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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Design, In Silico Modelling, and Functionality Theory of Novel Folate Receptor Targeted Rutin Encapsulated Folic Acid Conjugated Keratin Nanoparticles for Effective Cancer Treatment

Author(s): Selvaraj Kunjiappan, Theivendren Panneerselvam*, Saravanan Govindaraj, Pavadai Parasuraman, Suraj Baskararaj, Murugesan Sankaranarayanan, Sankarganesh Arunachalam, Ewa Babkiewicz, Aarthi Jeyakumar and Muthulakshmi Lakshmanan

Volume 19 , Issue 16 , 2019

Page: [1966 - 1982] Pages: 17

DOI: 10.2174/1871520619666190702145609

Price: $65


Objective: Site-specific and toxic-free drug delivery, is an interesting area of research. Nanoengineered drug delivery systems possess a remarkable potential for effective treatment of various types of cancers.

Methods: In this study, novel Folic Acid (FA) conjugated keratin nanoparticles (NPs) were assembled with encapsulation and delivery of Rutin (Rt) into breast cancer cells through the overexpressed folate receptor. The biocompatible, Rt encapsulated FA conjugated keratin NPs (FA@Ker NPs) were successfully formulated by a modified precipitation technique. Their morphological shape and size, size distribution, stability, and physical nature were characterized and confirmed. The drug (Rt) encapsulation efficiency, loading capacity and release kinetics were also studied.

Results: The observed results of molecular docking and density functionality theory of active drug (Rt) showed a strong interaction and non-covalent binding of the folate receptor and facilitation of endocytosis in breast cancer cells. Further, in vitro cytotoxic effect of FA@Ker NPs was screened against MCF-7 cancer cells, at 55.2 µg/mL of NPs and found to display 50% of cell death at 24h. Moreover, the NPs enhanced the uptake of Rt in MCF-7 cells, and the apoptotic effect of condensed nuclei and distorted membrane bodies was observed. Also, NPs entered into the mitochondria of MCF-7 cells and significantly increased the level of ROS which led to cell death.

Conclusion: The developed FA@Ker NPs might be a promising way to enhance anti-cancer activity without disturbing normal healthy cells.

Keywords: Rutin, folate receptor, drug delivery, breast cancer, keratin nanoparticles, MCF-7.

