Combine Drug Delivery of Thymoquinone-Doxorubicin by Cockle Shellderived pH-sensitive Aragonite CaCO3 Nanoparticles

Author(s): Kehinde M. Ibiyeye, Abu B.Z. Zuki*, Norshariza Nurdin, Mokrish Ajat

Journal Name: Nanoscience & Nanotechnology-Asia

Volume 10 , Issue 4 , 2020

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Graphical Abstract:


Background: Cockleshell-derived aragonite calcium carbonate nanoparticles were prepared by the top-down approach for combine delivery of two types of drugs.

Objective: The aim of this study was to synthesize and characterize thymoquinone-doxorubicin loaded cockle shell-derived aragonite calcium carbonate nanoparticle. Aragonite calcium carbonate nanoparticles encapsulating thymoquinone and doxorubicin alone were also prepared.

Methods: The blank and drug-loaded nanoparticles were characterized by field emission scanning electron microscopy, transmission electron microscopy, Zeta potential, Fourier transformed infrared and X-ray diffraction. Drug delivery properties, in vitro drug release study at pH 7.4, 6 and 4.8, and effect of blank nanoparticles on MCF10A, 3T3, MDA MB231 cells were also analyzed.

Results: The blank and drug-loaded nanoparticles were pleomorphic and their sizes varying from 53.65 ± 10.29 nm to 60.49 ± 11.36 nm with an overall negative charge. The entrapment efficiency of thymoquinone and doxorubicin were 41.6 and 95.8, respectively. The FTIR showed little alteration after loading thymoquinone and doxorubicin while XRD patterns revealed no changes in the crystallizations of nanoparticles after drug loading. The drug release kinetics of doxorubicin and thymoquinone from the nanoparticles showed a continuous and gradual release after an initial burst release was observed. At pH 4.8, about 100% of drug release was noticed, 70% at pH 6 while only 50% at pH 7.4. The cell viability was 80% at a concentration of 1000 ug/ml of blank nanoparticle.

Conclusion: The cockle shell-derived pH sensitive aragonite calcium carbonate nanoparticle provides an effective and simple means of multiple drug delivery and function as a platform for pH controlled release of loaded therapeutic agents.

Keywords: Cockleshell, nanocarrier, thymoquinone, doxorubicin, combine drug delivery, CaCO3 nanoparticles.

