Chitosan-based nanocomplexes for simultaneous loading, burst reduction and controlled release of doxorubicin and 5-fluorouracil

Di Martino, Antonio; Kucharczyk, Pavel; Capáková, Zdenka; Humpolíček, Petr; Sedlařík, Vladimír

dc.title	Chitosan-based nanocomplexes for simultaneous loading, burst reduction and controlled release of doxorubicin and 5-fluorouracil	en
dc.contributor.author	Di Martino, Antonio
dc.contributor.author	Kucharczyk, Pavel
dc.contributor.author	Capáková, Zdenka
dc.contributor.author	Humpolíček, Petr
dc.contributor.author	Sedlařík, Vladimír
dc.relation.ispartof	International Journal of Biological Macromolecules
dc.identifier.issn	0141-8130 Scopus Sources, Sherpa/RoMEO, JCR
dc.date.issued	2017
utb.relation.volume	102
dc.citation.spage	613
dc.citation.epage	624
dc.type	article
dc.language.iso	en
dc.publisher	Elsevier
dc.identifier.doi	10.1016/j.ijbiomac.2017.04.004
dc.relation.uri	https://www.sciencedirect.com/science/article/pii/S0141813016328501
dc.subject	5-Fluorouracil	en
dc.subject	Burst effect	en
dc.subject	Chitosan	en
dc.subject	Doxorubicin	en
dc.subject	Drug delivery	en
dc.subject	Polycomplexes	en
dc.description.abstract	In this work, nanocomplexes based on chitosan grafted by carboxy-modified polylactic acid (SPLA) were prepared with the aim of loading simultaneously two anticancer drugs – doxorubicin and 5-fluorouracil, as well as to control their release, reduce the initial burst and boost cytotoxicity. The SPLA was prepared by a polycondensation reaction, using pentetic acid as the core molecule, and linked to the chitosan backbone through a coupling reaction. Nanocomplexes loaded with both drugs were formulated by the polyelectrolyte complexation method. The structure of the SPLA was characterized by 1H NMR, while the product CS-SPLA was analyzed by FTIR-ATR to prove the occurrence of the reaction. Results showed that the diameters and ζ-potential of the nanocomplexes fall in the range 120–200 nm and 20–37 mV, respectively. SEM and TEM analysis confirmed the spherical shape and dimensions of the nanocomplexes. The presence of hydrophobic side chain SPLA did not influence the encapsulation efficiency of the drugs but strongly reduced the initial burst and prolonged release over time compared to unmodified chitosan. MS analysis showed that no degradation or interactions between the drugs and carrier were exhibited after loading or 24 h of release had taken place, confirming the protective role of the nanocomplexes. In vitro tests demonstrated an increase in the cytotoxicity of the drugs when loaded in the prepared carriers. © 2017 The Authors	en
utb.faculty	University Institute
dc.identifier.uri	http://hdl.handle.net/10563/1007343
utb.identifier.obdid	43876700
utb.identifier.scopus	2-s2.0-85018619672
utb.identifier.wok	000406984300068
utb.identifier.pubmed	28431942
utb.identifier.coden	IJBMD
utb.source	j-scopus
dc.date.accessioned	2017-09-08T12:14:43Z
dc.date.available	2017-09-08T12:14:43Z
dc.description.sponsorship	15-08287Y, GACR, Grantová Agentura České Republiky
dc.description.sponsorship	Czech Science Foundation [15-08287Y]; Ministry of Education, Youth and Sports of the Czech Republic [LO1504, CZ.1.05/2.1.00/19.0409]
utb.ou	Centre of Polymer Systems
utb.contributor.internalauthor	Di Martino, Antonio
utb.contributor.internalauthor	Kucharczyk, Pavel
utb.contributor.internalauthor	Capáková, Zdenka
utb.contributor.internalauthor	Humpolíček, Petr
utb.contributor.internalauthor	Sedlařík, Vladimír
utb.fulltext.affiliation	Antonio Di Martino, Pavel Kucharczyk, Zdenka Capakova, Petr Humpolicek, Vladimir Sedlarik ∗ Centre of Polymer Systems, University Institute, Tomas Bata University in Zlin, tr. T. Bati 5678, 76001 Zlin, Czech Republic ∗ Corresponding author. E-mail address: sedlarik@cps.utb.cz (V. Sedlarik).
