Sustained drug delivery system in fish and the potential for use of PLGA microparticles: a review J., Podhorec P. (2019): Sustained drug delivery system in fish and the potential for use of PLGA microparticles: a review. Veterinarni Medicina, 64: 287-293.
download PDF

Many fish species display some form of reproductive disorder in captivity. Captive fish reared in conditions outside the natural spawning environment show a failure of the pituitary to release the maturational gonadotropin luteinizing hormone thus necessitating administration of the hormone to induce spawning. A controlled sustained-release delivery system can conquer the issue of short half-life of gonadotropin releasing hormone (GnRH) in blood and avoid the necessity of using re-injections. Sustained release of GnRHa can induce long-term enhancement in semen production and multiple spawning in species with asynchronous or multiple batch group synchronous ovarian physiology. The most recent development is the incorporation of GnRHa into microparticles of biodegradable polymers that release the drug during a certain period of time ranging from days to weeks. The most attractive polymeric candidate used as a carrier for administering a pharmaceutical products is poly(lactic-co-glycolic acid); (PLGA). PLGA has excellent biodegradability and biocompatibility and is generally recognised as safe by international regulatory agencies including the European Medicines Agency and the United States Food and Drug Administration. This review describes methods of hormonal treatment in fish, highlights the advantage of sustained drug delivery system and discusses the potential of PLGA microparticles as a tool for achieving successful reproduction.

Abol-Munafi A, Liem P, Ambak M, Siraj S (2006): Effects of maturational hormone treatment on spermatogenesis of hybrid catfish (Clarias macrocephalus X C. gariepinus). Journal of Sustainability Science and Management 1, 24–31.
Adomako M, St-Hilaire S, Zheng Y, Eley J, Marcum R D, Sealey W, Donahower B C, LaPatra S, Sheridan P P (2012): Oral DNA vaccination of rainbow trout, Oncorhynchus mykiss (Walbaum), against infectious haematopoietic necrosis virus using PLGA [Poly(D,L-Lactic-Co-Glycolic Acid)] nanoparticles. Journal of Fish Diseases, 35, 203-214
Almendras J.M., Duenas Corazon, Nacario Jonathan, Sherwood Nancy M., Crim Laurence W. (1988): Sustained hormone release. III. Use of gonadotropin releasing hormone analogues to induce multiple spawnings in sea bass, Lates calcarifer. Aquaculture, 74, 97-111
Altun S, Kubilay A, Ekici S, Didinen BI, Diler O (2010): Oral vaccination against lactococcosis in rainbow trout (Oncorhynchus mykiss) using sodium alginate and poly (lactide-co-glycolide) carrier. Kafkas Universitesi Veteriner Fakultesi Dergisi 16, 211–217.
Anderson Kelli, Pankhurst Ned, King Harry, Elizur Abigail (2017): Effects of GnRHa treatment during vitellogenesis on the reproductive physiology of thermally challenged female Atlantic salmon ( Salmo salar ). PeerJ, 5, e3898-
Aramli Mohammad Sadegh, Nazari Rajab Mohammad, Farsi Parham, Mehdinejad Nooshin, Aramli Salim, Sotoudeh Ebrahim (2017): Retracted : Effectiveness of carp pituitary extract and luteinizing hormone releasing hormone analogue administration (by either injection or cholesterol pellet implantation) on spawning performance in female sturgeon, Huso huso. Aquaculture Research, 48, 1915-1922
Bai Xin-Lai, Yang Yi-Yan, Chung Tai-Shung, Ng Steve, Heller Jorge (2001): Effect of polymer compositions on the fabrication of poly(ortho-ester) microspheres for controlled release of protein. Journal of Applied Polymer Science, 80, 1630-1642
Birnbaum DT, Brannon-Peppas L (2004): Microparticle drug delivery systems. In: Brown DM (ed.): Drug Delivery Systems in Cancer Therapy. Humana Press, New Jersey. 117–136.