King, M.R.; Mohamed, Z.J. Dual nanoparticle drug delivery: The future of anticancer therapies? Nanomedicine, 2017, 12(2), 95-98.
Niero, E.; Rocha-Sales, B. The multiple facets of drug resistance: One history, different approaches. J. Exp. Clin. Cancer Res., 2014, 33(1), 37.
Markman, J.L.; Rekechenetskiy, A.; Holler, E.; Ljubimova, J.Y. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv. Drug Deliv. Rev., 2013, 65(13-14), 866-1879.
He, L. Jian Gu, Lee Y. Lim, Z. Y. and J. M. Nanomedicine-mediated therapies to target breast cancer stem cells. Nanomed. Mediat. Ther. Target Breast Cancer Stem Cell. Front. Pharmacol., 2016, 7, 313.
Ma, L.; Kohli, M.; Smith, A. Nanoparticles for combination drug therapy. ACS Nano, 2013, 7(11), 9518-9525.
Liu, B.Y.; Wu, C.; He, X.Y.; Zhuo, R.X.; Cheng, S.X. Multi-drug loaded vitamin E-TPGS nanoparticles for synergistic drug delivery to overcome drug resistance in tumor treatment. Sci. Bull., 2016, 61(7), 552-560.
Render, D.; Rangari, V.K.; Jeelani, S.; Fadlalla, K.; Samuel, T. Bio-based Calcium Carbonate (CaCO3) nanoparticles for drug delivery applications. Int. J. Biomed. Nanosci. Nanotechnol., 2014, 3(3), 221.
Soni, P.; Kaur, J.; Tikoo, K. Dual drug-loaded paclitaxel-thymoquinone nanoparticles for effective breast cancer therapy. J. Nanopart. Res., 2015, 17(1), 18.
Wu, J.L.; Wang, C.Q.; Zhuo, R.X.; Cheng, S.X. Multi-drug delivery system based on Alginate/Calcium carbonate hybrid nanoparticles for combination chemotherapy. Colloids Surf. B Biointerfaces, 2014, 123, 498-505.
Lakkakula, J.R.; Kurapati, R.; Tynga, I.; Abrahamse, H.; Raichur, A.M.; Krause, R.W. Cyclodextrin grafted Calcium Carbonate vaterite particles: Efficient system for tailored release of hydrophobic anticancer or hormone drugs. RSC Advances, 2016, 6(106), 104537-104548.
Som, A.; Raliya, R.; Tian, L.; Akers, W.; Ippolito, J.E.; Singamaneni, S.; Biswas, P.; Achilefu, S. Monodispersed Calcium Carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo. Nanoscale, 2016, 8(25), 12639-12647.
Boyjoo, Y.; Pareek, V.K.; Liu, J. Synthesis of micro and nano-sized calcium carbonate particles and their applications. J. Mater. Chem. A , 2014, 2(35), 14270-14288.
Kamba, A.; Ismail, M.; Ibrahim, T.A.; Zakaria, Z.A.B. A pH-sensitive, biobased Calcium Carbonate Aragonite nanocrystal as a novel anticancer delivery system. Biomed. Res. Int., 2013, 2013, 587451
Hammadi, N.I.; Abba, Y.; Hezmee, M.N.M.; Razak, I.S.A.; Jaji, A.Z.; Isa, T.; Mahmood, S.K.; Zakaria, M.Z.A.B. Formulation of a sustained release Docetaxel loaded cockle shell-derived Calcium Carbonate nanoparticles against breast cancer. Pharm. Res., 2017, 6, 1193-1203.
Kamba, A.S.; Ismail, M.; Ibrahim, T.A.T.; Zakaria, Z.A.B.; Gusau, L.H. In vitro ultrastructural changes of MCF-7 for metastasise bone cancer and induction of apoptosis via mitochondrial Cytochrome C released by CaCO3/Dox nanocrystals. Biomed. Res. Int., 2014, 2014, 391869
Jaji, A.Z.; Zakaria, Z.; Mahmud, R.; Loqman, M.Y.; Hezmee, M.N.M.; Isa, T.; Wenliang, F.; Hammadi, N.I. Synthesis, characterization, and cytocompatibility of potential cockle shell Aragonite nanocrystals for osteoporosis therapy and hormonal delivery. Nanotechnol. Sci. Appl., 2017, 10, 23-33.
Fu, W.; Hezmee, M.; Noor, M.; Yusof, L. M.; Azmi, T.; Ibrahim, T.; Keong, Y. S.; Jaji, A.Z.; Abu, Z.; Zakaria, B. In vitro evaluation of a novel pH sensitive drug delivery system based cockle shellderived Aragonite nanoparticles. J. Exp. Nanosci., 2017, 12, 1, 166-187.
Islam, K.N.; Zuki, A.B.Z.; Ali, M.E.; Bin Hussein, M.Z.; Noordin, M.M.; Loqman, M.Y.; Wahid, H.; Hakim, M.A.; Abd Hamid, S.B. Facile synthesis of calcium carbonate nanoparticles from Cockle Shells. J. Nanomater., 2012, 2012(1) 534010