utb.fulltext.dates	Received 14 December 2016 Received in revised form 9 March 2017 Accepted 2 April 2017 Available online 18 April 2017
utb.fulltext.references	[1] Kumari, K.Y. Sudesh, C.Y. Subhash, Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B 75 (1) (2010) 1–18. [2] H.P. James, R. John, A. Alex, K.R. Anoop, Smart polymers for the controlled delivery of drugs – a concise overview, APSB 4 (2) (2014) 120–127. [3] K. Park, Controlled drug delivery systems: past forward and future back, J. Control. Release 190 (2014) 3–8. [4] A.S. Hasan, M. Socha, A. Lamprecht, F. El Ghazouani, A. Sapin, M. Hoffman, N. Ubrich, Effect of the microencapsulation of nanoparticles on the reduction of burst release, Int. J. Pharm. 344 (1) (2007) 53–61. [5] X. Huang, C.S. Brazel, On the importance and mechanisms of burst release in matrix-controlled drug delivery systems, J. Control. Release 73 (2) (2001) 121–136. [6] P. Sriamornsak, G.L. Casallas-Hernández, S. Manchun, M. Kumpugdee-Vollrath, A burst drug release caused by imperfection of polymeric film-coated microparticles prepared by a fluidized bed coater, Pharmazie 66 (8) (2011) 576–583. [7] X. Huang, B.L. Chestang, C.S. Brazel, Minimization of initial burst in poly (vinyl alcohol) hydrogels by surface extraction and surface-preferential crosslinking, Int. J. Pharm. 248 (1) (2002) 183–192. [8] J. Qi, P. Yao, F. He, C. Yu, C. Huang, Nanoparticles with dextran/chitosan shell and BSA/chitosan core–doxorubicin loading and delivery, Int. J. Pharm. 393 (1) (2010) 177–185. [9] K.A. Janes, M.P. Fresneau, A. Marazuela, A. Fabra, M.J. Alonso, Chitosan nanoparticles as delivery systems for doxorubicin, J. Control. Release 73 (2) (2001) 255–267. [10] G. Odian, Principle of Polymerization, J. Wiley & Sons, New York, 2004. [11] R. Nagahata, D. Sano, H. Suzuki, K. Takeuchi, Microwave-assisted single-step synthesis of poly (lactic acid) by direct polycondensation of lactic acid, Macromol. Rapid Commun. 28 (4) (2007) 437–442. [12] S.I. Moon, C.W. Lee, M. Miyamoto, Y. Kimura, Melt polycondensation of l-lactic acid with Sn (II) catalysts activated by various proton acids: a direct manufacturing route to high molecular weight poly (l-lactic acid), J. Polym. Sci. A: Polym. Chem. 38 (9) (2000) 1673–1679. [13] D. Garlotta, A literature review of poly (lactic acid), J. Polym. Environ. 9 (2) (2001) 63–84. [14] O. Tacar, P. Sriamornsak, C.R. Dass, Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems, J. Pharm. Pharmacol. 65 (2) (2013) 157–170. [15] S.A. Kamba, M. Ismail, S.H. Hussein-Al-Ali, T.A.T. Ibrahim, Z.A.B. Zakaria, In vitro delivery and controlled release of doxorubicin for targeting osteosarcoma bone cancer, Molecules 18 (9) (2013) 10580–10598. [16] R. Chouhan, A.K. Bajpai, Real time in vitro studies of doxorubicin release from PHEMA nanoparticles, J. Nanobiotechnol. 7 (1) (2009) 5. [17] I. Amjadi, M. Rabiee, M.S. Hosseini, M. Mozafari, Synthesis and characterization of doxorubicin-loaded poly (lactide-co-glycolide) nanoparticles as a sustained-release anticancer drug delivery system, Appl. Biochem. Biotechnol. 168 (6) (2012) 1434–1447. [18] M. Mesumeci, C.A. Ventura, I. Giannone, B. Ruozi, L. Montenegro, R. Pignatello, G. Puglisi, Int. J. Pharm 325 (1-2) (2006) 172–179. [19] A. Di Martino, V. Sedlarik, Amphiphilic chitosan-grafted-functionalized polylactic acid based nanoparticles as a delivery system for doxorubicin and temozolomide co-therapy, Int. J. Pharm. 