Abstract
Patients with β-thalassemia and sickle cell disease often rely on blood transfusions which can lead to hemochromatosis and chronic oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat hemochromatosis but is suboptimal to patients due to its poor pharmacokinetics which requires long-term infusion regimens. Although the oral route is preferable, DFO has limited oral bioavailability. Studies have shown that hyaluronic acid (HA) and bile acid (BA) can enhance the oral absorption of poorly absorbed drugs. To improve upon the oral delivery of DFO, we report on the synthesis and characterization of HA (MW 15 kD) conjugated to two types of BA, deoxycholic acid (DOCA) and taurocholic acid (TCA), and DFO. The resulting seven polymeric conjugates all formed self-assembled nanoparticles. The degree of BA and DFO conjugation to the HA polymer was confirmed at each step through nuclear magnetic resonance, Fourier transform infrared spectroscopy, and UV–Vis spectroscopy. The best formulations for further in vitro testing were determined based on physicochemical characterizations and included HA-DFO, TCA9-HA-DFO, and DOCA9-HA-DFO. Results from in vitro assays revealed that TCA9-HA-DFO enhanced the permeation of DFO the most and was also less cytotoxic to cells compared to the free drug DFO. In addition, ferritin reduction studies indicated that the conjugation of DFO to TCA9-HA did not compromise its chelation efficiency at equivalent free DFO concentrations. This research provides supportive data for the idea that TCA conjugated to HA may enhance the oral absorption of DFO, improve its cytocompatibility, and maintain its iron chelation efficiency.
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References
Wang Y, Liu Z, Lin T-M, Chanana S, Xiong MP. Nanogel-DFO conjugates as a model to investigate pharmacokinetics, biodistribution, and iron chelation in vivo. Int J Pharm. 2018;538(1–2):79–86.
Liu Z, Qiao J, Nagy T, Xiong MP. ROS-triggered degradable iron-chelating nanogels: safely improving iron elimination in vivo. J Control Release. 2018;283:84–93.
Royal CD, Babyak M, Shah N, Srivatsa S, Stewart KA, Tanabe P, et al. Sickle cell disease is a global prototype for integrative research and healthcare. Adv Genet. 2021;2(1):e10037.
Farshadpour F, Taherkhani R, Farajzadeh H. Hepatitis B infection among β-thalassemia major patients in Bushehr province of southern Iran. J Immunoassay Immunochem. 2023;44(2):147–61.
ADMINISTRATION USFD: FDA approves first gene therapies to treat patients with sickle cell disease. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease (2023). Accessed 08 Dec 2023.
Sheridan C. The world’s first CRISPR therapy is approved: who will receive it? Nat Biotechnol. 2024;42(1):3–4.
Vakulskas CA, Behlke MA. Evaluation and reduction of CRISPR off-target cleavage events. Nucleic Acid Ther. 2019;29(4):167–74.
Liu Z, Simchick GA, Qiao J, Ashcraft MM, Cui S, Nagy T, et al. Reactive oxygen species-triggered dissociation of a polyrotaxane-based nanochelator for enhanced clearance of systemic and hepatic iron. ACS Nano. 2020;15(1):419–33.
Hershko C, Abrahamov A, Konijn A, Breuer W, Cabantchik I, Pootrakul P, et al. Objectives and methods of iron chelation therapy. Bioinorg Chem Appl. 2003;1(2):151–68.
Pawlaczyk M, Schroeder G. Deferoxamine-modified hybrid materials for direct chelation of Fe (III) ions from aqueous solutions and indication of the competitiveness of in vitro complexing toward a biological system. ACS Omega. 2021;6(23):15168–81.
Salimi A, Zadeh BSM, Kazemi M. Preparation and optimization of polymeric micelles as an oral drug delivery system for deferoxamine mesylate: in vitro and ex vivo studies. Res Pharm Sci. 2019;14(4):293.
Rassu G, Soddu E, Cossu M, Brundu A, Cerri G, Marchetti N, et al. Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. J Control Release. 2015;201:68–77.
Poggiali E, Cassinerio E, Zanaboni L, Cappellini MD. An update on iron chelation therapy. Blood Transfus. 2012;10(4):411.
Farr AC, Xiong MP. Challenges and opportunities of deferoxamine delivery for treatment of Alzheimer’s disease, Parkinson’s disease, and intracerebral hemorrhage. Mol Pharm. 2020;18(2):593–609.
Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood. 2006;107(9):3436–41.
Liu L, Yang S, Chen F, Cheng K-W. Hyaluronic acid–zein core-shell nanoparticles improve the anticancer effect of curcumin alone or in combination with oxaliplatin against colorectal cancer via CD44-mediated cellular uptake. Molecules. 2022;27(5):1498.
Aguilera-Garrido A, Molina-Bolívar J, Gálvez-Ruiz M, Galisteo-González F. Mucoadhesive properties of liquid lipid nanocapsules enhanced by hyaluronic acid. J Mol Liq. 2019;296:111965.
