Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads

Merve Olukman, Oya Şanlı, Ebru Kondolot Solak

Department of Chemistry and Chemical Processing Technology, Atatürk Vocational High School, Gazi University, Ankara, Turkey.
Department of Chemistry, Faculty of Science, Gazi University, Ankara, Turkey.

DOI: 10.4236/jbnb.2012.34048                

Abstract

In this research; the release of 5-Fluorouracil (5-FU) from different ionically crosslinked alginate (Alg) beads was investigated by using Fe³⁺, Al³⁺, Zn²⁺, and Ca²⁺, ions as crosslinking agent. The prepared beads were characterized by Fourier Transform Infrared Spectroscopy (FTIR) Differential Scanning Calorimetry (DSC) and Scanning Electron Micros-copy (SEM). The drug release studies were carried out at three pH values 1.2, 6.8 and 7.4 respectively each for two hours. The effects of the preparation conditions as crosslinker type, drug/polymer (w/w) ratio, crosslinker concentration and time of exposure to crosslinker on the release of 5-FU were investigated for 6 hours at 37℃. It was observed that 5-FU release from the beads followed the order of Fe > Zn > Al > Ca-Alg and increased with increasing drug/polymer ratio. At the end of 6 hours, the highest 5-FU release was found to be 90% (w/w) for Fe-Alg beads at the drug/polymer ratio of 1/8 (w/w), crosslinker concentration of 0.05 M, exposure time of 10 minutes respectively. The swelling measurements of the beads supported the release results. Release kinetics was described by Fickian and non-Fickian approaches.

Keywords

Anticancer Drug; pH Responsive Release; Alginate; Ionically Crosslinking; Controlled Release; 5-Fluorouracil