Breton Bernard, Weil Claudine, Sambroni Elisabeth, Zohar Yonathan (1990): Effects of acute versus sustained administration of GnRHa on GtH release and ovulation in the rainbow trout, Oncorhynchus mykiss. Aquaculture, 91, 373-383
Bromage NR (1995): Broodstock management and seed quality – General consideration. In: Bromage NR, Roberts R (eds): Broodstock Management and Egg and Larval Quality. Blackwell Science, London. 1–24.
Bromage Niall, Porter Mark, Randall Clive (2001): The environmental regulation of maturation in farmed finfish with special reference to the role of photoperiod and melatonin. Aquaculture, 197, 63-98
Brown L., Munoz C., Siemer L., Edelman E., Langer R. (1986): Controlled Release of Insulin From Polymer Matrices: Control of Diabetes in Rats. Diabetes, 35, 692-697
Cai Q (2003): Enzymatic degradation behavior and mechanism of Poly(lactide-co-glycolide) foams by trypsin. Biomaterials, 24, 629-638
Carolsfeld Joachim, Sherwood Nancy M., Kreiberg Henrik, Sower Stacia A. (1988): Induced sexual maturation of herring using GnRH ‘quick-release’ cholesterol pellets. Aquaculture, 70, 169-181
Carrillo M, Mananos E, Sorbera L, Milonas C, Cuisset B, Zohar Y, Zanuy S (2000): Effects of sustained administration of GnRHa on gonadotropin–II (GtH–II) and gonadal steroid levels in adult male sea bass (Dicentrarchus labrax). Proceedings of the 6th International Symposium on the Reproductive Physiology of Fish, 393–395.
Crim L.W., Sutterlin A.M., Evans D.M., Weil C. (1983): Accelerated ovulation by pelleted LHRH analogue treatment of spring-spawning rainbow trout (Salmo gairdneri) held at low temperature. Aquaculture, 35, 299-307
Crim LW, Bettles S (1997): Use of GnRH analogues in fish culture. Recent Advances in Marine Biotechnology 1, 369–382.
Crim Laurence W., Sherwood Nancy M., Wilson Connie E. (1988): Sustained hormone release. II. Effectiveness of LHRH analog (LHRHa) administration by either single time injection or cholesterol pellet implantation on plasma gonadotropin levels in a bioassay model fish, the juvenile rainbow trout. Aquaculture, 74, 87-95
Dabrowski K., Ciereszko A., Ramseyer L., Culver D., Kestemont P. (1994): Effects of hormonal treatment on induced spermiation and ovulation in the yellow perch (Perca flavescens). Aquaculture, 120, 171-180
De Leeuw R., Van 't Veer C., Smit-Van Dijk W., Goos H.J.Th., Van Oordt P.G.W.J. (1988): Binding affinity and biological activity of gonadotropin-releasing hormone analogs in the African catfish, Clarias gariepinus. Aquaculture, 71, 119-131
De Silva SS, Ingram B, Sungan S, Tinggi D, Gooley G, Sim SY (2004): Artificial propagation of the indigenous Tor species, empurau (T. tambroides) and semah (T. dou-ronensis), Sarawak, East Malaysia. Aquaculture Asia 9, 15–20.
Donaldson EM, Hunter GA (1983): Induced final maturation, ovulation, and spermiation in cultured fish. In: Hoar WS, Randall DJ, Donaldson EM (eds): Fish Physiology. Academic Press, New York. 351–403.
Donbrow M (1991): Microcapsules and Nanoparticles in Medicine and Pharmacy. CRC press, London. 347 pp.