Zhang M, Asghar S, Jin X, Hu Z, Ping Q, Chen Z, et al. The enhancing effect of N-acetylcysteine modified hyaluronic acid-octadecylamine micelles on the oral absorption of paclitaxel. Int J Biol Macromol. 2019;138:636–47.
Bhujbal S, Dash AK. Metformin-loaded hyaluronic acid nanostructure for oral delivery. AAPS PharmSciTech. 2018;19:2543–53.
Wu H, Guo T, Nan J, Yang L, Liao G, Park HJ, et al. Hyaluronic-acid-coated chitosan nanoparticles for insulin oral delivery: fabrication, characterization, and hypoglycemic ability. Macromol Biosci. 2022;22(7):2100493.
Zhao L, Ding J, He P, Xiao C, Tang Z, Zhuang X, et al. An efficient pH sensitive oral insulin delivery system enhanced by deoxycholic acid. J Control Release. 2011;152:e184–6.
Lei C, Liu X-R, Chen Q-B, Li Y, Zhou J-L, Zhou L-Y, et al. Hyaluronic acid and albumin based nanoparticles for drug delivery. J Control Release. 2021;331:416–33.
Tian H, He Z, Sun C, Yang C, Zhao P, Liu L, et al. Uniform core–shell nanoparticles with thiolated hyaluronic acid coating to enhance oral delivery of insulin. Adv Healthcare Mater. 2018;7(17):1800285.
Yegappan R, Selvaprithiviraj V, Mohandas A, Jayakumar R. Nano polydopamine crosslinked thiol-functionalized hyaluronic acid hydrogel for angiogenic drug delivery. Colloids Surf, B. 2019;177:41–9.
Zhu J, Tang X, Jia Y, Ho C-T, Huang Q. Applications and delivery mechanisms of hyaluronic acid used for topical/transdermal delivery–a review. Int J Pharm. 2020;578:119127.
Buckley C, Murphy EJ, Montgomery TR, Major I. Hyaluronic acid: a review of the drug delivery capabilities of this naturally occurring polysaccharide. Polymers. 2022;14(17):3442.
Wang S, Meng S, Zhou X, Gao Z, Piao MG. pH-Responsive and mucoadhesive nanoparticles for enhanced oral insulin delivery: the effect of hyaluronic acid with different molecular weights. Pharmaceutics. 2023;15(3):820.
Huang P, Yang C, Liu J, Wang W, Guo S, Li J, et al. Improving the oral delivery efficiency of anticancer drugs by chitosan coated polycaprolactone-grafted hyaluronic acid nanoparticles. J Mater Chem B. 2014;2(25):4021–33.
Lu Y, Wu L, Lin M, Bao X, Zhong H, Ke P, et al. Double layer spherical nanoparticles with hyaluronic acid coating to enhance oral delivery of exenatide in T2DM rats. Eur J Pharm Biopharm. 2023;191:205–18.
de Souza AB, Chaud MV, Santana MHA. Hyaluronic acid behavior in oral administration and perspectives for nanotechnology-based formulations: a review. Carbohyd Polym. 2019;222:115001.
Huang G, Huang H. Application of hyaluronic acid as carriers in drug delivery. Drug Deliv. 2018;25(1):766–72.
Samstein RM, Perica K, Balderrama F, Look M, Fahmy TM. The use of deoxycholic acid to enhance the oral bioavailability of biodegradable nanoparticles. Biomaterials. 2008;29(6):703–8.
Li Z, Zhang M, Liu C, Zhou S, Zhang W, Wang T, et al. Development of liposome containing sodium deoxycholate to enhance oral bioavailability of itraconazole. Asian J Pharm Sci. 2017;12(2):157–64.
Stojančević M, Pavlović N, Goločorbin-Kon S, Mikov M. Application of bile acids in drug formulation and delivery. Front Life Sci. 2013;7(3–4):112–22.
Hanafi NI, Mohamed AS, Sheikh Abdul Kadir SH, Othman MHD. Overview of bile acids signaling and perspective on the signal of ursodeoxycholic acid, the most hydrophilic bile acid, in the heart. Biomolecules. 2018;8(4):159.
Roda A, Minutello A, Angellotti M, Fini A. Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. J Lipid Res. 1990;31(8):1433–43.
Nurunnabi M, Khatun Z, Revuri V, Nafiujjaman M, Cha S, Cho S, et al. Design and strategies for bile acid mediated therapy and imaging. RSC Adv. 2016;6(78):73986–4002.
Han X, Wang Z, Wang M, Li J, Xu Y, He R, et al. Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration. Drug Deliv. 2016;23(5):1818–29.