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	R. S. Sastre, R. Olmo, C. Teijon, E. Muniz, J. M. Teijon and M. D. Blanco, “5-Fluorouracil Plasma Levels and Biodegradation of Subcutaneously Injected Drug-Loaded Microspheres Prepared by Spray-Drying Poly(D,L-lactide) and Poly(D,L-lactide-co-glycolide) Polymers,” International Journal of Pharmaceutics, Vol. 338, No. 1-2, 2007, pp. 180-190. doi:10.1016/j.ijpharm.2007.02.001
[2]	V. R. Babu, M. Sairam, K. M. Hosamani and T. M. Aminabhavi, “Development of 5-Fluorouracil Loaded Poly (Acrylamide-co-methylmethacrylate) Novel Core-Shell Microsheres: In Vitro Release Studies,” International Journal of Pharmaceutics, Vol. 325, No. 1-2, 2006, pp. 55-62. doi:10.1016/j.ijpharm.2006.06.020
[3]	Q. Wang, Y. Du and L. Fan, “Properties of Chitosan/ Poly(vinyl alcohol) Films for Drug-Controlled Release,” Journal of Applied Polymer Science, Vol. 96, No. 3, 2005, pp. 808-813. doi:10.1002/app.21518
[4]	E. Fournier, C. Passirani, A. Vo-narbourg, L. Lemaire, N. Colin, S. Sagodira, P. Menei and J. P. Benoit, “Therapeutic Efficacy Study of Novel 5-FU-Loaded PMM 2.1.2-Based Microspheres on C6 Glioma,” International Journal of Pharmaceutics, Vol. 268, No. 1-2, 2003, pp. 31-35. doi:10.1016/j.ijpharm.2003.08.014
[5]	J. M. Kauffman, S. K. Sengupta and W. O. Foye, “Cancer Chemoteraphy,” 3rd Edition, Varghese Publishing House, Bombay, 1989.
[6]	P. Menei, E. Jadaud, N. Faisant, M. Boisdron-Celle, S. Michalak, D. Fournier, M. Delhaye and J. P. Benoit, “Stereotaxic Implantation of 5-Fluorouracil-Releasing Microspheres in Malignant Glioma,” Cancer, Vol. 100, No. 2, 2004, pp. 405-410. doi:10.1002/cncr.11922
[7]	K. Ciftci H. S. Kas, A. A. Hincal, T. M. Ercan, O. Güven and S. Raucan, “In Vitro and In Vivo Evaluation of PLAGA (50/50) Microspheres Containing 5-Fluorouracil Prepared by a Solvent Evaporation Method,” International Journal of Pharmaceutics, Vol. 131, No. 1, 1996, pp. 73-82. doi:10.1016/0378-5173(95)04369-1
[8]	M. Hussain, G. Beale, M. Hughes, S. Akhtar, “Co-Delivery of an Antisense Oligonucleotide and 5-Fluorouracil Using Sustained Release Poly(Lactide-co-glycolide) Microsphere Formulations for Potential Combination Therapy in Cancer,” International Journal of Pharmaceutics, Vol. 234, No. 1-2, 2002, pp. 129-138. doi:10.1016/S0378-5173(01)00950-4
[9]	C. Zinutti, F. Kedzierewicz, M. Hoffman, J. P. Benoit, P. Maincent, “Influence of the Casting Solvent on the Physico-Chemical Properties of 5-Fluorouracil Loaded Microspheres,” International Journal of Pharmaceutics, Vol. 133, No. 1-2, 1996, pp. 97-105. doi:10.1016/0378-5173(95)04423-X
[10]	K. B. Gudasi, R. S. Vadavi, N. B. Shelke, M. Sairam, T. M. Aminabhavi, “Synthesis and Characterization of Novel Polyorganophosphazanes Substituted with 4-Meth- oxybenzylamine and 4-Methoxyphenethylamine for In Vitro Release of Indomethacin and 5-Fluorouracil,” Reactive and Functional Polymers, Vol. 66, No. 10, 2006, pp. 1149-1157. doi:10.1016/j.reactfunctpolym.2006.02.007
[11]	C. Zhang, Y. Cheng, G. Qu, X. Wu, Y. Ding, Z. Cheng, L. Yu and Q. Ping, “Preparation and Characterization of Galactosylated Chitosan Coated BSA Microspheres Containing 5-Fluorouracil,” Carbohydrate Polymer, Vol. 72, No. 3, 2008, pp. 390-397. doi:10.1016/j.carbpol.2007.09.004
[12]	M. G. Dodova, S. Calis, M. S. Crcarevskaa, N. Geskovski, V. Petrovskaa and K. Goracinova, “Wheat Germ Agglutinin-Conjugated Chitosan-Ca-Alginate Microparticles for Local Colon Delivery of 5-FU: Development and In Vitro Characterization,” International Journal of Pharmaceutics, Vol. 381, No. 2, 2009, pp. 166-175. doi:10.1016/j.ijpharm.2009.06.037
