Bioengineering Functional Copolymers. XVII. Interaction of Organoboron Amide-Ester Branched Derivatives of Poly(Acrylic Acid) with Cancer Cells


Novel bioengineering functional organoboron polymers were synthesized by 1) amidolysis of poly(acrcylic acid) (PAA) with 2-aminoethyldiphenyl borinate (2-AEPB), 2) esterification of organoboron PAA polymer (PAA-B) with a-hydroxy-methoxypoly(ethylene oxide) (PEO) as a compatibilizer and 3) conjugation of organoboron PEO branches (PAA-B-PEO) with folic acid (FA) as a targeting agent. Structure and composition of the synthesized polymers were characterized by FTIR-ATR and 1H (13C) NMR spectroscopy, chemical and physical analysis methods. Anti-tumor activity of organoboron functional polymer and its complex with FA (PAA-B-PEO-F) against cancer and normal cells were evaluated by using different biochemical methods such as cytotoxicity, statistical, apoptotic and necrotic cell indexes, double staining and caspase-3 immune staining, light and fluorescence inverted microscope analyses. It was found that citotoxicity and apoptotic/necrotic effects of polymers significantly depend on the structure and composition of studied polymers, and increase the following raw: PAA << PAA-B < PAA-B-PEO < PAA-B-PEO-F. Among them, PAA-B-PEO-F complex at 400 mg mL–1 concentration as a therapeutic drug exhibits minimal toxicity toward the nor-mal cells, but influential for HeLa cancer cells.