Duncan Neil J., Rodriguez M. de O. G.A., Alok D., Zohar Y. (2003): Effects of controlled delivery and acute injections of LHRHa on bullseye puffer fish (Sphoeroides annulatus) spawning. Aquaculture, 218, 625-635
Fontenele Osmar (1955): Injecting Pituitary (Hypophyseal) Hormones into Fish to Induce Spawning. The Progressive Fish-Culturist, 17, 71-75[71:IPHHIF]2.0.CO;2
Forniés M.A, Mañanós E, Carrillo M, Rocha A, Laureau S, Mylonas C.C, Zohar Y, Zanuy S (2001): Spawning induction of individual European sea bass females (Dicentrarchus labrax) using different GnRHa-delivery systems. Aquaculture, 202, 221-234
Freiberg S., Zhu X.X. (2004): Polymer microspheres for controlled drug release. International Journal of Pharmaceutics, 282, 1-18
Garcia L. Ma. B. (1996): Bioactivity of stored luteinizing hormone-releasing hormone analogue (LHRHa) in sea bass, Lates calcarifer Bloch. Journal of Applied Ichthyology, 12, 91-93
Goetz F, Garczynski M (1997): The ovarian regulation of ovulation in teleost fish. Fish Physiology and Biochemistry 17, 33–38.
Goren A., Zohar Y., Fridkin M., Elhanati E., Koch Y. (1990): Degradation of gonadotropin-releasing hormones in the gilthead seabream, Sparus aurata. General and Comparative Endocrinology, 79, 291-305
Gothilf Y (1990): Pharmacokinetics, metabolism and bioactivity of gonadotropin releasing hormone (GnRH) and its analogs in the gilthead seabream (Sparus aurata). [M.Sc. Thesis] The Hebrew University, Jerusalem. 78 pp.
Gothilf Y, Zohar Y (1991): Clearance of different forms of GnRH from the circulation of the gilthead seabream, Sparus aurata, in relation to their degradation and bioactivities. Reproductive physiology of fish. Fish Symposium 91, 35–37.
Harikrishnan Ramasamy, Balasundaram Chellam, Heo Moon-Soo (2012): Poly d,l-lactide-co-glycolic acid-liposome encapsulated ODN on innate immunity in Epinephelus bruneus against Vibrio alginolyticus. Veterinary Immunology and Immunopathology, 147, 77-85
Hoffman Allan S. (2008): The origins and evolution of “controlled” drug delivery systems. Journal of Controlled Release, 132, 153-163
Holy Chantal E., Dang Stephen M., Davies John E., Shoichet Molly S. (1999): In vitro degradation of a novel poly(lactide-co-glycolide) 75/25 foam. Biomaterials, 20, 1177-1185
Houchin M. L., Topp E. M. (2009): Physical properties of PLGA films during polymer degradation. Journal of Applied Polymer Science, 114, 2848-2854
Chen C.-C., Fernald R. D. (2008): GnRH and GnRH receptors: distribution, function and evolution. Journal of Fish Biology, 73, 1099-1120
Ibarra-Castro L, Navarro-Flores J, Sanchez-Tellez JL, Martinez-Brown JM, Ochoa-Bojorquez LA, Rojo-Cebreros AH (2017): Hatchery production of Pacific white snook at CIAD-Unity Mazatlan, Mexico. World Aquaculture 48, 25–29.
Jerez Salvador, Fakriadis Ioannis, Papadaki Maria, Martín M., Cejas Juana, Mylonas Constantinos (2018): Spawning Induction of First-Generation (F1) Greater Amberjack Seriola dumerili in the Canary Islands, Spain Using GnRHa Delivery Systems. Fishes, 3, 35-
Kuradomi Rafael Yutaka, Foresti Fausto, Batlouni Sergio Ricardo (2017): The effects of sGnRHa implants on Piaractus mesopotamicus female breeders. An approach addressed to aquaculture. Aquaculture International, 25, 2259-2273
Lam T. J. (1982): Applications of Endocrinology to Fish Culture. Canadian Journal of Fisheries and Aquatic Sciences, 39, 111-137
Lewis DH (1990): Controlled release of bioactive agents from lactide/glycolide polymers. Drugs and the Pharmaceutical Sciences 45, 1–41.