474 (1) (2014) 134–145. [20] P. Bernabé, C. Peniche, W. Argüelles-Monal, Swelling behavior of chitosan/pectin polyelectrolyte complex membranes. Effect of thermal cross-linking, Polym. Bull. 55 (5) (2005) 367–375. [21] X. Ma, Z. Cheng, Y. Jin, X. Liang, X. Yang, Z. Dai, J. Tian, SM5-1-conjugated PLA nanoparticles loaded with 5-fluorouracil for targeted hepatocellular carcinoma imaging and therapy, Biomaterials 35 (9) (2014) 2878–2889. [22] Bozkir, O.M. Saka, Formulation and investigation of 5-FU nanoparticles with factorial design-based studies, Farmaco 60 (10) (2005) 840–846. [23] P. Li, Y. Wang, Z. Peng, F. She, L. Kong, Development of chitosan nanoparticles as drug delivery systems for 5-fluorouracil and leucovorin blends, Carbohydr. Polym. 85 (3) (2011) 698–704. [24] A. Di Martino, P. Kucharczyk, J. Zednik, V. Sedlarik, Chitosan grafted low molecular weight polylactic acid for protein encapsulation and burst effect reduction, Int. J. Pharm. 496 (2) (2015) 912–921. [25] J.L. Espartero, I. Rashkov, S.M. Li, N. Manolova, M. Vert, NMR analysis of low molecular weight poly (lactic acid)s, Macromolecules 29 (1996) 3535. [26] W. Chaiyasan, S.P. Srinivas, W. Tiyaboonchai, Crosslinked chitosan-dextran sulfate nanoparticle for improved topical ocular drug delivery, Mol. Vis. 21 (2015) 1224. [27] W. Chaiyasan, S.P. Srinivas, W. Tiyaboonchai, Mucoadhesive chitosan–dextran sulfate nanoparticles for sustained drug delivery to the ocular surface, J. Ocul. Pharmacol. Ther. 29 (2) (2013) 200–207. [28] M.R. Saboktakin, R.M. Tabatabaie, A. Maharramov, M.A. Ramazanov, Synthesis and characterization of pH-dependent glycol chitosan and dextran sulfate nanoparticles for effective brain cancer treatment, Int. J. Biol. Macromol. 49 (4) (2011) 747–751. [29] K.M. Usman, M. Zia, Zuber, S. Tabasum, S. Rehman, F. Zia, Chitin and chitosan based polyurethanes: a review of recent advances and prospective biomedical applications, Int. J. Biol. Macromol. 86 (2016) 630–645. [30] T.S. Anirudhan, P.L. Divya, J. Nima, Synthesis and characterization of novel drug delivery system using modified chitosan based hydrogel grafted with cyclodextrin, Chem. Eng. J. 284 (2016) 1259–1269. [31] Li, M. Kong, X.J. Cheng, Q.F. Dang, X. Zhou, Y.N. Wei, X.G. Chen, Preparation of biocompatible chitosan grafted poly (lactic acid) nanoparticles, Int. J. Biol. Macromol. 51 (3) (2012) 221–227. [32] W. Abdelwahed, G. Degobert, S. Stainmesse, H. Fessi, Freeze-drying of nanoparticles: formulation, process and storage considerations, Adv. Drug Deliv. Rev. 58 (15) (2006) 1688–1713. [33] A. Saez, M. Guzman, J. Molpeceres, M.R. Aberturas, Freeze-drying of polycaprolactone and poly (d,l-lactic-glycolic) nanoparticles induce minor particle size changes affecting the oral pharmacokinetics of loaded drugs, Eur. J. Pharm. Biopharm. 50 (3) (2000) 379–387. [34] P. Fonte, S. Soares, F. Sousa, A. Costa, V. Seabra, S. Reis, B. Sarmento, Stability study perspective of the effect of freeze-drying using cryoprotectants on the structure of insulin loaded into PLGA nanoparticles, Biomacromolecules 15 (10) (2014) 3753–3765. [35] S. Lv, M. Li, Z. Tang, W. Song, H. Sun, H. Liu, X. Chen, Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy, Acta Biomater. 