[13]	C.-Y. Yu, X.-C. Zhang, F.-Z. Zhou, X.-Z. Zhang, S.-X. Cheng and R.-X. Zhuo, “Sustained Release of Antineo-plastic Drugs from Chitosan-Reinforced Alginate Micro-particle Drug Delivery Systems,” International Journal of Pharmaceutics, Vol. 357, No. 1-2, 2008, pp. 15-21. doi:10.1016/j.ijpharm.2008.01.030
[14]	R. Jeyanthi and K. P. Rao, “Release Characteristics of Bleomycin Mitomycin C and 5-Fluorouracil from Gelatin Microspheres,” International Journal of Pharmaceutics, Vol. 55, No. 1, 1989, pp. 31-37. doi:10.1016/0378-5173(89)90273-1
[15]	L. Huang, W. Sui, Y. Wang and Q. Jiao, “Preparation of Chitosan/Chondroitin Sulfate Complex Microcapsules and Application in Controlled Release of 5-Fluorouracil,” Carbohydrate Polymer, Vol. 80, No. 1, 2010, pp. 168-173. doi:10.1016/j.carbpol.2009.11.007
[16]	A. Gupte and K. Ciftci, “Formulation and Characterization of Paclitaxel, 5-Fu and Paclitaxel + 5-Fu Microspheres,” International Journal of Pharmaceutics, Vol. 276, No. 1, 2004, pp. 93-106.
[17]	B. Arica, S. Calis, H. S. Kas, M. F. Sargon and A. A. Hincal, “5-Fluorouracil Encapsulated Alginate Beads for the Treatment of Breast Cancer,” International Journal of Pharmaceutics, Vol. 242, No. 1-2, 2002, pp. 267-269. doi:10.1016/S0378-5173(02)00172-2
[18]	M. G. Dodova, S. Calis, M. S. Crcarevskaa, N. Geskovski, V. Petrovskaa and K. Goracinova, “Wheat Germ Agglutinin-Conjugated Chitosan-Ca-Alginate Microparticles for Local Colon Delivery of 5-FU: Development and In Vitro characterization,” Interna-tional Journal of Pharmaceutics, Vol. 381, No. 2, 2009, pp. 166-175. doi:10.1016/j.ijpharm.2009.06.037
[19]	A. B. Pepperman and J. C. W. Kuan, “Controlled Release Formulations of Alachlor Based on Calcium Alginate,” Journal of Controlled Release, Vol. 34, No. 1, 1995, pp. 17-23. doi:10.1016/0168-3659(94)00111-7
[20]	S. G. Kumbar and T. M. Aminabhavi, “Preparation and Characterization of Interpenetrating Network Beads of Poly(Vinyl Alcohol)-Grafted-Poly(Acrylamide) with Sodium Alginate and Their Controlled Release Characteristics for Cypermethrin Pesticide,” Journal of Applied Polymer Science, Vol. 84, No. 3, 2002, pp. 552-560. doi:10.1002/app.10306
[21]	O. Sanli, N. Ay and N. Isiklan, “Release Characteristics of Diclofenac Sodium from Poly(Vinyl Alcohol)/Sodium Alginate and Poly(Vinyl Alcohol)-Grafted Poly(Acry-lamide)/Sodium Alginate Blend Beads,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 65, No. 2, 2007, pp. 204-214. doi:10.1016/j.ejpb.2006.08.004
[22]	V. Pillay, C. M. Dangor, T. Govender, K. R. Moopanar and N. Hurbans, “Ionotropic Gelation: Encapsulation of Indomethacin in Calcium Alginate Gel Disks,” Journal of Microencapsulation, Vol. 15, No. 2, 1998, pp. 215-226. doi:10.3109/02652049809006851
[23]	V. R. Babu, S. Malladi, K. M. Hasamani, T. M. Aminabhavi, “Preparation of Sodium Alginate-Methylcellulose Blend Microspheres for Controlled Release of Nifedipine,” Carbohydrate Polymer, Vol. 69, No. 2, 2007, pp. 241-250. doi:10.1016/j.carbpol.2006.09.027
[24]	A. R. Kulkarni, K. S. Soppimath, T. M. Aminabhavi, W. E. Rudzinski, “In Vitro Release Kinetics of Cefadroxil- Loaded Sodium Alginate Interpenetrating Network Beads,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 51, No. 2, 2001, pp. 127-133. doi:10.1016/S0939-6411(00)00150-8
