In Vitro Synergistic Action of Geldanamycin- and Docetaxel-Containing HPMA Copolymer–RGDfK Conjugates Against Ovarian Cancer
Nate Larson
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorSarah Roberts
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Search for more papers by this authorAbhijit Ray
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorBrandon Buckway
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorDarwin L. Cheney
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Search for more papers by this authorCorresponding Author
Hamidreza Ghandehari
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Department of Bioengineering, University of Utah, 36 South Wasatch Drive, Salt Lake City, UT, 84112 USA
Search for more papers by this authorNate Larson
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorSarah Roberts
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Search for more papers by this authorAbhijit Ray
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorBrandon Buckway
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Search for more papers by this authorDarwin L. Cheney
TheraTarget, Inc., 615 Arapeen Dr., Suite 302-Y, Salt Lake City, UT, 84108 USA
Search for more papers by this authorCorresponding Author
Hamidreza Ghandehari
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Nanomedicine, Nano Institute of Utah, Salt Lake City, UT, 84112 USA
Department of Bioengineering, University of Utah, 36 South Wasatch Drive, Salt Lake City, UT, 84112 USA
Search for more papers by this authorAbstract
HPMA copolymer–RGDfK (HPMA-RGDfK) conjugates bearing either aminohexylgeldanamycin (AHGDM) or docetaxel (DOC) were synthesized and characterized. In vitro stability and binding were evaluated. Cytotoxicity toward ovarian cancer cells was evaluated and the ability of the conjugates to induce cell death was assessed by combination index analysis. Conjugates bearing AHGDM were more stable and exhibited slower drug release than those bearing DOC. Both conjugates demonstrated the ability to bind to avb3 integrins. In combination, HPMA–RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA–RGDfK conjugates bearing AHGDM and DOC induce synergistic cytotoxicity in vitro, suggesting their potential as a promising combination therapy.
Supporting Information
| Filename | Description |
|---|---|
| mabi201400360-sm-0001-SuppFig-S1.docx407.1 KB |
Figure S1: HPLC chromatograph of free AHGDM and p-AHGDM-RGDfK. At similar AHGDM equvalent concentrations of approximately 0.1 mg/mL, no evidence of unbound AHGDM is present in p-AHGDM-RGDfK. Figure S2: HPLC chromatograph of free DOC and p-DOC-RGDfK. At similar DOC equivalent concentrations of approximately 0.2 mg/mL, no evidence of unbound DOC is present in p-DOC-RGDfK. Figure S3: In vitro growth inhibition of HPMA copolymer conjugates in A2780 human ovarian cancer cells. Data expressed as mean ± SD of three independent experiments, with 3 samples per experiment. Figure S4: In vitro growth inhibition of HPMA copolymer conjugates in OVCAR-3 human ovarian cancer cells. Data expressed as mean ± SD of three independent experiments, with 3 samples per experiment. Figure S5: Drug release based on Cathepsin B enzymatic cleavage. Data expressed as the mean ± SE (n = 3). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1American Cancer Society, http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-key-statistics, assessed: July 2013.
- 2 P. Gonzalez-Diego, G. Lopez-Abente, M. Pollan, Eur. J. Cancer 2000, 36, 1816.
- 3 J. H. Rowland, N. Aziz, G. Tesauro, E. J. Feuer, Semin. Oncol. Nurs. 2001, 17, 236.
- 4 V. Guarneri, F. Piacentini, E. Barbieri, P. F. Conte, Gynecol. Oncol. 2009, 117, 152.
- 5 A. Gadducci, E. Sartori, T. Maggino, P. Zola, F. Landoni, A. Fanucchi, N. Palai, C. Alessi, A. M. Ferrero, S. Cosio, R. Cristofani, Gynecol. Oncol. 1998, 68, 150.
- 6 A. Gadducci, S. Cosio, P. F. Conte, A. R. Genazzani, Crit. Rev. Oncol. Hematol. 2005, 55, 153.
- 7 Y. Fu, S. Li, Y. Zu, G. Yang, Z. Yang, M. Luo, S. Jiang, M. Wink, T. Efferth, Curr. Med. Chem. 2009, 16, 3966.
