Generic placeholder image

Current Drug Delivery


ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

Formulation and Characterization of Genistein-loaded Nanostructured Lipid Carriers: Pharmacokinetic, Biodistribution and In vitro Cytotoxicity Studies

Author(s): Pooja Mittal, Harsh Vrdhan, Gufran Ajmal, Gunjan Bonde, Ramit Kapoor and Brahmeshwar Mishra*

Volume 16 , Issue 3 , 2019

Page: [215 - 225] Pages: 11

DOI: 10.2174/1567201816666181120170137


Background: Genistein (Gen) is a naturally occurring soy isoflavonoid, possessing anticancer, antiproliferation & antioxidant-like properties. The disadvantage of poor solubility and less oral bioavailability restrict its use as a potential anticancer agent.

Objectives: The current work was focused on the formulation and characterization of the genistein loaded nanostructured lipid carriers that can entrap enough quantity of the drug which will provide sustained release of the drug for the treatment of ovarian cancer.

Methods: The nanostructure lipid carriers of genistein were developed with the aid of solvent emulsification and evaporation technique by employing TPGS as a surfactant. The resultant formulation was characterized by various physicochemical properties. Pharmacokinetics and biodistribution studies were carried out to estimate the mean plasma concentrations of the drug. Percentage cytotoxicity was evaluated by using PA-1 ovarian cancer cell lines.

Results: The resultant formulation exhibited a particle size of 130.23 nm, and entrapment efficiency of 94.27 %, & zeta potential of -20.21 mV with unimodal size distribution. Pharmacokinetics and biodistribution studies revealed that the formulation was able to provide sufficient plasma drug concentration for the longer period of time and the drug was more distributed in ovarian cancer tissues. Results of MTT assay concluded that GenNLC were more effective in comparison to pristine Gen.

Conclusion: In a nutshell, GenNLC seems to be a superior alternative carrier system for the formulation industry to obtain the higher entrapment with excellent stability of the formulation.

Keywords: Nanostructure lipid carriers, Genistein, Pharmacokinetics, Biodistribution, MTT assay, cytotoxicity.

