Preparation and In-vitro Evaluation of Levan Micelles: A Polyfructan Based Nano-carrier for Breast Cancer Targeted Delivery

Page: [97 - 107] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Levans are biopolymers of fructose, produced by different microorganisms. Fructose present in the levan micelles binds with the Glucose Transporter 5 (GLUT 5) which is overexpressed in the breast cancer cells.

Objective: Increased solubility of paclitaxel by loading in the GLUT 5 transporter targeted levan-based micelles may enhance its bioavailability and facilitate a targeted delivery to the breast cancer cells.

Methods and Results: Critical micelle concentration of levan with an average molecular weight of 800,000 Dalton was found to be 0.125µM corresponding to 0.1mg/mL using pyrene I3/I1 method. At critical micelle concentration (CMC), levan formed very mono-disperse (PDI-0.082) micellar particles with a particle size of 153.1 ± 2.31nm and -14.6 ± 2mV zeta potential. In-vitro drug release study was performed to identify the fit kinetic model along with Fourier transform infrared analysis and Differential scanning calorimetry studies. In-vitro kinetic model fitting revealed first-order drug release from the prepared micellar composition. The drug-loaded micellar composition was studied for its anticancer activity in breast cancer cell line. The IC50 value obtained was 1.525 ± 0.11nM on MCF7 cell line.

Conclusion: Paclitaxel micelles showed a nineteen-fold improvement in the IC50 value compared to free paclitaxel. Hemocompatibility study was performed with a view to parenteral administration. This solution containing drug was found to be hemocompatible when added to bovine blood in 1:4 ration. Micelles are proven fairly compatible on the basis of hemolysis test results.

Keywords: Levan polymer, paclitaxel, targeted delivery, metastatic breast cancer, IC50 value, MCF7 cell line.

