Abstract
The aim of this study was to evaluate the antitumor effect of combinatorial targeted therapy with paclitaxel and all-trans retinoic acid (ATRA) nanoparticles in vitro. Paclitaxel-incorporated pullulan acetate (PA) nanoparticles were prepared by the nanoprecipitation-solvent evaporation method. ATRA-incorporated nanoparticles were prepared by dialysis using a methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) copolymer. Particle sizes of paclitaxel-incorporated nanoparticles and ATRA-incorporated nanoparticles were about 160 nm and 60 nm, respectively. Nanoparticles were reconstituted in various aqueous media such as deionized water, phosphate-buffered saline, and fetal bovine serum-supplemented cell culture media. The combination of paclitaxel + ATRA (10 + 10 μg/mL) delivered by nanoparticles showed a synergistic antiproliferative effect against CT26 cells that was not observed with other combinations. Furthermore, the activity of MMP-2, a key enzyme in tumor cell invasion, was significantly decreased in cells treated with the combination of paclitaxel and ATRA while other combinations and single agents did not significantly affect its activity. A matrigel assay supported these results, indicating that paclitaxel/ATRA combination nanoparticles are effective for the inhibition of the invasion of tumor cells. The results of the present study suggest that combination treatment with paclitaxel and ATRA could be an effective treatment for the inhibition of tumor cell proliferation and invasion, and that nanoparticles are promising candidates for antitumor drug delivery.
Similar content being viewed by others
References
Arbuck, S. G., Taxol (paclitaxel): future directions. Ann. Oncol., 5, S59–S62 (1994).
Bouterfa, H., Picht, T., Kess, D., Herbold, C., Noll, E., Black, P. M., Roosen, K., and Tonn, J. C., Retinoids inhibit human glioma cell proliferation and migration in primary cell cultures but not in established cell lines. Neurosurgery, 46, 419–430 (2000).
Bussemer, T., Dashevsky, A., and Bodmeier, R., A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. J. Control. Release, 93, 331–339 (2003).
Cabrespine, A., Bay, J. O., Barthomeuf, C., Curé, H., Chollet, P., and Debiton, E., In vitro assessment of cytotoxic agent combinations for hormone-refractory prostate cancer treatment. Anticancer Drugs, 16, 417–422 (2005).
Conley, B. A., Egorin, M. J., Sridhara, R., Finley, R., Hemady, R., Wu, S., Tait, N. S., and Van Echo, D. A., Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics. Cancer Chemother. Pharmacol., 39, 291–299 (1997).
Croy, S. R. and Kwon, G. S., Polymeric micelles for drug delivery. Curr. Pharm. Des., 12, 4669–4684 (2006).
Cryan, S. A., Carrier-based strategies for targeting protein and peptide drugs to the lungs. AAPS J., 7, E20–E41 (2005).
Das, A., Banik, N. L., and Ray, S. K., Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells. J. Neurooncol., 87, 9–22 (2008).
Eniola, A. O. and Hammer, D. A., Artificial polymeric cells for targeted drug delivery. J. Control. Release, 87, 15–22 (2003).
Ettinger, D. S., Taxol in the treatment of lung cancer. J. Natl. Cancer Inst. Monogr., 15, 177–179 (1993).
Ferraresi, V., Giampaolo, M. A., Gabriele, A., Mansueto, G., Buccilli, A., Giannarelli, D., Ciccarese, M., and Gamucci, T., Activity and toxicity of oxaliplatin and bolus fluorouracil plus leucovorin in pretreated colorectal cancer patients: a phase II study. J. Exp. Clin. Cancer Res., 24, 187–196 (2005).
Forastiere, A. A., Current and future trials of Taxol (paclitaxel) in head and neck cancer. Ann. Oncol., 5, S51–S54 (1994).
Frankel, S. R., Eardley, A., Lauwers, G., Weiss, M., and Warrell, R. P. Jr., The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann. Intern. Med., 117, 292–296 (1992).
García-García, H. M., Vaina, S., Tsuchida, K., and Serruys, P. W., Drug-eluting stents. Arch. Cardiol. Mex., 76, 297–319 (2006).
Giannini, F., Maestro, R., Vukosavljevic, T., Pomponi, F., and Boiocchi, M., All-trans, 13-cis and 9-cis retinoic acids induce a fully reversible growth inhibition in HNSCC cell lines: implications for in vivo retinoic acid use. Int. J. Cancer, 70, 194–200 (1997).