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M. Türk, G. Kahraman, S. Khalilova, Z. Rzayev and S. Oguztüzün, "Bioengineering Functional Copolymers. XVII. Interaction of Organoboron Amide-Ester Branched Derivatives of Poly(Acrylic Acid) with Cancer Cells," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 266-275. doi: 10.4236/jct.2011.22034.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] L. Seymour, “Synthetic Polymers with Intrinsic Anti-Cancer Activity,” Journal of Bioactive and Compatible Polymers, Vol. 6, No. 2, 1991, pp. 178-216. doi:10.1177/088391159100600205
[2] J. Liao and R. M. Ottenbrite, “Controlled Drug Delivery: Challenges and Strategies,” ACS, Washington DC, 1997.
[3] S. Akhtar, “Non-Viral Cancer Gene Therapy: Beyond Delivery,” Gene Therapy, Vol. 13, No. 5, 2006, pp. 739- 740. doi:10.1038/
[4] M. Dittgen, M. Durrani and K. Lehmann, “Acrylic Polymers. A Review of Pharmaceutical Applications,” S. T. P. Pharma Science, Vol. 7, No. 6, 1997, pp. 403-437.
[5] M. Dimitrov, M. Lambovi, S. Shenkov, V. Dosseva and V. Y. Baranovski, “Hydrogels Based on the Chemically Crosslinked Polyacrylic Acid: Biopharmaceutical Characterization,” Acta Pharmaceutica, Vol. 53, No. 1, 2003, pp. 25-31.
[6] W. Lee, T. G. Lee and W.-G. Koh, “Grafting of Poly-(Acrylic Acid) on the Poly(Ethylene Glycol) Hydrogel Using Surface-Initiated Photopolymerization for Covalent Immobilization of Collagen,” Industrial & Engineering Chemistry Research, Vol. 13, No. 7, 2007, pp. 1195-1200.
[7] Y. Onuki, M. Nishikawa, M. Morishita and K. Takayama, “Development of Photocrosslinked Polyacrylic Acid Hydrogel as an Adhesive for Dermotological Patches: Involvement of Formulation Factors in Physical Properties and Pharmacological Effects,” International Journal of Pharmacology, Vol. 349, No. 1-2, 2008, pp. 47-52. doi:10.1016/j.ijpharm.2007.07.021
[8] B. R. Saunders, H. M. Crowther and B. Vincent, “Poly-[(methyl methacrylate)-co-(methacrylic acid)] Microgel particles: Swelling Control Using pH, Cononsolvency, and Osmotic Deswelling,” Macromolecules, Vol. 30, No. 3, 1997, pp. 482-487. doi:10.1021/ma961277f
[9] T. Sawai, S. Yamazaki, Y. Ikariyama and M. Aizawa, “pH-Responsive Swelling of the Ultrafine Microsphere,” Macromolecules, Vol. 24, No. 8, 1991, pp. 2117-2118. doi:10.1021/ma00008a067
[10] S. Argentiere, L. Blasi, G. Ciccarella, G. Barbarella, R. Cingolani and G. Gigli, “Synthesis of Poly(Acrylic Acid) Nanogels and Application in Loading and Release of on Oligothiophene Fluorophore and Its Bovine Albumin Conjugate,” Macromolecular Symposia, Vol. 281, No. 1, 2009, pp. 69-76. doi:10.1002/masy.200950709
[11] N. A. Petasis, “Expanding Roles for Organoboron Compounds–Versatile and Valuable Molecules for Synthetic, BIOLOGICal and Medicinal Chemistry,” Australian Journal of Chemistry, Vol. 60, No. 11, 2007, pp. 795-798. doi:10.1071/CH07360
[12] W. Yang, S. Gao and B. Wang, “Boronic Acid Compounds as Potential Pharmaceutical Agents,” Medicinal Research Reviews, Vol. 23, 2003, pp. 346-368. doi:10.1002/med.10043
[13] V. M. Dembitsky and M. Srebnik, “Synthesis and Biological Activity of a-Aminoboronic Acid, Aminocarboranes and Their Derivatives,” Tetrahedron, Vol. 59, No. 5, 2003, pp. 579-593. doi:10.1016/S0040-4020(02)01618-6
[14] P. G. Richardson, C. Mitsiades, T. Hideshima and K. C. Anderson, “Bortezomib: Proteasome Inhibition as an Effective Anticancer Therapy,” Annual Review of Medicine, Vol. 57, 2006, pp. 33-47. doi:10.1146/
[15] H. S. Ban, H. Minegishi, K. Shimizu, M. Maruyama, Y. Yasui and H. Nakamura, “Discovery of Carboranes as Inducers of 20S Proteasome Activity,” Chemistry & Medicinal Chemistry, Vol. 5, No. 8, 2010, pp. 1236-1241. doi:10.1002/cmdc.201000112
[16] C. Morin, “The Chemistry of Boron Analogues of Bio Molecules,” Tetrahedron, Vol. 50, No. 44, 1994, pp. 12521-12569. doi:10.1016/S0040-4020(01)89389-3
[17] C. Baldock, G.-J. de Boer, J. B. Rafferty, A. R. Stuitje and D. W. Rice, “Mechanism of Action of Diazaborines,” Biochemical Pharmacology, Vol. 55, No. 10, 1998, pp. 1541- 1549.
[18] A. Jabbour, D. Steinberg, V. M. Dembitsky, A. Mous- saieff, B. Zaks and M. Srebnik, “Synthesis and Evaluation of Oxazaborolidines for Antibacterial Activity against Streptococcus Mutants,” Journal of Medicinal Chemistry, Vol. 47, No. 10, 2004, pp. 2409-2410. doi:10.1021/jm049899b
[19] S. J. Benkovic, S. J. Baker, M. R. K. Alley, Y.-H. Woo, Y.-K. Zhang, T. Akama, W. Mao, J. Baboval, P. T. Ravi Rajagopalan, W. Wall, L. S. Kahng, A.Tavassoli and L. Shapiro, “Identitication of Borinic Esters as Inhibitors of Bacterial Cell Growth and Bacterial Methyltransferases, CcrM and MenH,” Journal of Medicinal Chemistry, Vol. 48, No. 23, 2005, pp. 7468-7476. doi:10.1021/jm050676a
[20] S. J. Baker, Y.-K. Zhang, T. Akama, A. Lau, H. Zhou, V. Hernandez, W. Mao, M. R. K. Alley, V. Sanders and J. J. Plattner, “Discovery of a New Boron-Containing Antifungal Agent,” Fluoro-1,3-dihydro-1-hydroxy-2,1-ben-zoxaborole (AN2690), for the potential treatment of onychomycosis,” Journal of Medicinal Chemistry, Vol. 49, No. 15, 2006, pp. 4447-4450. doi:10.1021/jm0603724
[21] H. B. Zhou, K. W. Nettles, J. B. Bruning, Y. Kim, A. Joachimiak, S. Sharma, K. E. Carlson, F. Stossi, B. S. Katzenellenbogen, G. L. Greene and J. A. Katzenellen-bogen, “Elemental Isomerism: A Boron-Nitrogen Surro- gate for a Carbon-Carbon Double Bond Increases the Chemical Diversity of Estrogen Receptor Ligands,” Che- mistry & Biology, Vol. 14, No. 5, 2007, pp. 659-669. doi:10.1016/j.chembiol.2007.04.009
[22] J. F. Valliant, K. J. Guenther, A. S. King, P. Morel, P. Schaffer, O. O. Sogbein and K. A. Stephenson, “The Me- dical Chemistry of Carborones,” Coordination Chemistry Reviews, Vol. 232, No. 1-2, 2002, pp. 173-230. doi:10.1016/S0010-8545(02)00087-5
[23] W. Chen, S. C. Mehta and D. R. Lu, “Selective Boron Drug Delivery to Brain Tumors for Boron Neutron Capture Therapy,” Advanced Drug Delivery Reviews, Vol. 26, No. 2-3, 1997, pp. 231-247. doi:10.1016/S0169-409X(97)00037-9
[24] F. Shosseler, F. Ilmain and S. J. Candau, “Structure and Properties of Partially Neutralized Poly(Acrylic Acid) Gels,” Macromolecules, Vol. 24, No. 1, 1991, pp. 225- 234. doi:10.1021/ma00001a035
[25] M. Türk, Z. M. O. Rzayev and S. A. Khalilova, “Bioengineering Functional Copolymers. XIV. Synthesis and Interaction of Poly(N-isopropyl Acrylamide-co-2,3-dihydro-2H-pyran-alt-maleic Anhydride)s with SCLC Cancer Cells,” Bioorganic & Medicinal Chemistry, Vol. 18, No. 22, 2010, pp. 7975-7984. doi:10.1016/j.bmc.2010.09.031
[26] Türk, Z. M. O. Rzayev and G. Kurucu, “Bioengineering Functional Copolymers. XII. Interaction of Boron-Contai- ning and PEO Branched Derivatives of Poly(MA-alt-MVE) with HeLa Cells,” Health, Vol. 2, No. 1, 2010, pp. 51-61. doi:10.4236/health.2010.21009
[27] T. Shimisu and A. Minakata, “Effect of Divalent Cations on the Volume of a Maleic Acid Copolymer Gel Examined by Incorporating Lysozyme,” European Polymer Journal, Vol. 38, No. 6, 2002, pp. 1113-1120. doi:10.1016/S0014-3057(01)00283-X
[28] O. Nobumichi and S. Shintaro, “Conformational Characterization of a Maleic Acid Copolymer with an Inflexible Side Chain,” Journal of Macromolecular Science: Pure and Applied Chemistry, Vol. 27, No. 7, 1990, pp. 861-873. doi:10.1080/10601329008544810

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