Graphical Abstract
Jain, A.; Gulbake, A.; Jain, A.; Shilpi, S.; Hurkat, P.; Kashaw, S.; Jain, S.K. Development and validation of the HPLC method for simultaneous estimation of paclitaxel and topotecan. J. Chromatogr. Sci., 2013, 52(7), 697-703.
(a) Banerjee, S.; Li, Y.; Wang, Z.; Sarkar, F.H. Multi-targeted therapy of cancer by genistein. Cancer Lett., 2008, 269(2), 226-242.
(b) Feng, D.; Qiu, F.; Tong, Z.; Xie, C. Oral pharmacokinetic comparison of different genistein tablets in Beagle dogs. J. Chromatogr. Sci., 2012, 51(4), 335-340.
(c) Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Sci. World J., 2013, 2013
Aditya, N.; Shim, M.; Lee, I.; Lee, Y. Im, M.-H.; Ko, S. Curcumin and genistein coloaded nanostructured lipid carriers: In vitro digestion and antiprostate cancer activity. J. Agric. Food Chem., 2013, 61(8), 1878-1883.
(a) Glasgow, M.D.; Chougule, M.B. Recent developments in active tumor targeted multifunctional nanoparticles for combination chemotherapy in cancer treatment and imaging. J. Biomed. Nanotechnol., 2015, 11(11), 1859-1898.
(b) Natarajan, J.V.; Darwitan, A.; Barathi, V.A.; Ang, M.; Htoon, H.M.; Boey, F.; Tam, K.C.; Wong, T.T.; Venkatraman, S.S. Sustained drug release in nanomedicine: A long-acting nanocarrier-based formulation for glaucoma. ACS Nano, 2014, 8(1), 419-429.
(c) Hare, J.I.; Lammers, T.; Ashford, M.B.; Puri, S.; Storm, G.; Barry, S.T. Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. Adv. Drug Deliv. Rev., 2017, 108, 25-38.
(a) Komiyama, M.; Yoshimoto, K.; Sisido, M.; Ariga, K. Commemorative account: Self-organization: chemistry can make strict and fuzzy controls for bio-systems: DNA nanoarchitectonics and cell-macromolecular nanoarchitectonics. Bull. Chem. Soc. Jpn., 2017, 90(9), 967-1004.
(b) Xiao, Z.; Ji, C.; Shi, J.; Pridgen, E.M.; Frieder, J.; Wu, J.; Farokhzad, O.C. DNA self‐assembly of targeted near‐infrared‐responsive gold nanoparticles for cancer thermo‐chemotherapy. Angew. Chem. Int. Ed. Engl., 2012, 51(47), 11853-11857.
(c) Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal formulations in clinical use: An updated review. Pharmaceutics, 2017, 9(2), 12.
(a) Negi, L.M.; Jaggi, M.; Talegaonkar, S. A logical approach to optimize the nanostructured lipid carrier system of irinotecan: Efficient hybrid design methodology. Nanotechnology, 2012, 24(1), 015104.
(b) Negi, L.M.; Jaggi, M.; Talegaonkar, S. Development of protocol for screening the formulation components and the assessment of common quality problems of nano-structured lipid carriers. Int. J. Pharm., 2014, 461(1), 403-410.
(c) Singh, B.; Dahiya, M.; Saharan, V.; Ahuja, N. Optimizing drug delivery systems using systematic “design of experiments.” Part II: Retrospect and prospects. Crit. Rev. Ther. Drug Carrier Syst., 2005, 22(3), 215-294.
(d) Singh, B.; Kumar, R.; Ahuja, N. Optimizing drug delivery systems using systematic “design of experiments.” Part I: Fundamental aspects. Crit. Rev. Ther. Drug Carrier Syst., 2005, 22(1), 27-105.
(a) Müller, R.H.; Radtke, M.; Wissing, S.A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev., 2002, 54, S131-S155.
(b) Mehnert, W.; Mäder, K. Solid lipid nanoparticles: production, characterization and applications. Adv. Drug Deliv. Rev., 2001, 47(2), 165-196.
Shah, R.; Eldridge, D.; Palombo, E.; Harding, I. Lipid nanoparticles: Production, characterization and stability; Springer, 2015.
Wissing, S.; Müller, R. The influence of the crystallinity of lipid nanoparticles on their occlusive properties. Int. J. Pharm., 2002, 242(1), 377-379.
Severino, P.; Pinho, S.C.; Souto, E.B.; Santana, M.H. Crystallinity of dynasan® 114 and dynasan® 118 matrices for the production of stable miglyol®-loaded nanoparticles. J. Thermal Analysis calorimetry, 2011, 108(1), 101-108.
Fontell, K. Liquid crystallinity in lipid-water systems. Mol. Cryst. Liq. Cryst., 1981, 63(1), 59-82.
(a) Vardhan, H.; Mittal, P.; Adena, S.K.R.; Mishra, B. Long-circulating polyhydroxybutyrate-co-hydroxyvalerate nanoparticles for tumor targeted docetaxel delivery: Formulation, optimization and in vitro characterization. Eur. J. Pharm. Sci., 2017, 99, 85-94.
(b) Yadav, S.K.; Khan, G.; Bansal, M.; Vardhan, H.; Mishra, B. Screening of ionically crosslinked chitosan-tripolyphosphate microspheres using plackett-burman factorial design for the treatment of intrapocket infections. Drug Dev. Ind. Pharm., 2017, 43(11), 1801-1816.
(a) Vuddanda, P.R.; Rajamanickam, V.M.; Yaspal, M.; Singh, S. Investigations on agglomeration and haemocompatibility of vitamin E TPGS surface modified berberine chloride nanoparticles. BioMed Res. Int., 2014, 2014, 951942.