Graphical Abstract

[1]
Suri, S.S.; Fenniri, H.; Singh, B. Nanotechnology-based drug delivery systems. J. Occup. Med. Toxicol., 2007, 2, 16.
[2]
Pison, U.; Welte, T.; Giersig, M.; Groneberg, D.A. Nanomedicine for respiratory diseases. Eur. J. Pharmacol., 2006, 533, 341-350.
[3]
Allena, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev., 2013, 65, 36-48.
[4]
Sezer, D.; Kazak, H.; Oner, E.T.; Akbuga, J. Levan-based nanocarrier system for peptide and protein drug delivery: Optimization and influence of experimental parameters on the nanoparticle characteristics. Carbohydr. Polym., 2011, 84, 358-363.
[5]
Yezhelyev, M.V.; Gao, X.; Xing, Y.; Al-Hajj, A.; Nie, S.; O’Regan, R.M. Emerging use of nanoparticles in diagnosis and treatment of breast cancer. Lancet Oncol., 2007, 7, 657-667.
[6]
Ghersi, D.; Willson, M.L.; Chan, M.M.K.; Simes, J.; Donoghue, E.; Wilcken, N. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst. Rev., 2015, 6, 1-170.
[7]
Cardoso, F.; Costa, A.; Norton, L.; Senkus, E.; Aapro, M.; Andre, F.; Barrios, C.H.; Bergh, J.; Biganzoli, L.; Blackwell, K.L.; Cardoso, M.J.; Cufer, T.; Saghir, N.E.; Fallowfield, L.; Fenech, D.; Francis, P.; Gelmon, K.; Giordano, S.H.; Gligorov, J.; Goldhirsch, A.; Harbeck, N.; Houssami, N.; Hudis, C.; Kaufman, B.; Krop, I.; Kyriakides, S.; Lin, U.N.; Mayer, M.; Merjaver, S.D.; Nordstrom, E.B.; Pagani, O.; Partridge, A.; Penault-Llorca, F.; Piccart, M.J.; Rugo, H.; Sledge, G.; Thomssen, C.; Van’t Veer, L.; Vorobiof, D.; Vrieling, C.; West, N.; Xu, B.; Winer, E. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann. OncoL., 2014, 23, 1871-1888.
[8]
Guarneri, V.; Dieci, M.V.; Conte, P. Enhancing intracellular taxane delivery: Current role and perspectives of nanoparticle albumin-bound paclitaxel in the treatment of advanced breast cancer. Expert Opin. Pharmacother., 2012, 13, 395-406.
[9]
Robinson, D.M.; Keating, G.M. Albumin-bound paclitaxel: In metastatic breast cancer. Drugs, 2006, 66, 941-948.
[10]
Han, Y.W.; Watson, M.A. Production of microbial levan from sucrose, sugarcane juice and beet molasses. J. Ind. Microbiol. Biotechnol., 1992, 9, 257-260.
[11]
Vereyken, J.; Chupin, V.; Hoekstra, F.A.; Smeekens, S.C.M.; Kruijff, B. The effect of fructan on membrane lipid organization and dynamics in the dry state. Biophys. J., 2003, 84, 3759-3766.
[12]
Cook, S.E.; Park, I.K.; Kim, E.M.; Jeong, H.J.; Park, T.G.; Choi, Y.J.; Akaike, T.; Choa, C.S. Galactosylated polyethylenimine-graft-poly(vinyl pyrrolidone) as a hepatocyte-targeting gene carrier. J. Control. Release, 2005, 105, 151-163.
[13]
Hashida, M.; Takemura, S.; Nishikawa, M.; Takakura, Y. Targeted delivery of plasmid DNA complexed with galactosylated poly(l-lysine). J. Control. Release, 1998, 53, 301-310.
[14]
Wijagkanalan, W.; Kawakami, S.; Takenaga, M.; Igarashi, R.; Yamashita, F.; Hashida, M. Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats. J. Control. Release, 2008, 125, 121-130.
[15]
Bernardes, G.J.; Kikkeri, R.; Maglinao, M.; Laurino, P.; Collot, M.; Hong, S.Y.; Lepeniesab, B.; Seeberger, P.H. Design, synthesis and biological evaluation of carbohydrate-functionalized cyclodextrins and liposomes for hepatocyte-specific targeting. Org. Biomol. Chem., 2010, 8, 4987-4996.
[16]
Gallego-Yerga, L.; Lomazzi, M.; Sansone, F.; Mellet, C.O.; Casnati, A.; Fernandez, J.M.G. Glycoligand-targeted core–shell nanospheres with tunable drug release profiles from calixarene–cyclodextrin heterodimers. Chem. Comm., 2014, 50, 7440-7443.
[17]
Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. . J. Gen. Physiol., 1927, 8, 519-530.
[18]
Warburg, O. On the origin of cancer cells. Science, 1956, 123, 3191.
[19]
Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol., 2007, 2, 751-760.
[20]
Byrne, J.D.; Betancourt, T.; Brannon-Peppas, L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv. Drug Deliv. Rev., 2008, 60, 1615-1626.
[21]
Berthold, A.; Cremer, K.; Kreuter, J. Preparation and characterization of chitosan microspheres as drug carriers for prednisolone sodium phosphate as model for anti-inflammatory drugs. J. Control. Release, 1996, 39, 17-25.
[22]
Tamizharasi, S.; Dubey, A.; Rathi, V.; Rathi, J.C. Development and characterization of niosomal drug delivery of gliclazide. J. Young Pharm., 2009, 1, 205-209.
[23]
Huh, K.M.; Lee, S.C.; Cho, Y.W.; Lee, J.; Jeong, J.H.; Park, K. Hydrotropic polymer micelle system for delivery of paclitaxel. J. Control. Release, 2005, 101, 59-68.
[24]
Xu, G.; Sunada, H. Influence of formation changes on drug release kineticsfrom hydroxypropylmethylcellulose matrix tablets. Chem. Pharm. Bull., 1995, 43, 483-487.
[25]
Higuchi, T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci., 1963, 52, 1145-1149.
[26]
Hixson, W.; Crowell, J.H. Dependence of reaction velocity upon surface and agitation. Ind. Eng. Chem. Res., 1931, 23, 923-931.
[27]
Choi, J.; Reipa, V.; Hitchins, V.M.; Goering, P.L.; Malinauskas, R.A. Physicochemical characterization and in vitro hemolysis evaluation of silver nanoparticles. Toxicol. Sci., 2011, 123, 133-143.
[28]
Trivedi, R.; Kompella, U.B. Nanomicellar formulations for sustained drug delivery: Strategies and underlying principles. Nanomedicine (Lond.), 2010, 5, 485-505.
[29]
Kim, S.J.; Bae, P.K.; Chung, B.H. Self-assembled levan nanoparticles for targeted breast cancer imaging. Chem. Comm., 2015, 51, 107.
[30]
Jones, O.G.; Decker, E.A.; McClements, D.J. Formation of biopolymer particles by thermal treatment of beta-lactoglobulin–pectin complexes. Food Hydrocoll., 2009, 23, 1312-1321.
[31]
Jung, T.; Kamm, W.; Breitenbach, A.; Kaiserling, E.; Xiao, J.X.; Kissel, T. Biodegradable nanoparticle for oral delivery of peptides: Is there a role for polymers to affect mucosal uptake? Eur. J. Pharm. Biopharm., 2000, 50, 147-160.
[32]
D., Drooge J.V.; Hinrichs, W.L.J.; Frijlink, H.W. Incorporation of lipophilic drugs in sugar glasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent. J. Pharm. Sci., 2004, 93, 713-725.
[33]
Liggins, R.T. hunter, W.L.; Burt, H.M. Solid-state characterization of paclitaxel. J. Pharm. Sci., 1997, 86, 1458-1463.
[34]
Nasir, D.Q.; Deana, W.; Rukman, H. Screening and characterization of levan secreted by Halophilic bacterium of Halomonas and chromohalobacter genuses originated from bledug kuwu mud crater. Procedia Chem., 2015, 16, 272-278.
[35]
Kulkarni, R.; Soppimath, K.S.; Aminabhavi, T.M. Controlled release of diclofenac sodium from sodium alginate beads crosslinked with glutaraldehyde. Pharm. Acta Helv., 1999, 74, 29-36.
[36]
Yessinea, M.A.; Lafleurb, M.; Meierc, C.; Petereitc, H.U.; Leroux, J.C. Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers. Biochim. Biophys. Acta. Biomembr., 2003, 1613, 28-38.
[37]
Domingues, C.C.; Malheiros, S.V.P.; Paula, E. Solubilization of human erythrocyte membranes by ASB detergents. Braz. J. Med. Biol. Res., 2008, 41, 758-764.
[38]
Zhang, H.; Holden-Wiltse, J.; Wang, J.; Liang, H. A strategy to model nonmonotonic dose-response curve and estimate IC50. PLoS One, 2013, 8, 1-7.
[39]
Tommasi, S.; Mangia, A.; Lacalamita, R.; Bellizzi, A.; Fedele, V.; Chiriatti, A.; Thomssen, C.; Kendzierski, N.; Latorre, A.; Lorusso, V.; Schittulli, F.; Zito, F.; Kavallaris, M.; Paradiso, A. Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of b-tubulins. Int. J. Cancer, 2007, 120, 2078-2085.