Mohan, P.; Rapoport, N. Doxorubicin as a molecular nanotheranostic agent: Effect of Doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. Mol. Pharm., 2010, 7(6), 1959-1973.
Efferth, T.; Dajani, E.Z.; Fu, J.; Shahdaat, M.; Sayeed, B.; Mostofa, A.G.M.; Hossain, M.K.; Basak, D. Thymoquinone as a potential adjuvant therapy for cancer treatment: Evidence from preclinical studies. Front. Pharmacol., 2017, 8, 295.
Ke, X.; Zhao, Y.; Lu, X.; Wang, Z.; Liu, Y.; Ren, M.; Lu, G.; Zhang, D.; Sun, Z.; Xu, Z. TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of notch signaling. Oncotarget, 2015, 6(32), 32610-32621.
Alobaedi, O.H.; Talib, W.H.; Basheti, I.A. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pac. J. Trop. Med., 2017, 10(4), 400-408.
Mistry, V.D. Understanding the mechanistic aspect of Thymo-quinone in breast cancer by employing different nanocomposites., PhD Thesis. 2016.
Dehghani, H.; Hashemi, M.; Entezari, M.; Mohsenifar, A. The comparison of anticancer activity of thymoquinone and nanothymoquinone on human breast adenocarcinoma. Iran. J. Pharm. Res., 2015, 14(2), 539-546.
Singh, A.; Ahmad, I.; Akhter, S.; Jain, G.K.; Iqbal, Z.; Talegaonkar, S.; Ahmad, F.J. Nanocarrier based formulation of Thymoquinone improves oral delivery: Stability assessment, in vitro and in vivo studies. Colloids Surf. B Biointerfaces, 2013, 102, 822-832.
Danmaigoro, A.; Selvarajah, G.T.; Noor, M.H.M.; Mahmud, R.; Zakaria, M.Z.A.B. Development of Cockleshell (Anadara Granosa) derived CaCO3 nanoparticle for Doxorubicin delivery. J. Comput. Theor. Nanosci., 2017, 14(10), 5074-5086.
Saidykhan, L.; Bakar, M.Z.B.A.; Rukayadi, Y.; Kura, A.U.; Latifah, S.Y. Development of nanoantibiotic delivery system using Cockle shell-derived aragonite nanoparticles for treatment of osteomyelitis. Int. J. Nanomedicine, 2016, 11, 661-673.
Zhang, Y.; Yang, C.; Wang, W.; Liu, J.; Liu, Q.; Huang, F.; Chu, L.; Gao, H.; Li, C.; Kong, D. Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer. Sci. Rep., 2016, 6, 21225.
Salmani, J.; Asghar, S.; Lv, H.; Zhou, J. Aqueous solubility and degradation kinetics of the phytochemical anticancer Thymoquinone; Probing the effects of solvents, pH and light. Molecules, 2014, 19(5), 5925-5939.
Kamba, S.A.; Ismail, M.; Hussein-Al-Ali, S.H.; Ibrahim, T.A.T.; Zakaria, Z.A.B. In vitro delivery and controlled release of Doxorubicin for targeting osteosarcoma bone cancer. Molecules, 2013, 18(9), 10580-10598.
Ghaji, M.S.; Zakaria, Z.A.B.; Shameha, A.R.I.; Noor, M.H.M.; Hazilawati, H. Novel synthesis of nanoparticles from Cockle shells via mechanical method for Cytarabine drug release. J. Comput. Theor. Nanosci., 2018, 15(4), 1128-1136.
Honary, S.; Zahir, F. Effect of zeta potential on the properties of nano-drug delivery systems-A review (Part 1). Trop. J. Pharm. Res. April J. Cit. Reports Sci. Ed., 2013, 12(122), 255-255.
Luo, Y.; Zhao, R.; Pendry, J.B. Van Der Waals interactions at the nanoscale The effects of nonlocality, 2014, 111(52), 18422-18427.
[, 1420551111]
Mark, P.R. Forces and interactions between nanoparticles for controlled structures. Semantic Scholar, 2013, 2013, 110805185
Surekha, R.; Sumathi, T. An efficient encapsulation of thymo-quinone using solid lipid nanoparticle for brain targeted drug delivery: Physicochemical characterization, pharmacokinetics and bio-distribution studies. IJPCR, 2016, 8(12), 1616-1624.

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Article Details

Year: 2020
Published on: 25 August, 2020
Page: [518 - 533]
Pages: 16
DOI: 10.2174/2210681209666190508122540
Price: $25

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