(b) Vijayakumar, M.R.; Kumari, L.; Patel, K.K.; Vuddanda, P.R.; Vajanthri, K.Y.; Mahto, S.K.; Singh, S. Intravenous administration of trans-resveratrol-loaded TPGS-coated solid lipid nanoparticles for prolonged systemic circulation, passive brain targeting and improved in vitro cytotoxicity against C6 glioma cell lines. RSC Advances, 2016, 6(55), 50336-50348.
Coward, L.; Barnes, N.C.; Setchell, K.D.; Barnes, S. Genistein, daidzein, and their. beta.-glycoside conjugates: Antitumor isoflavones in soybean foods from American and Asian diets. J. Agric. Food Chem., 1993, 41(11), 1961-1967.
(a) Kim, J.T.; Barua, S.; Kim, H.; Hong, S-C.; Yoo, S-Y.; Jeon, H.; Cho, Y.; Gil, S.; Oh, K.; Lee, J. Absorption study of genistein using solid lipid microparticles and nanoparticles: Control of oral bioavailability by particle sizes. Biomol. Ther. (Seoul), 2017, 25(4), 452.
(b) Schlosser, P.M.; Borghoff, S.J.; Coldham, N.G.; David, J.A.; Ghosh, S.K. Physiologically‐based pharmacokinetic modeling of genistein in rats, part I: Model development. Risk Anal., 2006, 26(2), 483-500.
(c) Yang, Z.; Kulkarni, K.; Zhu, W.; Hu, M. Bioavailability and pharmacokinetics of genistein: Mechanistic studies on its ADME. Anticancer. Agents Med. Chem., 2012, 12(10), 1264-1280.
(a) Lasoń, E.; Sikora, E.; Ogonowski, J. Influence of process parameters on properties of Nanostructured Lipid Carriers (NLC) formulation. Acta Biochim. Pol., 2013, 60(4), 773-777.
(b) Lawrence, X.Y.; Amidon, G.; Khan, M.A.; Hoag, S.W.; Polli, J.; Raju, G.; Woodcock, J. Understanding pharmaceutical quality by design. AAPS J., 2014, 16(4), 771.
(a) Bender, E.A.; Adorne, M.D.; Colomé, L.M.; Abdalla, D.S.; Guterres, S.S.; Pohlmann, A.R. Hemocompatibility of poly (ɛ-caprolactone) lipid-core nanocapsules stabilized with polysorbate 80-lecithin and uncoated or coated with chitosan. Int. J. Pharm., 2012, 426(1), 271-279.
(b) Constantinou, C.; Papas, A.; Constantinou, A.I. Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. Int. J. Cancer, 2008, 123(4), 739-752.
(c) Guo, Y.; Chu, M.; Tan, S.; Zhao, S.; Liu, H.; Otieno, B.O.; Yang, X.; Xu, C.; Zhang, Z. Chitosan-g-TPGS nanoparticles for anticancer drug delivery and overcoming multidrug resistance. Mol. Pharm., 2013, 11(1), 59-70.
(d) Patel, R.R.; Khan, G.; Chaurasia, S.; Kumar, N.; Mishra, B. Rationally developed core-shell polymeric-lipid hybrid nanoparticles as a delivery vehicle for cromolyn sodium: implications of lipid envelop on in vitro and in vivo behaviour of nanoparticles upon oral administration. RSC Advances, 2015, 5(93), 76491-76506.
(a) Jain, K.; Sood, S.; Gowthamarajan, K. Optimization of artemether-loaded NLC for intranasal delivery using central composite design. Drug Deliv., 2015, 22(7), 940-954.
(b) Matovic, M.; van Miltenburg, J.C.; Los, J.; Gandolfo, F.G.; Flöter, E. Thermal properties of tristearin by adiabatic and differential scanning calorimetry. J. Chem. Eng. Data, 2005, 50(5), 1624-1630.
Sichina, W. DSC as problem solving tool: Measurement of percent crystallinity of thermoplastics; PerkinElmer Instruments, 2011.
(d) Simpson, T.; Hockett, D.; Harris, L. Specific heats of the solid-state phases of trimargarin and tristearin. J. Am. Oil Chem. Soc., 1984, 61(5), 883-886.
(e) Velmurugan, R.; Selvamuthukumar, S. Development and optimization of ifosfamide nanostructured lipid carriers for oral delivery using response surface methodology. Appl. Nanosci., 2016, 6(2), 159-173.
(f) Windbergs, M.; Strachan, C.J.; Kleinebudde, P. Investigating the principles of recrystallization from glyceride melts. AAPS PharmSciTech, 2009, 10(4), 1224.
Müller, R.; Radtke, M.; Wissing, S. Nanostructured lipid matrices for improved microencapsulation of drugs. Int. J. Pharm., 2002, 242(1), 121-128.
(a) Shah, N.V.; Seth, A.K.; Balaraman, R.; Aundhia, C.J.; Maheshwari, R.A.; Parmar, G.R. Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study. J. Adv. Res., 2016, 7(3), 423-434.
(b) Wissing, S.; Kayser, O.; Müller, R. Solid lipid nanoparticles for parenteral drug delivery. Adv. Drug Deliv. Rev., 2004, 56(9), 1257-1272.
Mishra, B.; Padaliya, R.; Patel, R.R. Exemestane encapsulated vitamin E-TPGS-polymeric nanoparticles: Preparation, optimization, characterization, and in vitro cytotoxicity assessment. Artif. Cells Nanomed. Biotechnol., 2017, 45(3), 522-534.
Bian, Q.; Liu, J.; Tian, J.; Hu, Z. Binding of genistein to human serum albumin demonstrated using tryptophan fluorescence quenching. Int. J. Biol. Macromol., 2004, 34(5), 275-279.
Jia, Y.; Ji, J.; Wang, F.; Shi, L.; Yu, J.; Wang, D. Formulation, characterization, and in vitro/vivo studies of aclacinomycin A-loaded solid lipid nanoparticles. Drug Deliv., 2016, 23(4), 1317-1325.

© 2022 Bentham Science Publishers | Privacy Policy