9 (12) (2013) 9330–9342. [36] P. Shan, J.W. Shen, D.H. Xu, L.Y. Shi, J. Gao, Y.W. Lan, X.H. Wei, Molecular dynamics study on the interaction between doxorubicin and hydrophobically modified chitosan oligosaccharide, RSC Adv. 4 (45) (2014) 23730–23739. [37] T.S. Anirudhan, P.L. Divya, J. Nima, Synthesis and characterization of novel drug delivery system using modified chitosan based hydrogel grafted with cyclodextrin, Chem. Eng. 284 (2016) 1259–1269. [38] D. Hynek, L. Krejčová, O. Zítka, V. Adam, L. Trnková, J. Sochor, R. Kizek, Electrochemical study of doxorubicin interaction with different sequences of single stranded oligonucleotides, Part I, Int. J. Electrochem. (2012) 1452–3981. [39] M. Gallois, A. Fiallo, Garnier-Suillerot, Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles: circular dichroism study, Biochim. Biophys. Acta 1370 (1) (1998) 31–40. [40] F. Lince, S. Bolognesi, B. Stella, D.L. Marchisio, F. Dosio, Preparation of polymer nanoparticles loaded with doxorubicin for controlled drug delivery, Chem. Eng. Res. Des. 89 (11) (2011) 2410–2419. [41] H. Ocal, I. Arica-Yegin, K. Vural, S. Goracinova, S. Caliş, 5-Fluorouracil-loaded PLA/PLGA PEG-PPG-PEG polymeric nanoparticles: formulation, in vitro characterization and cell culture studies, Drug Dev. Ind. Pharm. 40 (4) (2014), 560-567.41. [42] A.C. de Mattos, C. Altmeyer, T.T. Tominaga, N.M. Khalil, R.M. Mainardes, Polymeric nanoparticles for oral delivery of 5-fluorouracil: formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study, Eur. J. Pharm. Sci. 84 (2016) 83–91. [43] A. Khdair, I. Hamad, H. Alkhatib, Y. Bustanji, M. Mohammad, R. Tayem, K. Aiedeh, Modified-chitosan nanoparticles: novel drug delivery systems improve oral bioavailability of doxorubicin, Eur. J. Pharm. Sci. 93 (2016) 38–44. [44] M. Fernández-Gutiérrez, S. Fusco, L. Mayol, J. San Román, A. Borzacchiello, L. Ambrosio, Ambrosio, Stimuli-responsive chitosan/poly (N-isopropylacrylamide) semi-interpenetrating polymer networks: effect of pH and temperature on their rheological and swelling properties, J. Mater. Sci. Mater. Med. 27 (6) (2016), 1–8.45. [45] A.M. Murad, F.F. Santiago, A. Petroianu, P.R. Rocha, M.A. Rodrigues, M. Rausch, Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer, Cancer 72 (1) (1993) 37–41. [46] X. Zou, X. Zhao, L. Ye, Q. Wang, H. Li, Preparation and drug release behavior of pH-responsive bovine serum albumin-loaded chitosan microspheres, JIEC 21 (2015) 1389–1397. [47] Y. Shao, L. Li, X. Gu, L. Wang, S. Mao, Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs, Asian J. Pharmacol. 10 (1) (2015) 24–30. [48] J.Z. Du, X.J. Du, C.Q. Mao, J. Wang, Tailor-made dual pH-sensitive polymer–doxorubicin nanoparticles for efficient anticancer drug delivery, J. Am. Chem. Soc. 133 (44) (2011) 17560–17563. [49] H.L. Wong, A.M. Rauth, R. Bendayan, J.L. Manias, M. Ramaswamy, Z. Liu, X.Y. Wu, A new polymer–lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells, Pharm. Res. 23 (7) (2006) 1574–1585. [50] Zhu, J. Ma, N. Jia, Y. Zhao, H. Shen, Chitosan-coated magnetic nanoparticles as carriers of 5-fluorouracil: preparation, characterization and cytotoxicity studies, Colloids Surf. B 68 (1) (2009) 1–6. [51] D. Kaushik, G. Bansal, Four new degradation products of doxorubicin: an application of forced degradation study and hyphenated chromatographic techniques, J. Pharm. Anal. 5 (5) (2015) 285–295. [52] A.B.P. Van Kuilenburg, H. Van Lenthe, J.G. Maring, A.H. Van Gennip, Determination of 5-fluorouracil in plasma with HPLC-tandem mass spectrometry, Nucleosides Nucleotides Nucleic Acids 25 (9–11) (2006) 1257–1260. [53] J.E. Kosovec, M.J. Egorin, S. Gjurich, J.H. Beumer, Quantitation of 5-fluorouracil (5-FU) in human plasma by liquid chromatography/electrospray ionization tandem mass spectrometry, Rapid Commun. Mass Spectrom. 22 (2) (2008) 224–230.
utb.fulltext.sponsorship	This work was funded by the Czech Science Foundation (grant no. 15-08287Y) and the Ministry of Education, Youth and Sports of the Czech Republic (grant no. LO1504 and CZ.1.05/2.1.00/19.0409).