Controlled release of cisplatin and cancer cell apoptosis with cisplatin encapsulated poly(lactic-co-glycolic acid) nanoparticles

DOI: 10.4236/jbise.2013.65074   PDF   HTML   XML   5,132 Downloads   8,051 Views   Citations


The goal of the present study is to utilize cis-diamminedichloroplatinum (cisplatin) loaded polymer nanoparticles (NPs) to give a controlled, extended, and local drug therapy for the treatment of cancer. We have used biodegradable and biocompatible poly(lactic-co-glycolic acid) (PLGA) to prepare the NPs by adjusting the double emulsion technique using poly(vinylalcohol) as a surface active agent. The PLGA NPs were characterized for particle size and shape, controlled release of cisplatin, and degradation. Cisplatin solubility in deionized water was increased up to 4 mg/mL by simply changing the solution parameters. Cisplatin encapsulated NPs were incubated in phosphate buffered saline (PBS) at 37?C to study the release kinetics of cisplatin. Cisplatin was released in a sustained manner with less than 20% release during a 3-day period followed by 50% release during a 21-day period. A degradation study of PLGA NPs demonstrated the loss of spherical shape during a 21-day period. We also examined the cisplatin sensitive A2780 cell apoptosis when cells were incubated with cisplatin encapsulated PLGA NPs. A large number of cell apoptosis occurred as a result of cisplatin release from the PLGA NPs. These results suggest that cisplatin encapsulated PLGA NPs can be used to treat the cancer cells by injecting them into a localized site minimizing the side effects.

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Jayasuriya, A. and Darr, A. (2013) Controlled release of cisplatin and cancer cell apoptosis with cisplatin encapsulated poly(lactic-co-glycolic acid) nanoparticles. Journal of Biomedical Science and Engineering, 6, 586-592. doi: 10.4236/jbise.2013.65074.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Bagi, C.M. (2005) Targeting of therapeutic agents to bone to treat metastatic cancer. Advanced Drug Delivery Reviews, 57, 995-1010. doi:10.1016/j.addr.2004.12.014
[2] Hunter, W., Burt, H.M. and Machan, L. (1997) Local delivery of chemotherapy: A supplement to existing cancer treatments. A case for surgical pastes and coated stents. Advanced Drug Delivery Reviews, 26, 199-207. doi:10.1016/S0169-409X(97)00035-5
[3] Santini, J.T., Richards, A.C., Scheidt, R.A., Cima, M.J. and Langer, R.S. (2000) Microchip technology in drug delivery. Annals of Medicine, 32, 377-379. doi:10.3109/07853890008995941
[4] Frank, A., Rath, S.K. and Venkatraman, S.S. (2005) Controlled release from bioerodible polymers: Effect of drug type and polymer composition. Journal of Controlled Release, 102, 333-344. doi:10.1016/j.jconrel.2004.10.019
[5] Vogelhuber, W., Rotunno, P., Magni, E., Gazzaniga, A., Sprub, T., Bernhardt, G., Buschauer, A. and Gopferich, A. (2001) Programmable biodegradable implants. Journal of Controlled Release, 73, 75-88. doi:10.1016/S0168-3659(01)00282-6
[6] Langer, R. (1990) New methods of drug delivery. Science, 249, 1527-1533. doi:10.1126/science.2218494
[7] Vogelhuber, W., Spruss, T., Bernhardt, G., Buschaue, A. and Gopferich, A. (2002) Efficacy of BCNU and paclitaxel loaded subcutaneous implants in the interstitial chemotherapy of U-87 MG human glioblastoma xenografts. International Journal of Pharmaceutics, 238, 111-121. doi:10.1016/S0378-5173(02)00061-3
[8] Attwood, D. (1994) Microemulsions. In: Kreuter, J., Ed., Colloidal Drug Delivery Systems, Drugs and the Pharmaceutical Sciences, Marcel Dekker, New York, 31-71.