Lin Zhiqiang, Gao Wei, Hu Hongxiang, Ma Kun, He Bing, Dai Wenbing, Wang Xueqing, Wang Jiancheng, Zhang Xuan, Zhang Qiang (2014): Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: High drug-loading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity. Journal of Controlled Release, 174, 161-170
Marte Clarissa L., Sherwood Nancy, Crim Lawrence, Tan Josefa (1988): Induced spawning of maturing milkfish (Chanos chanos) using human chorionic gonadotropin and mammalian and salmon gonadotropin releasing hormone analogues. Aquaculture, 73, 333-340
Mogi Takao, Ohtake Naoko, Yoshida Masaru, Chimura Rumi, Kamaga Yumi, Ando Shizutoshi, Tsukamoto Takeyo, Nakajima Takehisa, Uenodan Hiroyuki, Otsuka Makoto, Matsuda Yoshihisa, Ohshima Hiroyuki, Makino Kimiko (2000): Sustained release of 17β-estradiol from poly (lactide-co-glycolide) microspheres in vitro and in vivo. Colloids and Surfaces B: Biointerfaces, 17, 153-165
Mugnier C, Guennoc M, Lebegue E, Fostier A, Breton B (2000): Induction and synchronisation of spawning in cultivated turbot (Scophthalmus maximus L.) broodstock by implantation of a sustained-release GnRH-a pellet. Aquaculture, 181, 241-255
Mylonas C.C., Tabata Y., Langer R., Zohar Y. (1995): Preparation and evaluation of polyanhydride microspheres containing gonadotropin-releasing hormone (GnRH), for inducing ovulation and spermiation in fish. Journal of Controlled Release, 35, 23-34
Mylonas Constantinos C., Bridges Christopher, Gordin Hillel, Ríos Antonio Belmonte, García Antonio, De La Gándara Fernando, Fauvel Christian, Suquet Marc, Medina Antonio, Papadaki Maria, Heinisch Gilad, De Metrio Gregorio, Corriero Aldo, Vassallo-Agius Robert, Guzmán Jose-María, Mañanos Evaristo, Zohar Yonathan (2007): Preparation and Administration of Gonadotropin-Releasing Hormone Agonist (GnRHa) Implants for the Artificial Control of Reproductive Maturation in Captive-Reared Atlantic Bluefin Tuna ( Thunnus thynnus thynnus ). Reviews in Fisheries Science, 15, 183-210
Mylonas CC, Zohar Y (2000): Use of GnRHa–delivery systems for the control of reproduction in fish. Reviews in Fish Biology and Fisheries 10, 463–491.
Nagahama Y, Yamashita M (2008): Regulation of oocyte maturation in fish. Development, Growth & Differentiation 50, S195–S219.
O'Donnell Patrick B, McGinity James W (1997): Preparation of microspheres by the solvent evaporation technique. Advanced Drug Delivery Reviews, 28, 25-42
Pankhurst N, Van Der Kraak G, Peter R (1986): Effects of human chorionic gonadotropin, DES–GLYº (D–ALA“) LHRH-ethylamide and pimozide on oocyte final maturation, ovulation and levels of plasma sex steroids in the walleye (Stizostedion vitreum). Fish Physiology and Biochemistry 1, 45–54.