[25]	A. Nokhodchi and A. Tailor, “In Situ Cross-Linking of Sodium Alginate with Calcium and Aluminum Ions to Sustain the Release of Theo-phyline from Polymeric Matrices,” II. Farmaco, Vol. 59, No. 12, 2004, pp. 999-1004. doi:10.1016/j.farmac.2004.08.006
[26]	M. O. Taha, W. Nasser, A. Ardakani and H. S. AlKhatib, “Sodium Laurly Sulfate Impedesdrug Release from Zinc-Crosslinked Alginate Beads: Swithching from Enteric Coating Release into Biphasic Profiles,” International Journal of Pharmaceutics, Vol. 350, No. 1-2, 2008, pp. 291-300. doi:10.1016/j.ijpharm.2007.09.010
[27]	B. Arica, S. Calis, H. S. Kas, M. F. Sargon and A. A. Hincal, “5-Fluorouracil Encapsulated Alginate Beads for the Treatment of Breast Cancer,” International Journal of Pharmaceutics, Vol. 242, No. 1-2, 2002, pp. 267-269. doi:10.1016/S0378-5173(02)00172-2
[28]	S. Nagaich, A. J. Khopade and N. K. Jain, “Lipid Grafts Egg-Box Complex: A New Supramolecular Biovector for 5-Fluorouracil Delivery,” Pharmaceutica Acta Helvetiae, Vol. 73, No. 5, 1999, pp. 227-236. doi:10.1016/S0031-6865(98)00027-2
[29]	S. Al-Musa, D. A. Fara and A. A. Badwan, “Evaluation of Parameters Involved in Preparation and Release of Drug Loaded in Crosslinked Matrices of Alginate,” Journal of Controlled Release, Vol. 57, No. 3, 1999, pp. 223-232. doi:10.1016/S0168-3659(98)00096-0
[30]	M. S. Kim, S. J. Park, B. K. Gu and C. H. Kim, “Ionically crosslinked alginate-carboxymethyl cellulose beads for the delivery of protein therapeutics,” Applied Surface Science, In Press, 2012.
[31]	G. Li, Y. Du, Y. Tao, H. Deng, X. Luo and J. Yang, “Iron (II) Cross-Linked Chitin-Based Gel Beads: Preparation, Magnetic Property and Adsorption of Methyl Orange,” Carbohydrate Polymers, Vol. 82, No. 3, 2010, pp. 706- 713. doi:10.1016/j.carbpol.2010.05.040
[32]	O. Sanli and N. Isiklan, “Controlled Release Formulations of Carbaryl Based on Copper Alginate, Barium Alginate and Alginic Acid Beads,” Journal of Applied Polymer Science, Vol. 102, No. 5, 2006, pp. 4245-4253. doi:10.1002/app.24882
[33]	E. Akalin, S. Akyuz and T. Akyuz, “Adsorption and Interaction of 5-Fluorouracil with Montromorillonite and Sponite by FTIR Spectroscopy,” Journal of Molecular Structure, Vol. 834-836, 2007, pp. 477-481. doi:10.1016/j.molstruc.2006.11.061
[34]	I. M. El-Sherbiny, R. J. Lins, E. M. Abdel-Bary and D. R. K. Harding, “Preparation, Characterization, Swelling and In Vitro Drug Release Behaviour of Poly[N-acryloylgly- cine-chitosan] Interpolymeric pH and Thermally-Responsive Hydrogels,” European Polymer Journal, Vol. 41, No. 11, 2005, pp. 2584-2591. doi:10.1016/j.eurpolymj.2005.05.035
[35]	A. K. Bajpai and M. Sharma, “Preparation and Characterization of Binary Grafted Polymeric Blends of Polyvinyl Alcohol and Gelatin and Evaluation of Their Water Uptake Potential Part A,” Pure and Applied Chemistry, Vol. 42, No. 5, 2005, pp. 663-682.
[36]	N. A. Peppas, “Analysis of Fickian and Non-Fickian Drug Release from Polymers,” Pharmaceutica Acta Helvetiae, Vol. 60, No. 4, 1985, pp. 110-111.
[37]	P. L. Ritger and N. A. Peppas, “A Simple Equation for Description of Solute Release II. Fickian and Anomalous Release from Swellable Devices,” Journal of Controlled Release, Vol. 5, No. 1, 1987, pp. 37-42. doi:10.1016/0168-3659(87)90035-6
[38]	V. R. Babu, K. S. V. Krishna Rao, M. Sairam, B. Vijaya Kumar Naidu, K. M. Hosamani and T. M. Aminabhavi, “pH Sensitive Interpenetrating Network Microgels of Sodium Alginate-Acrylic Acid for the Controlled Release of Ibuprofen,” Journal of Applied Polymer Science, Vol. 99, No. 5, 2006, pp. 2671-2678. doi:10.1002/app.22760