[9] Maincent, P., Thouvenot, P., Amicabile, C., Hoffman, M., Kreuter, J., Couvreur, P. and Devissaguet, J.P. (1992) Lymphatic targeting of polymeric nanoparticles after intraperitoneal administration in rats. Pharmaceutical Research, 9, 1534-1539. doi:10.1023/A:1015895804597
[10] Nakada, Y., Fattal, E., Foulquier, M. and Couvreur, P. (1996) Pharmacokinetics and biodistribution of oligonucleotide adsorbed onto poly(isobutylcyanoacrylate) nanoparticles after intravenous administration in mice. Pharmaceutical Research, 13, 38-43. doi:10.1023/A:1016017014573
[11] Sabate, R., Barnadas-Rodriguez, R., Callejas-Fernandez, J., Hidalgo-Alvarez, R. and Estelrich, J. (2008) Preparation and characterization of extruded magnetoliposomes. International Journal of Pharmaceutics, 347, 156-162. doi:10.1016/j.ijpharm.2007.06.047
[12] Sahoo, S.K., Ma, W. and Labhasetwar, V. (2004) Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. International Journal of Cancer, 112, 335-340. doi:10.1002/ijc.20405
[13] Fukui, H., Koike, T., Nakagawa, T., Saheki, A., Sonoke, S., Tomii, Y. and Seki, J. (2003) Comparison of LNSAmB, a novel low-dose formulation of amphotericin B with lipid nano-sphere (LNS), with commercial lipidbased formulations. International Journal of Pharmaceutics, 267, 101-112. doi:10.1016/j.ijpharm.2003.08.002
[14] Ai, H., Jones, S. A., de Villiers, M.M. and Lvov, Y.M. (2003) Nano-encapsulation of furosemide microcrystals for controlled drug release. Journal of Controlled Release, 86, 59-68. doi:10.1016/S0168-3659(02)00322-X
[15] Astete, C.E. and Sabliov, C.M. (2006) Synthesis and characterization of PLGA nanoparticles. Journal of Biomaterials Science, Polymer Edition, 17, 247-289.
[16] Lamprecht, A., Ubrich, N., Hombreiro Pérez, M., Lehr, C.-M., Hoffman, M. and Maincent P. (1999) Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification. International Journal of Pharmaceutics, 184, 97-105. doi:10.1016/S0378-5173(99)00107-6
[17] Avgoustakis, K. (2004) Pegylated poly(lactide) and poly(lactide-co-glycolide) nanoparticles: Preparation, properties and possible applications in drug delivery. Current Drug Delivery, 1, 321-333. doi:10.2174/1567201043334605
[18] Lamprecht, A., Yamamoto, H., Takeuchi, H. and Kawashima, Y. (2005) Nanoparticles enhance therapeutic efficiency by selectively increased local drug dose in experimental colitis in rats. Journal of Pharmacology and Experimental Therapeutics, 315, 196-202. doi:10.1124/jpet.105.088146
[19] Barratt, G. (2003) Colloidal drug carriers: Achievements and perspectives. Cellular and Molecular Life Sciences, 60, 21-37. doi:10.1007/s000180300002
[20] Alyautdin, R.N., Petrov, V.E., Langer, K., Berthold, A., Kharkevich, D.A. and Kreuter, J. (1997) Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharmaceutical Research, 14, 325-328. doi:10.1023/A:1012098005098
[21] Bourel, D., Rolland, A., Le Verge, R. and Genetet, B. (1988) A new immunoreagent for cell labeling. CD3 monoclonal antibody covalently coupled to fluorescent polymethacrylic nanoparticles. Journal of Immunological Methods, 106, 161-167. doi:10.1016/0022-1759(88)90192-5
[22] O’Dwyer, P.J., Stevenson, J.P. and Johnson, S.W. (1999) Clinical status of cisplatin, carboplatin, and other platinum-based antitumor drugs. In: Lippert, B., Ed., Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug, Wiley-VCH, Zürich, 31-72.