Gogate, U. S., Schwartz, P. A., and Agharkar, S. N., Effect of unpurified Cremophor EL on the solution stability of paclitaxel. Pharm. Dev. Technol., 14, 1–8 (2009).
Gray, W. A. and Granada, J. F., Drug-coated balloons for the prevention of vascular restenosis. Circulation, 121, 2672–2680 (2010).
Gref, R., Minamitake, Y., Peracchia, M. T., Trubetskoy, V., Torchilin, V., and Langer, R., Biodegradable long-circulating polymeric nanospheres. Science, 263, 1600–1603 (1994).
Hardman, W. E., Moyer, M. P., and Cameron, I. L., Efficacy of treatment of colon, lung and breast human carcinoma xenografts with: doxorubicin, cisplatin, irinotecan or topotecan. Anticancer Res., 19, 2269–2274 (1999).
Horwitz, S. B., Mechanism of action of taxol. Trends Pharmacol. Sci., 13, 134–136 (1992).
Hruby, M., Konak, C., and Ulbrich, K., Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J. Control. Release, 103, 137–148 (2005).
Huang, M. E., Ye, Y. C., Chen, S. R., Chai, J. R., Lu, J. X., Zhoa, L., Gu, L. J., and Wang, Z. Y., Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood, 72, 567–572 (1988).
Jeong, Y. I., Nah, J. W., Lee, H. C., Kim, S. H., and Cho, C. S., Adriamycin release from flower-type polymeric micelle based on star-block copolymer composed of poly(gamma-benzyl l-glutamate) as the hydrophobic part and poly (ethylene oxide) as the hydrophilic part. Int. J. Pharm., 188, 49–58 (1999).
Jeong, Y. I., Seo, S. J., Park, I. K., Lee, H. C., Kang, I. C., Akaike, T., and Cho, C. S., Cellular recognition of paclitaxelloaded polymeric nanoparticles composed of poly(gammabenzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety. Int. J. Pharm., 296, 151–161 (2005).
Jeong, Y. I., Kim, S. H., Jung, T. Y., Kim, I. Y., Kang, S. S., Jin, Y. H., Ryu, H. H., Sun, H. S., Jin, S. G., Kim, K. K., Ahn, K. Y., and Jung, S., Polyion complex micelles composed of all-trans retinoic acid and poly(ethylene glycol)-grafted-chitosan. J. Pharm. Sci., 95, 2348–2360 (2006a).
Jeong, Y. I., Na, H. S., Oh, J. S., Choi, K. C., Song, C. E., and Lee, H. C., Adriamycin release from self-assembling nanospheres of poly(DL-lactide-co-glycolide)-grafted pullulan. Int. J. Pharm., 322, 154–160 (2006b).
Jeong, Y. I., Na, H. S., Cho, K. O., Lee, H. C., Nah, J. W., and Cho, C. S., Antitumor activity of adriamycin-incorporated polymeric micelles of poly(γ-benzyl L-glutamate)/poly (ethylene oxide). Int. J. Pharm., 365, 150–156 (2009).
Jung, S. W., Jeong, Y. I., Kim, Y. H., and Kim, S. H., Self-assembled polymeric nanoparticles of poly(ethylene glycol) grafted pullulan acetate as a novel drug carrier. Arch. Pharm. Res., 27, 562–569 (2004).
Kalemkerian, G. P., Jasti, R. K., Celano, P., Nelkin, B. D., and Mabry, M., All-trans retinoic acid alters myc gene expression and inhibits in vitro progression in small cell lung cancer. Cell Growth Differ., 5, 55–60 (1994).
Karmakar, S., Banik, N. L., Patel, S. J., and Ray, S. K., Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice. Apoptosis, 12, 2077–2087 (2007).
Karmakar, S., Banik, N. L., and Ray, S. K., Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice. Cancer, 112, 596–607 (2008).
Kim, D. G., Jeong, Y. I., and Nah, J. W., All-trans retinoic acid release from polyion-complex micelles of methoxy poly(ethylene glycol) grafted chitosan. J. Appl. Polym. Sci., 105, 3246–3254 (2007).
Krupitza, G., Hulla, W., Harant, H., Dittrich, E., Kallay, E., Huber, H., Grunt, T., and Dittrich, C., Retinoic acid induced death of ovarian carcinoma cells correlates with c-myc stimulation. Int. J. Cancer, 61, 649–657 (1995).