Ossipov DA, Piskounova S, Varghese OP, Hilborn J. Functionalization of hyaluronic acid with chemoselective groups via a disulfide-based protection strategy for in situ formation of mechanically stable hydrogels. Biomacromolecules. 2010;11(9):2247–54.
Li N-N, Fu C-P, Zhang L-M. Using casein and oxidized hyaluronic acid to form biocompatible composite hydrogels for controlled drug release. Mater Sci Eng, C. 2014;36:287–93.
Ujhelyi Z, Fenyvesi F, Váradi J, Fehér P, Kiss T, Veszelka S, et al. Evaluation of cytotoxicity of surfactants used in self-micro emulsifying drug delivery systems and their effects on paracellular transport in Caco-2 cell monolayer. Eur J Pharm Sci. 2012;47(3):564–73.
Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007;2(9):2111–9.
Li J, Huo M, Wang J, Zhou J, Mohammad JM, Zhang Y, et al. Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials. 2012;33(7):2310–20.
Dong X, Liu C. Preparation and characterization of self-assembled nanoparticles of hyaluronic acid-deoxycholic acid conjugates. J Nanomater. 2010;2010:1–9.
Wei W-H, Dong X-M, Liu C-G. In vitro investigation of self-assembled nanoparticles based on hyaluronic acid-deoxycholic acid conjugates for controlled release doxorubicin: effect of degree of substitution of deoxycholic acid. Int J Mol Sci. 2015;16(4):7195–209.
Lee E, Kim YS, Bae SM, Kim SK, Jin S, Chung SW, et al. Polyproline-type helical-structured low-molecular weight heparin (LMWH)-taurocholate conjugate as a new angiogenesis inhibitor. Int J Cancer. 2009;124(12):2755–65.
Lai J-Y. Biofunctionalization of gelatin microcarrier with oxidized hyaluronic acid for corneal keratocyte cultivation. Colloids Surf, B. 2014;122:277–86.
Cui S, Liu Z, Nagy T, Agboluaje EO, Xiong MP. Oral non-absorbable polymer-deferoxamine conjugates for reducing dietary iron absorption. Mol Pharmaceutics. 2023;20(2):1285–95.
Han L, Zhao Y, Yin L, Li R, Liang Y, Huang H, et al. Insulin-loaded pH-sensitive hyaluronic acid nanoparticles enhance transcellular delivery. AAPS PharmSciTech. 2012;13:836–45.
Li L, Wang N, Jin X, Deng R, Nie S, Sun L, et al. Biodegradable and injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for postoperative adhesion prevention. Biomaterials. 2014;35(12):3903–17.
Brittenham GM. Iron-chelating therapy for transfusional iron overload. N Engl J Med. 2011;364(2):146–56.
Bayanzay K, Alzoebie L. Reducing the iron burden and improving survival in transfusion-dependent thalassemia patients: current perspectives. J Blood Med. 2016;7:159–69.
Annaba F, Kumar P, Dudeja AK, Saksena S, Gill RK, Alrefai WA. Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT. Am J Physiol-Gastrointest Liver Physiol. 2010;298(3):G467–73.
Yao W, Xu Z, Sun J, Luo J, Wei Y, Zou J. Deoxycholic acid-functionalised nanoparticles for oral delivery of rhein. Eur J Pharm Sci. 2021;159:105713.
Park J, Choi JU, Kim K, Byun Y. Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials. 2017;147:145–54.
Kim SK, Vaishali B, Lee E, Lee S, Lee Y-K, Kumar TS, et al. Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. Thromb Res. 2006;117(4):419–27.
Kim SK, Huh J, Kim SY, Byun Y, Lee DY, Moon HT. Physicochemical conjugation with deoxycholic acid and dimethylsulfoxide for heparin oral delivery. Bioconjug Chem. 2011;22(7):1451–8.
Khatun Z, Nurunnabi M, Cho KJ, Byun Y, Bae YH, Lee Y-K. Oral absorption mechanism and anti-angiogenesis effect of taurocholic acid-linked heparin-docetaxel conjugates. J Control Release. 2014;177:64–73.
Chen Z, Han S, Yang X, Xu L, Qi H, Hao G, Cao J, Liang Y, Ma Q, Zhang G, Sun Y. Overcoming multiple absorption barrier for insulin oral delivery using multifunctional nanoparticles based on chitosan derivatives and hyaluronic acid. Int J Nanomedicine. 2020;15:4877–98.
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E.A. wrote the initial draft of the manuscript and performed all the experiments. N.G. assisted with the microscopy experiments and image processing analysis. All authors have edited and approved the final version of the manuscript.
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Agboluaje, E.O., Cui, S., Grimsey, N.J. et al. Bile Acid–Targeted Hyaluronic Acid Nanoparticles for Enhanced Oral Absorption of Deferoxamine. AAPS J 26, 46 (2024). https://doi.org/10.1208/s12248-024-00911-z
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DOI: https://doi.org/10.1208/s12248-024-00911-z