- 8 A. Montero, F. Fossella, G. Hortobagyi, V. Valero, Lancet Oncol. 2005, 6, 229.
- 9 I. Ringel, S. B. Horwitz, J. Natl. Cancer Inst. 1991, 83, 288.
- 10 M. Belfiglio, C. Fanizza, N. Tinari, C. Ficorella, S. Iacobelli, C. Natoli, J. Cancer Res. Clin. Oncol. 2012, 138, 221.
- 11 K. Amarantidis, N. Xenidis, L. Chelis, E. Chamalidou, P. Dimopoulos, P. Michailidis, A. Tentes, S. Deftereos, M. Karanikas, A. Karayiannakis, S. Kakolyris, Oncology 2011, 80, 359.
- 12 A. G. Pallis, S. Agelaki, A. Agelidou, I. Varthalitis, K. Syrigos, N. Kentepozidis, G. Pavlakou, A. Kotsakis, E. Kontopodis, V. Georgoulias, BMC Cancer 2010, 10, 633.
- 13 M. Markman, K. Zanotti, K. Webster, G. Peterson, B. Kulp, J. Belinson, Gynecol. Oncol. 2003, 91, 573.
- 14 M. Benjapibal, A. P. Kudelka, A. Vasuratna, C. L. Edwards, C. F. Verschraegen, V. Valero, S. Vadhan-Raj, J. J. Kavanagh, Anticancer Drugs 1998, 9, 577.
- 15 S. Sato, J. Kigawa, Y. Kanamori, H. Itamochi, T. Oishi, M. Shimada, T. Iba, J. Naniwa, K. Uegaki, N. Terakawa, Cancer Chemother. Pharmacol. 2004, 53, 247.
- 16 Z. Kafri, L. K. Heilbrun, A. Sukari, G. Yoo, J. Jacobs, H. S. Lin, H. Mulrenan, D. Smith, O. Kucuk, ISRN Oncol. 2012, 2012, 159568.
- 17 S. Tamura, M. Imano, H. Takiuchi, K. Kobayashi, H. Imamoto, H. Miki, Y. Goto, T. Aoki, Y. F. Peng, T. Tsujinaka, H. Furukawa, Anticancer Res. 2012, 32, 1403.
- 18 S. Fu, B. T. Hennessy, C. S. Ng, Z. Ju, K. R. Coombes, J. K. Wolf, A. K. Sood, C. F. Levenback, R. L. Coleman, J. J. Kavanagh, D. M. Gershenson, M. Markman, K. Dice, A. Howard, J. Li, Y. Li, K. Stemke-Hale, M. Dyer, E. Atkinson, E. Jackson, V. Kundra, R. Kurzrock, R. C. Bast, Jr., G. B. Mills, Gynecol. Oncol. 2012, 126, 47.
- 19 A. A. Garcia, A. Yessaian, H. Pham, G. Facio, L. Muderspach, L. Roman, Cancer Invest. 2012, 30, 295.
- 20 G. Sorbe, M. Graflund, G. Horvath, M. Swahn, K. Boman, R. Bangshoj, M. Lood, H. Malmstrom, Int. J. Gynecol. Cancer 2012, 22, 47.
- 21 K. Ushijima, T. Kamura, K. Tamura, K. Kuzuya, T. Sugiyama, K. Noda, K. Ochiai, Int. J. Clin. Oncol. 2013, 18, 126.
- 22 Q. Tan, X. Liu, X. Fu, Q. Li, J. Dou, G. Zhai, Expert Opin. Drug Deliv. 2012, 9, 975.
- 23 F. K. Engels, R. A. Mathot, J. Verweij, Anticancer Drugs 2007, 18, 95.
- 24 L. Neckers, P. Workman, Clin. Cancer Res. 2012, 18, 64.
- 25 A. Kamal, L. Thao, J. Sensintaffar, L. Zhang, M. F. Boehm, L. C. Fritz, F. J. Burrows, Nature 2003, 425, 407.