Kwon, G., Suwa, S., Yokoyama, M., Okano, T., Sakurai, Y., and Kataoka, K., Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates. J. Control. Release, 29, 17–23 (1994).
Kwon, G. S., Naito, M., Yokoyama, M., Okano, T., Sakurai, Y., and Kataoka, K., Physical entrapment of adriamycin in AB block copolymer micelles. Pharm. Res., 12, 192–195 (1995).
Lim, S. J. and Kim, C. K., Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid. Int. J. Pharm., 243, 135–146 (2002).
Lotan, R., Retinoids as modulators of tumor cell invasion and metastasis. Semin. Cancer Biol., 2, 197–208 (1991).
Muindi, J. R. F., Frankel, S. R., Miller, W. H. Jr., Jakubowski, A., Scheinberg, D. A., Young, C. W., Dmitrovsky, E., and Warrell, R. P. Jr., Continuous treatment with all-transretinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood, 79, 299–303 (1992).
Na, H. S., Lim, Y. K., Jeong, Y. I., Lee, H. S., Lim, Y. J., Kang, M. S., Cho, C. S., and Lee, H. C., Combination antitumor effects of micelle-loaded anticancer drugs in a CT-26 murine colorectal carcinoma model. Int. J. Pharm., 383, 192–200 (2010).
Nagai, S., Takenaka, K., Sonobe, M., Wada, H., and Tanaka, F., Schedule-dependent synergistic effect of pemetrexed combined with gemcitabine against malignant pleural mesothelioma and non-small cell lung cancer cell lines. Chemotherapy, 54, 166–175 (2008).
Neijt, J. P., New therapy for ovarian cancer. N. Engl. J. Med., 334, 50–51 (1996).
Noguchi, Y., Wu, J., Duncan, R., Strohalm, J., Ulbrich, K., Akaike, T., and Maeda, H., Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn. J. Cancer Res., 89, 307–314 (1998).
Petrak, K., Essential properties of drug-targeting delivery systems. Drug Discov. Today, 10, 1667–1673 (2005).
Ravi Kumar, M. N., Nano and microparticles as controlled drug delivery devices. J. Pharm. Pharm. Sci., 3, 234–258 (2000).
Ridwelski, K., Gebauer, T., Fahlke, J., Kroning, H., Kettner, E., Meyer, F., Eichelmann, K., and Lippert, H., Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann. Oncol., 12, 47–51 (2001).
Rowinsky, E. K. and Donehower, R. C., Paclitaxel (taxol). N. Engl. J. Med., 332, 1004–1014 (1995).
Saltz, L. B., Cox, J. V., Blanke, C., Rosen, L. S., Fehrenbacher, L., Moore, M. J., Maroun, J. A., Ackland, S. P., Locker, P. K., Pirotta, N., Elfring, G. L., and Miller, L. L., Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N. Engl. J. Med., 343, 905–914 (2000).
Sarkar, K. and Yang, H., Encapsulation and extended release of anti-cancer anastrozole by stealth nanoparticles. Drug Deliv., 15, 343–346 (2008).
Sofou, S., Radionuclide carriers for targeting of cancer. Int. J. Nanomed., 3, 181–199 (2008).
Soriano, A. F., Helfrich, B., Chan, D. C., Heasley, L. E., Bunn, P. A. Jr., and Chou, T. C., Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer Res., 59, 6178–6184 (1999).
Szuts, E. Z. and Harosi, F. I., Solubility of retinoids in water. Arch. Biochem. Biophys., 287, 297–304 (1991).
ten Tije, A. J., Verweij, J., Loos, W. J., and Sparreboom, A., Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin. Pharmacokinet., 42, 665–685 (2003).
Torchilin, V., Antibody-modified liposomes for cancer chemotherapy. Expert Opin. Drug Deliv., 5, 1003–1025 (2008).
Vaishampayan, U., Flaherty, L., Du, W., and Hussain, M., Phase II evaluation of paclitaxel, α-interferon, and cisretinoic acid in advanced renal cell carcinoma. Cancer, 92, 519–523 (2001).
Yokoyama, M., Miyauchi, M., Yamada, N., Okano, T., Sakurai, Y., and Kataoka, K., Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. Cancer Res., 50, 1693–1700 (1990).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hong, GY., Jeong, YI., Lee, S.J. et al. Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma. Arch. Pharm. Res. 34, 407–417 (2011). https://doi.org/10.1007/s12272-011-0308-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-011-0308-8