Raman Chandrashekar, Berkland Cory, Kim Kyekyoon (Kevin), Pack Daniel W. (2005): Modeling small-molecule release from PLG microspheres: effects of polymer degradation and nonuniform drug distribution. Journal of Controlled Release, 103, 149-158
Rather Mohd Ashraf, Sharma Rupam, Gupta Subodh, Ferosekhan S., Ramya V. L., Jadhao Sanjay B., Ceña Valentin (2013): Chitosan-Nanoconjugated Hormone Nanoparticles for Sustained Surge of Gonadotropins and Enhanced Reproductive Output in Female Fish. PLoS ONE, 8, e57094-
Rhine William D., Hsieh Dean S.T., Langer Robert (1980): Polymers for Sustained Macromolecule Release: Procedures to Fabricate Reproducible Delivery Systems and Control Release Kinetics. Journal of Pharmaceutical Sciences, 69, 265-270
Rosenfeld H., Mylonas C.C., Bridges C.R., Heinisch G., Corriero A., Vassallo-Aguis R., Medina A., Belmonte A., Garcia A., De la Gándara F., Fauvel C., De Metrio G., Meiri-Ashkenazi I., Gordin H., Zohar Y. (2012): GnRHa-mediated stimulation of the reproductive endocrine axis in captive Atlantic bluefin tuna, Thunnus thynnus. General and Comparative Endocrinology, 175, 55-64
Ruan Gang, Feng Si-Shen (2003): Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel. Biomaterials, 24, 5037-5044
Sherwood Nancy M., Crim L.W., Carolsfeld J., Walters Sandra M. (1988): Sustained hormone release. I. Characteristics of in vitro release of gonadotropin-releasing hormone analogue (GnRH-A) from pellets. Aquaculture, 74, 75-86
Schreck Carl B, Contreras-Sanchez Wilfrido, Fitzpatrick Martin S (2001): Effects of stress on fish reproduction, gamete quality, and progeny. Aquaculture, 197, 3-24
Siepmann J, Siepmann F (2006): Microparticles used as drug delivery systems. Smart Colloidal Materials: Progress in Colloid and Polymer Science 133, 15–21.
Slater Caleb H., Schreck Carl B., Amend Donald F. (1995): GnRHa injection accelerates final maturation and ovulation/spermiation of sockeye salmon (Oncorhynchus nerka) in both fresh and salt water. Aquaculture, 130, 279-285
U.S. Fish & Wildlife Service (2016): Ovaplant®; Salmon Gonadotropin–Releasing Hormone Analogue (sGnRHa) INAD #11–375.
Burkersroda Friederike von, Schedl Luise, Göpferich Achim (2002): Why degradable polymers undergo surface erosion or bulk erosion. Biomaterials, 23, 4221-4231
WAKIYAMA NAOKI, JUNI KAZUHIKO, NAKANO MASAHIRO (1981): Preparation and evaluation in vitro of polylactic acid microspheres containing local anesthetics.. CHEMICAL & PHARMACEUTICAL BULLETIN, 29, 3363-3368
Weil C., Crim L.W. (1983): Administration of LHRH analogues in various ways: Effect on the advancement of spermiation in prespawning landlocked salmon, Salmo salar. Aquaculture, 35, 103-115
Well C., Breton B., Sambroni S., Zmora N., Zohar Y. (1992): In vitro bioactivities of various forms of GnRH in relation to their susceptibility to degradation at the pituitary level in the rainbow trout, oncorhynchus mykiss. General and Comparative Endocrinology, 87, 33-43
Yaron Zvi (1995): Endocrine control of gametogenesis and spawning induction in the carp. Aquaculture, 129, 49-73
Zakes Z, Demska-Zakes K (2005): Artificial spawning of pikeperch (Sander lucioperca (L.)) stimulated with human chorionic gonadotropin (hCG) and mammalian GnRH analogue with a dopamine inhibitor. Archiwum Rybactwa Polskiego 13, 63–76.
Zohar Y (1996): New approaches for the manipulation of ovulation and spawning in farmed fish. Bulletin of National Research Institute of Aquaculture 2, 43–48.
Zohar Y, Mylonas CC (2001): Endocrine manipulations of spawning in cultured fish: from hormones to genes. In: Donaldson EM, Lee CS (eds): Reproductive Biotechnology in Finfish Aquaculture. Elsevier, Amsterdam. 99–136.
Zolnik Banu S., Burgess Diane J. (2007): Effect of acidic pH on PLGA microsphere degradation and release. Journal of Controlled Release, 122, 338-344
download PDF

© 2019 Czech Academy of Agricultural Sciences