Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells

Abstract

A novel targeted drug delivery system, glucose-conjugated chitosan nanoparticles (GCNPs), was developed for specific recognition and interaction with glucose transporters (Gluts) over-expressed by tumor cells. GC was synthesized by using succinic acid as a linker between glucosamine and chitosan (CS), and successful synthesis was confirmed by NMR and elemental analysis. GCNPs were prepared by ionic crosslinking method, and characterized in terms of morphology, size, and zeta potential. The optimally prepared nanoparticles showed spherical shapes with an average particle size of (187.9±3.8) nm and a zeta potential of (-15.43±0.31) mV. The GCNPs showed negligible cytotoxicity to mouse embryo fibroblast and 4T1 cells. Doxorubicin (DOX) could be efficiently entrapped into GCNPs, with a loading capacity and encapsulation efficiency of 20.11% and 64.81%, respectively. DOX-loaded nanoparticles exhibited sustained-release behavior in phosphate buffered saline (pH 7.4). In vitro cellular uptake studies showed that the GCNPs had better endocytosis ability than CSNPs, and the antitumor activity of DOX/GCNPs was 4–5 times effectiveness in 4T1 cell killing than that of DOX/CSNPs. All the results demonstrate that nanoparticles decorated with glucose have specific interactions with cancer cells via the recognition between glucose and Gluts. Therefore, Gluts-targeted GCNPs may be promising delivery agents in cancer therapies.

Keywords

drug delivery / target / nanoparticle / glucose transporter (Glut) / chitosan (CS)

References

[1] Chen C, Yu C H, Cheng Y C, . Biodegradable nanoparticles of amphiphilic triblock copolymers based on poly(3-hydroxybutyrate) and poly(ethylene glycol) as drug carriers. Biomaterials, 2006, 27(27): 4804–4814

[2] Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment. Urologic Oncology, 2008, 26(1): 57–64

[3] Malam Y, Loizidou M, Seifalian A M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends in Pharmacological Sciences, 2009, 30(11): 592–599

[4] Byrne J D, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Advanced Drug Delivery Reviews, 2008, 60(15): 1615–1626

[5] Sudimack J, Lee R J. Targeted drug delivery via the folate receptor. Advanced Drug Delivery Reviews, 2000, 41(2): 147–162

[6] Hruz P W, Mueckler M M. Structural analysis of the GLUT1 facilitative glucose transporter. Molecular Membrane Biology, 2001, 18(3): 183–193

[7] Olson A L, Pessin J E. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annual Review of Nutrition, 1996, 16(1): 235–256

[8] Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. The Journal of General Physiology, 1927, 8(6): 519–530

[9] Cullinane C, Solomon B, Hicks R J. Imaging of molecular target modulation in oncology: challenges of early clinical trials. Clinical and Translational Imaging, 2014, 2(1): 5–12

[10] Liu D Z, Sinchaikul S, Reddy P V G, . Synthesis of 2′-paclitaxel methyl 2-glucopyranosyl succinate for specific targeted delivery to cancer cells. Bioorganic & Medicinal Chemistry Letters, 2007, 17(3): 617–620

[11] Airley R, Evans A, Mobasheri A, . Glucose transporter Glut-1 is detectable in peri-necrotic regions in many human tumor types but not normal tissues: Study using tissue microarrays. Annals of Anatomy, 2010, 192(3): 133–138

[12] Jóźwiak P, Lipińska A. The role of glucose transporter 1 (GLUT1) in the diagnosis and therapy of tumors. Postępy Higieny i Medycyny Doświadczalnej, 2012, 66: 165–174 (in Polish)

[13] Ravi Kumar M N V. A review of chitin and chitosan applications. Reactive and Functional Polymers, 2000, 46(1): 1–27

[14] Li J, Kong M, Cheng X J, . A facile method for preparing biodegradable chitosan derivatives with low grafting degree of poly(lactic acid). International Journal of Biological Macromolecules, 2011, 49(5): 1016–1021

[15] Yang K, Gao T, Bao Z, . Preparation and characterization of a novel thermosensitive nanoparticle for drug delivery in combined hyperthermia and chemotherapy. Journal of Materials Chemistry B, 2013, 1(46): 6442–6448

[16] Li P, Wang Y, Zeng F, . Synthesis and characterization of folate conjugated chitosan and cellular uptake of its nanoparticles in HT-29 cells. Carbohydrate Research, 2011, 346(6): 801–806

[17] Chen X G, Li J, Cheng X J, . Process for preparing compounds of chitosan saccharified with aminosugar. US Patent, 8 202 971 B2, 2012-06-<day>19</day>

[18] Hansen M B, Nielsen S E, Berg K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. Journal of Immunological Methods, 1989, 119(2): 203–210

[19] Dong Y, Feng S S. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials, 2004, 25(14): 2843–2849

[20] Wang H, Zhao P, Su W, . PLGA/polymeric liposome for targeted drug and gene co-delivery. Biomaterials, 2010, 31(33): 8741–8748

[21] Li J, Kong M, Cheng X J, . Preparation of biocompatible chitosan grafted poly(lactic acid) nanoparticles. International Journal of Biological Macromolecules, 2012, 51(3): 221–227

[22] Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release, 2010, 148(2): 135–146

[23] Yoo J W, Doshi N, Mitragotri S. Adaptive micro and nanoparticles: Temporal control over carrier properties to facilitate drug delivery. Advanced Drug Delivery Reviews, 2011, 63(14–15): 1247–1256

[24] Hashida M, Takemura S, Nishikawa M, . Targeted delivery of plasmid DNA complexed with galactosylated poly(L-lysine). Journal of Controlled Release, 1998, 53(1–3): 301–310

[25] Peer D, Karp J M, Hong S, . Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology, 2007, 2(12): 751–760

[26] Choucair A, Soo P L, Eisenberg A. Active loading and tunable release of doxorubicin from block copolymer vesicles. Langmuir, 2005, 21(20): 9308–9313

[27] Xun W, Wang H Y, Li Z Y, . Self-assembled micelles of novel graft amphiphilic copolymers for drug controlled release. Colloids and Surfaces B: Biointerfaces, 2011, 85(1): 86–91

Acknowledgements

This research was supported by the National Natural Science Foundation of China (Grant Nos. 31000423 and 31301420) and the China Postdoctoral Science Foundation (Grant No. 2014M551965).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg