Abstract
Purpose
Non-specific extracellular contrast agents have been on the market for more than 15 years. Here, we report on the synthesis of new selective lectin–gadolinium (Gd)-loaded chitosan nanoparticles with a prolonged clearance time and a much higher relaxivity in comparison to other preparations.
Procedures
Chitosan nanoparticles were prepared from 85% deacetylated chitin by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of n-hexane using sodium bis(ethylhexyl)sulfosuccinate as a surfactant.
Results
Several crucial parameters, namely, the Gd and protein content of the nanoparticles, their size and dispersity were determined. Magnetic resonance measurements were carried out by intravenous perfusion of mono-disperse suspensions of the nanoparticles into mice.
Conclusions
Chitosan nanoparticles can be used as contrast agents in magnetic resonance imaging (MRI). They are excellent candidates for controlled delivery of bioactive compounds to molecular targets and as biospecific diagnostic tools in MRI.
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References
Lanza GM, Yu X, Winter PM, Abendschein DR, Karukstis KK, Scott MJ, Chinen LK, Fuhrhop RW, Scherrer DE, Wickline SA (2002) Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 106(22):2842–2847
Flacke S, Fischer S, Scott MJ, Fuhrhop RJ, Allen JS, McLean M, Winter P, Sicard G, Gaffney PJ, Wickline SA, Lanza GM (2001) Novel contrast agent for molecular imaging of fibrin. Implications for detecting vulnerable plaques. Circulation 104:1280–1285
Wolf GL (1999) Delivery of diagnostic agents: achievements and challenges. Adv Drug Deliv Rev 37:1–12
Bernkop-Schnürch A, Krajicek ME (1998) Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan–EDTA conjugates. J Control Release 50:215−223
Jameela SR, Jayakrishnan A (1995) Glutaraldehyde cross-linked chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle. Biomaterials 16:769–775
Kabalka GW, Davis MA, Holmberg E, Maruyama K, Huang L (1991) Gadolinium-labeled liposomes containing amphiphilic Gd-DTPA derivatives of varying chain length: targeted MRI contrast enhancement agents for the liver. Magn Reson Imaging 9(3):373–377
Kumbar SG, Kulkarni AR, Aminabhavi TM (2002) Crosslinked chitosan microspheres for encapsulation of diclofenac sodium: effect of crosslinking agent. J Microencapsul 19:173–180
Mitra S, Gaur U, Ghosh PC, Maitra AN (2001) Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. J Control Release 74:317–323
Paschkunova-Martic I, Kremser C, Mistlberger K, Shcherbakova N, Dietrich H, Talasz H, Zou Y, Hugl B, Galanski M, Sölder E, Pfaller K, Höliner I, Buchberger W, Keppler B, Debbage P (2005) Design, synthesis, physical and chemical characterisation, and biological interactions of lectin-targeted latex nanoparticles bearing Gd-DTPA chelates: an exploration of magnetic resonance molecular imaging (MRMI). Histochem Cell Biol 123:283–301
Roberts TP, Roberts HC, Brasch RC (1996) Optimizing imaging techniques to reduce errors in microvascular quantitation with macromolecular MR contrast agents. Acad Radiol 5(suppl 1):133–136
Lanza GM, Abendschein DR, Yu X, Winter PM, Karukstis KK, Scott MJ, Fuhrhop RW, Scherrer DE, Wickline SA (2002) Molecular imaging and targeted drug delivery with a novel, ligand-directed paramagnetic nanoparticle technology. Acad Radiol 9(Suppl 2):330–331
Hoegmann D, Josephson L, Wiessleder R, Basilion JP (2000) Improvement of MRl probes to allow efficient detection of gene expression. Bioconjug Chem 11:941–946
Shen I, Weissleder R, Papisov M, Bogdanov A Jr, Brady IJ (1993) Monocrystalline iron oxide nanocompounds (MlON): physicochemical properties. Magn Reson Med 29:599–604
King CP, Li MD, Bednarski MD (2002) Vascular-targeted molecular imaging using functionalized polymerized vesicles. J Magn Reson Imaging 16:388–393
Anderson SA, Rader RK, Westlin WF, Null C, Jackson D, Lanza GM, Wickline SA, Kotyk JJ (2000) Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles. Magn Reson Med 44(3):433–439
Yu X, Song SK, Chen J, Scott MJ, Fuhrhop RJ, Hall CS, Gaffney PJ, Wickline SA, Lanza GM (2000) High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent. Magn Reson Med 44(6):867–872
Lanza GM, Lorenz CH, Fischer SE, Scott MJ, Cacheris WP, Kaufmann RJ, Gaffney PJ, Wickline SA (1998) Enhanced detection of thrombi with a novel fibrin-targeted magnetic resonance imaging agent. Acad Radiol 5(Suppl 1):173–176; discussion 183–4
Wiener EC, Brechbiel MW, Brothers H, Magin RL, Gansow OA, Tomalia DA, Lauterbur PC (1994) Dendrimer-based metal chelates: a new class of magnetic resonance imaging contrast agents. Magnet Reson Med 31:1–84
Alhaique F, Bertini I, Fergai M, Carafa M, Luchinat C, Parigi G (2002) Solvent 1H NMRD study of biotinylated paramagnetic liposomes containing Gd-bis-SDA-DTPA or Gd-DMPE-DTPA. Inorg Chim Acta 331:151–157
Debbage PL, Seidl S, Kreczy A, Hutzler P, Pavelka M, Lukas P (2000) Vascular permeability and hyperpermeability in a murine adenocarcinoma after fractionated radiotherapy: an ultra structural tracer study. Histochem Cell Biol 114:259–275
Porter GA, Palade GE, Milici AJ (1990) Differential binding of the lectins Griffonia simplicifolia I and Lycopersicon esculentum to microvascular endothelium: organ-specific localization and partial glycoprotein characterization. Eur J Cell Biol 51:85–95
Ogan MD, Schmiedl U, Moselay ME, Grodd W, Paajanen H, Brasch RC (1987) Albumin labeled with Gd-DTPA: an intravascular contrast-enhancing agent for magnetic resonance blood pool imaging; preparation and characterization. Invest Radiol 22:665–671
Torchilin VP (2002) PEG-based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev 54:235–252
Vander Elst L, Laurent S, Bintoma HM, Muller RN (2001) Albumin-bound MRI contrast agents: the dilemma of the rotational correlation time. MAGMA 12:135–140
Van Dijke CF, Brasch RC, Roberts TP et al (1996) Mammary carcinoma model: correlation of macromolecular contrast-enhanced MR imaging characterizations of tumor microvasculature and histologic capillary density. Radiology 198:813–818
Brasch A, Pham C, Shames D et al (1997) Assessing tumor angiogenesis using macromolecular MR imaging contrast media. J Magn Reson Imaging 7:68–74
Aicher KP, Dupon JW, White DL et al (1990) Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha. Cancer Res 50:7376–7361
Kang HW, Josephson L, Petrovsky A, Weissleder R, Bogdanov A Jr (2002) Magnetic resonance imaging of inducible E-selectin expression in human endothelial cell culture. Bioconjug Chem 13:122–127
Weissig V, Babich J, Torchilin V (2000) Long-circulating gadolinium-loaded liposomes: potential use for magnetic resonance imaging of the blood pool. Colloids Surf B 18: 293–299
Shames DM, Kuwatsuru R, Vexler V, Muhler A, Brasch RC (1993) Measurement of capillary permeability to macromolecules by dynamic magnetic resonance imaging: a quantitative noninvasive technique. Magn Reson Med 29:616–622
Aime S, Gabella C, Colombatto S, Geninatti S, Gianoli E, Maggioni F (2002) Insights into the use of paramagnetic Gd(III) complexes in MRI-molecular imaging investigations. J Magn Reson Imaging 16:394–406
Acknowledgements
We gratefully appreciate the support of the Austrian National Bank, Jubilee project Number 2793, Central Research Animal Facility of the University of Innsbruck (Prof. H. Dietrich) and Kristian Pfaller, Ms. Silvia Fill and Ms. Angelika Flörl for the excellent technical assistance.
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Significance: polymeric nanoparticles can be used as contrast agents in magnetic resonance imaging. They are excellent candidates for the controlled release of many pharmaceutical compounds to molecular targets because of their biodegradable nature.
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Pashkunova-Martic, I., Kremser, C., Galanski, M.S. et al. Lectin–Gd-Loaded Chitosan Hydrogel Nanoparticles: A New Biospecific Contrast Agent for MRI. Mol Imaging Biol 13, 16–24 (2011). https://doi.org/10.1007/s11307-010-0309-x
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DOI: https://doi.org/10.1007/s11307-010-0309-x