[23] Goldberg, E.P., Hadba, A.R., Almond, B.A. and Marotta, J.S. (2002) Intratumoral cancer chemotherapy and immunotherapy: Opportunities for nonsystemic preoperative drug delivery. Journal of Pharmacy and Pharmacology, 54, 159-180. doi:10.1211/0022357021778268
[24] Tahara, Y. and Ishii, Y. (2001) Apatite cement containing cis-diamminedichloroplatinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation. Journal of Orthopaedic Science, 6, 556-565. doi:10.1007/s007760100012
[25] Fujiwara, K., Armstrong, D., Morgan, M. and Markman, M. (2007) Principles and practice of intraperitoneal chemotherapy for ovarian cancer. International Journal of Gynecological Cancer, 17, 1-20. doi:10.1111/j.1525-1438.2007.00809.x
[26] Wenzel, L.B., Huang, H.Q., Armstrong, D.K., Walker, J.L. and Cella, D. (2007) Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: A gynecologic oncology group study. Journal of Clinical Oncology, 25, 437-443. doi:10.1200/JCO.2006.07.3494
[27] Anderson, J.M. and Shive, M.S. (1997) Biodegradation and biocompatibility of PLA and PLGA microspheres. Advanced Drug Delivery Reviews, 28, 5-24. doi:10.1016/S0169-409X(97)00048-3
[28] Panyam, J., Dali, M.M., Sahoo, S.K., Ma, W., Chakravarthi, S.S., Amidon, G.L., Levy, R.J. and Labhasetwar, V. (2003) Polymer degradation and in vitro release of a model protein from poly(d,l-lactide-co-glycolide) nanoand microparticles. Journal of Controlled Release, 19, 173-187. doi:10.1016/S0168-3659(03)00328-6
[29] Riley, C.M. and Sternson, L.A. (1985). Cisplatin. In: Florey, K., Ed., Analytical Profiles of Drug Substances, Academic Press, New York, 78-105.
[30] Czarnobaj, K. and Lukasiak, J. (2004) In vitro release of cisplatin from solgel processed porous silica xerogels. Drug Delivery, 11, 341-344. doi:10.1080/10717540490507451
[31] De Spiegeleer, B., Slegers, G., Vandecasteele, C., Van den Bossche, W., Schelstraete, K., Claeys, A. and De Moerloose, P. (1986) Microscale synthesis of nitrogen13-labeled cisplatin. Journal of Nuclear Medicine, 27, 399-403.
[32] Jeong, Y.I., Kim, S.T., Jin, S.G., Ryu, H.H., Jin, Y.H., Jung, T.Y., Kim, I.Y. and Jung, S. (2008) Cisplatin-Incorporated Hyaluronic Acid Nanoparticles Based on IonComplex Formation,” Journal of Pharmaceutical Sciences, 97, 1268-1276. doi:10.1002/jps.21103
[33] Li, S., Girod, H.S. and Vert, M. (1994) Crystalline oligomeric stereocomplex as intermediate compound in racemic poly(DL-lactic acid) degradation. Polymer International, 33, 37-41. doi:10.1002/pi.1994.210330105
[34] Li, S. (1999) Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids. Journal of Biomedical Materials Research, 48, 342-353. doi:10.1002/(SICI)1097-4636(1999)48:3<342::AID-JBM20>3.0.CO;2-7
[35] “The Merck Index,” 12th Edition, Merck & Co., Whitehouse Station, 1996.
[36] Moreno, D., Zalba, S., Colom, H., Trocóniz, I.F., Tros de Ilarduya, C. and Garrido, M.J. (2009) Biopharmaceutic and pharmacodynamic modeling of the in vitro antiproliferative effect of new controlled delivery systems of cisplatin. European Journal of Pharmaceutical Sciences, 37, 341-350. doi:10.1016/j.ejps.2009.03.005
[37] Moreno, D., de Ilarduya, C.T., Bandrés, E., Buñuales, M., Azcona, M., García-Foncillas, J. and Garrido, M.J. (2008) Characterization of cisplatin cytotoxicity delivered from PLGA-systems. European Journal of Pharmaceutics and Biopharmaceutics, 68, 503-512. doi:10.1016/j.ejpb.2007.08.006
[38] Huo, D., Deng, S., Li, L. and Ji, J. (2005) Studies on the poly(lactic-co-glycolic) acid microspheres of cisplatin for lung-targeting. International Journal of Pharmaceutics, 289, 63-67. doi:10.1016/j.ijpharm.2004.10.017
[39] Owens III, D.E. and Peppas, N.A. (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. International Journal of Pharmaceutics, 307, 93-102. doi:10.1016/j.ijpharm.2005.10.010

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