal transporter-1) pathway that is shared with manganese [7], [8]. In iron deficiency, large quantities of both mobilferrin and DMT-1 are found in goblet cells and intraluminal mucin suggesting that they are secreted with mucin into the intestinal lumen where they bind either ferric or ferrous iron to maintain the iron available for absorption by the enterocytes [7], [9], [10], [11], [12], [13]. Furthermore, it was demonstrated that colon (both proximal and distal portion) is a good site for iron absorption, even more significantly, in condition of iron deficiency since in such circumstance, iron transport systems, including DMT1, were expressed in the large intestine at high levels [7], [14], [15], [16], [17], [18]. For these reasons, oral administration of iron can be successfully exploited to treat iron deficiency. The main drawbacks of oral iron administration are nausea, epigastric discomfort, diarrhoea, and constipation occurring within 1 h or two of ingestion [19], [3]. These symptoms vary proportionally to the concentration of ionizable iron in the upper gastrointestinal tract and they can be reduced by taking iron with food or using a chelated form. Other problems associated with the use of iron are the low solubility of uncomplexed form and its propensity to catalyze formation of toxic oxidants. In the last years, it was demonstrated that some naturally occurring nondigestible fructooligosaccharides such as inulin, with prebiotic effect, and their products of fermentation into the colon, could have an enhancing effect in iron absorption [20], [21], [22], [23], [24]. The mechanisms involved in this enhancer effect can be various; among all, the production of short-chain fatty acids, due to fermentation of inulin into the colon, determines a lowering in luminal pH of the colon with consequent increase in iron solubility and absorption [20]. Considering the potential to improve iron absorption by the co-administration of fructooligosaccharides such as inulin and the need to decrease side effects caused by the conventional iron administration eventually also with chelate forms, our idea was that to design and synthesize macromolecular derivatives of inulin able to complex iron and useful for oral iron administration. To this aim two different copolymers based on inulin have been prepared: a carboxylated derivative of inulin obtained by derivatization of inulin with succinic anhydride (SA) called INU–SA. The introduction of carboxylic moieties into inulin structure should enhance the iron complexation properties of INU. Furthermore, the reduction of intra-luminal pH, determined by carboxyl acid groups, should promote iron solubility [25], [26], [20]. Subsequently a thiolated/carboxylated derivative has been prepared by the reaction of INU–SA with cysteine (Cys) called INU–SA–Cys. The thiolated/carboxylated inulin has been ideated in order to enhance the interaction of inulin with intestinal mucosa [27] (by its interaction with mucin) with the aim to increase the residence time into the intestinal tract and to promote the absorption of iron consequently to colonic degradation of inulin backbone. The obtained INU–SA and INU–SA–Cys derivatives have been characterized and tested as iron complexing agents obtaining two different complexes INU–SA–FeIII and INU–SA–Cys–FeIII.
Section snippets
Materials
All reagents were of analytical grade. Succinic anhydride (SA), inulin from Dahlia Tubers Mw ≈ 5000 Da, inulinase from Aspergillus niger (INU-ase), cysteine hydrochloride anhydrous >99.5% (Cys), butanol 99.5%, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride >99% (EDC), dl-dithiothreitol 99.5% (DTT) and triethylamine (TEA) were from Fluka (Italy). Anhydrous N,N-dimethylformamide 99.9% (DMF), N,N-dimethylacetamide 99.8% (DMA), orcinol 97%, d-(−)-fructose (Fru), 1,10-phenanthroline >99%,
Results and discussion
In this paper a new approach to delivery iron ions into the gastrointestinal tract was designed. In order to obtain novel materials able to form complexes with iron ions useful as potential systems for the oral treatment of iron deficiency anaemia, we have performed suitable chemical modifications on inulin backbone. Inulin, a fructose polymer, was chosen for its colon biodegradability, biocompatibility, prebiotic properties and for the role played by itself and its degradation products in iron
Conclusions
This work proposed a new approach to delivery iron ion into intestinal tract designing new macromolecular chelating systems based on inulin. The choice of inulin as material to design a iron delivery system was based on its great biocompatibility and biodegradability into the intestinal tract. Furthermore, the formation of complexes with iron ion could assure the presence of the FeIII in a more available form, as reported in the literature for complexed forms of iron. Both obtained INU–SA and
Acknowledgement
Authors thank the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) for financial support.
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