- 26 K. K. Sankhala, M. M. Mita, A. C. Mita, C. H. Takimoto, Curr. Drug Targets 2011, 12, 2001.
- 27 T. W. Schulte, L. M. Neckers, Cancer Chemother. Pharmacol. 1998, 42, 273.
- 28 W. Xu, E. Mimnaugh, M. F. Rosser, C. Nicchitta, M. Marcu, Y. Yarden, L. Neckers, J. Biol. Chem. 2001, 276, 3702.
- 29 S. Sato, N. Fujita, T. Tsuruo, Proc. Natl. Acad. Sci. USA 2000, 97, 10832.
- 30 M. V. Blagosklonny, J. Toretsky, L. Neckers, Oncogene 1995, 11, 933.
- 31 S. Sharp, P. Workman, Adv. Cancer Res. 2006, 95, 323.
- 32 M. Gorska, U. Popowska, A. Sielicka-Dudzin, A. Kuban-Jankowska, W. Sawczuk, N. Knap, G. Cicero, F. Wozniak, Front. Biosci. 2012, 17, 2269.
- 33 N. Larson, H. Ghandehari, Chem. Mater. 2012, 24, 840.
- 34 F. Canal, J. Sanchis, M. J. Vicent, Curr. Opin. Biotechnol. 2011, 22, 894.
- 35 R. Duncan, Nat. Rev. Cancer 2006, 6, 688.
- 36 J. Fang, H. Nakamura, H. Maeda, Adv. Drug Deliv. Rev. 2011, 63, 136.
- 37 H. Maeda, J. Control. Release 2012, 164, 138.
- 38 R. Duncan, M. J. Vicent, Adv. Drug Deliv. Rev. 2010, 62, 272.
- 39 J. Kopecek, P. Kopeckova, Adv. Drug Deliv. Rev. 2010, 62, 122.
- 40 V. Subr, J. Kopecek, J. Pohl, M. Baudys, V. Kostka, J. Control. Release 1988, 8, 133.
- 41
N. A. Pepas,
R. S. Langer, in:
Biopolymers II, Vol.
122,
Springer,
Berlin
1995, pp. 55–123.
10.1007/3-540-58788-8 Google Scholar
- 42 R. Duncan, Adv. Drug Deliv. Rev. 2009, 61, 1131.
- 43 L. W. Seymour, D. R. Ferry, D. J. Kerr, D. Rea, M. Whitlock, R. Poyner, C. Boivin, S. Hesslewood, C. Twelves, R. Blackie, A. Schatzlein, D. Jodrell, D. Bissett, H. Calvert, M. Lind, A. Robbins, S. Burtles, R. Duncan, J. Cassidy, Int. J. Oncol. 2009, 34, 1629.
- 44 R. R. Sawant, V. P. Torchilin, AAPS J. 2012, 14, 303.
- 45 D. Sutton, N. Nasongkla, E. Blanco, J. Gao, Pharm. Res. 2007, 24, 1029.
- 46 L. Dykman, N. Khlebtsov, Chem. Soc. Rev. 2012, 41, 2256.
- 47 D. B. Pike, H. Ghandehari, Adv. Drug Deliv. Rev. 2010, 62, 167.
- 48 J. W. Hopewel, R. Duncan, D. Wilding, K. Chakrabarti, Hum. Exp. Toxicol. 2001, 20, 461.
- 49 A. Ray, N. Larson, D. B. Pike, M. Gruner, S. Naik, H. Bauer, A. Malugin, K. Greish, H. Ghandehari, Mol. Pharm. 2011, 8, 1090.
- 50 K. Greish, A. Ray, H. Bauer, N. Larson, A. Malugin, D. Pike, M. Haider, H. Ghandehari, J. Control. Release 2011, 151, 263.
- 51 B. Felding-Habermann, B. M. Mueller, C. A. Romerdahl, D. A. Cheresh, J. Clin. Invest. 1992, 89, 2018.
- 52 L. Bello, M. Francolini, P. Marthyn, J. Zhang, R. S. Carroll, D. C. Nikas, J. F. Strasser, R. Villani, D. A. Cheresh, P. M. Black, Neurosurgery 2001, 49, 380 discussion 390.
- 53 G. Gasparini, P. C. Brooks, E. Biganzoli, P. B. Vermeulen, E. Bonoldi, L. Y. Dirix, G. Ranieri, R. Miceli, D. A. Cheresh, Clin. Cancer Res. 1998, 4, 2625.
- 54 M. Janssen, W. J. Oyen, L. F. Massuger, C. Frielink, I. Dijkgraaf, D. S. Edwards, M. Radjopadhye, F. H. Corstens, O. C. Boerman, Cancer Biother. Radiopharm. 2002, 17, 641.
- 55 C. N. Landen, T. J. Kim, Y. G. Lin, W. M. Merritt, A. A. Kamat, L. Y. Han, W. A. Spannuth, A. M. Nick, N. B. Jennnings, M. S. Kinch, D. Tice, A. K. Sood, Neoplasia 2008, 10, 1259.
- 56 C. Aghajanian, S. V. Blank, B. A. Goff, P. L. Judson, M. G. Teneriello, A. Husain, M. A. Sovak, J. Yi, L. R. Nycum, J. Clin. Oncol. 2012, 30, 2039.
- 57 X. Lu, L. Xiao, L. Wang, D. M. Ruden, Biochem. Pharmacol. 2012, 83, 995.
- 58 M. Scaltriti, S. Dawood, J. Cortes, Clin. Cancer Res. 2012, 18, 4508.
- 59 D. M. Nguyen, D. Lorang, G. A. Chen, J. H. Stewart, IV, E. Tabibi, D. S. Schrump, Ann. Thorac. Surg. 2001, 72, 371.
- 60 V. Smith, S. Hobbs, W. Court, S. Eccles, P. Workman, L. R. Kelland, Anticancer Res. 2002, 22, 1993.
- 61 D. B. Solit, A. D. Basso, A. B. Olshen, H. I. Scher, N. Rosen, Cancer Res. 2003, 63, 2139.
- 62 J. Strohalm, J. Kopecek, Makromol. Chem. 1978, 70, 109.
- 63 P. Rejmanova, J. Labsky, J. Kopecek, Makromol. Chem. 1977, 178, 2159.
- 64 K. Ulbrich, V. Subr, J. Strohalm, D. Plocova, M. Jelinkova, B. Rihova, J. Control. Release 2000, 64, 63.
- 65 J. H. Lee, P. Kopeckova, J. Kopecek, J. D. Andrade, Biomaterials 1990, 11, 455.
- 66 Y. Kasuya, Z. R. Lu, P. Kopeckova, S. E. Tabibi, J. Kopecek, Pharm. Res. 2002, 19, 115.
- 67 M. P. Borgman, A. Ray, R. B. Kolhatkar, E. A. Sausville, A. M. Burger, H. Ghandehari, Pharm. Res. 2009, 26, 1407.
- 68 T. C. Chou, P. Talalay, Adv. Enzyme Regul. 1984, 22, 27.
- 69 T. Lammers, R. Kuhnlein, M. Kissel, V. Subr, T. Etrych, R. Pola, M. Pechar, K. Ulbrich, G. Storm, P. Huber, P. Peschke, J. Control. Release 2005, 110, 103.
- 70 M. P. Borgman, O. Aras, S. Geyser-Stoops, E. A. Sausville, H. Ghandehari, Mol. Pharm. 2009, 6, 1836.
- 71 A. Mitra, J. Mulholland, A. Nan, E. McNeill, H. Ghandehari, B. R. Line, J. Control. Release 2005, 102, 191.
- 72 L. J. Gamble, A. V. Borovjagin, Q. L. Matthews, Exp. Ther. Med. 2010, 1, 233.
- 73 S. Cruet-Hennequart, S. Maubant, J. Luis, P. Gauduchon, C. Staedel, S. Dedhar, Oncogene 2003, 22, 1688.
- 74 T. C. Chou, Cancer Res. 2010, 70, 440.