Graphical Abstract
Ahlquist, D.A. Universal cancer screening: Revolutionary, rational, and realizable. NPJ Precis. Oncol., 2018, 2(1), 23.
[] [PMID: 30393772]
Kunjiappan, S.; Theivendren, P.; Sankaranarayanan, M.; Somasundaram, B.; Subbarayan, S.; Arunachalam, S.; Parasuraman, P.; Sivakumar, V.; Murugan, I.; Baskararaj, S. Design, graph theoretical analysis and bioinformatic studies of Proanthocyanidins encapsulated ethyl cellulose nanoparticles for effective anticancer activity. Biomed. Phys. Eng. Express, 2018, 5(2)025004
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[] [PMID: 30207593]
Kelsey, J.L. A review of the epidemiology of human breast cancer. Epidemiol. Rev., 1979, 1, 74-109.
[] [PMID: 398270]
Singh, S.K.; Singh, S.; Lillard, J.W., Jr; Singh, R. Drug delivery approaches for breast cancer. Int. J. Nanomedicine, 2017, 12, 6205-6218.
[] [PMID: 28883730]
Park, J.W. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res., 2002, 4(3), 95-99.
[] [PMID: 12052251]
Jani, M.; Ambrus, C.; Magnan, R.; Jakab, K.T.; Beéry, E.; Zolnerciks, J.K.; Krajcsi, P. Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. Arch. Toxicol., 2014, 88(6), 1205-1248.
[] [PMID: 24777822]
Beckwitt, C.H.; Clark, A.M.; Ma, B.; Whaley, D.; Oltvai, Z.N.; Wells, A. Statins attenuate outgrowth of breast cancer metastases. Br. J. Cancer, 2018, 119(9), 1094-1105.
[] [PMID: 30401978]
Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial Reactive Oxygen Species (ROS) and ROS-induced ROS release. Physiol. Rev., 2014, 94(3), 909-950.
[] [PMID: 24987008]
Low, P.S.; Henne, W.A.; Doorneweerd, D.D. Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc. Chem. Res., 2008, 41(1), 120-129.
[] [PMID: 17655275]
Wang, J.; Sui, M.; Fan, W. Nanoparticles for tumor targeted therapies and their pharmacokinetics. Curr. Drug Metab., 2010, 11(2), 129-141.
[] [PMID: 20359289]
Jahanshahi, M.; Babaei, Z. Protein nanoparticle: A unique system as drug delivery vehicles. Afr. J. Biotechnol., 2008, 7(25), 4926-4934.
Maeda, H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv. Rev., 2015, 91, 3-6.
[] [PMID: 25579058]
Kunjiappan, S.; Panneerselvam, T.; Prasad, P.; Sukumaran, S.; Somasundaram, B.; Sankaranarayanan, M.; Murugan, I.; Parasuraman, P. Design, graph theoretical analysis and in silico modeling of Dunaliella bardawil biomass encapsulated keratin nanoparticles: a scaffold for effective glucose utilization. Biomed. Mater., 2018, 13(4)045012
[] [PMID: 29727301]
Metcalfe, A.D.; Ferguson, M.W. Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration. J. R. Soc. Interface, 2007, 4(14), 413-437.
[] [PMID: 17251138]
Li, Y.; Zhi, X.; Lin, J.; You, X.; Yuan, J. Preparation and characterization of DOX loaded keratin nanoparticles for pH/GSH dual responsive release. Mater. Sci. Eng. C, 2017, 73, 189-197.
[] [PMID: 28183597]
An, F.F.; Cao, W.; Liang, X.J. Nanostructural systems developed with positive charge generation to drug delivery. Adv. Healthc. Mater., 2014, 3(8), 1162-1181.
[] [PMID: 24550201]
Sutradhar, K.B.; Amin, M.L. Nanotechnology in cancer drug delivery and selective targeting. ISRN Nanotechnol., 2014, 2014, 1-12.
Dobson, P.D.; Kell, D.B. Carrier-mediated cellular uptake of pharmaceutical drugs: An exception or the rule? Nat. Rev. Drug Discov., 2008, 7(3), 205-220.
[] [PMID: 18309312]
Bharali, D.J.; Lucey, D.W.; Jayakumar, H.; Pudavar, H.E.; Prasad, P.N. Folate-receptor-mediated delivery of InP quantum dots for bioimaging using confocal and two-photon microscopy. J. Am. Chem. Soc., 2005, 127(32), 11364-11371.
[] [PMID: 16089466]
Gosselin, M.A.; Lee, R.J. Folate receptor-targeted liposomes as vectors for therapeutic agents. Biotechnol. Annu. Rev., 2002, 8, 103-131.
[] [PMID: 12436917]
Sudimack, J.; Lee, R.J. Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev., 2000, 41(2), 147-162.
[] [PMID: 10699311]
Reddy, J.A.; Allagadda, V.M.; Leamon, C.P. Targeting therapeutic and imaging agents to folate receptor positive tumors. Curr. Pharm. Biotechnol., 2005, 6(2), 131-150.
[] [PMID: 15853692]
Wang, T-Y.; Li, Q.; Bi, K-S. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J. Pharmaceut. Sci., 2018, 13(1), 12-23.
Selvaraj, K.; Chowdhury, R.; Bhattacharjee, C. Isolation and structural elucidation of flavonoids from aquatic fern Azolla microphylla and evaluation of free radical scavenging activity. Int. J. Pharm. Pharm. Sci., 2013, 5(3), 743-749.
Mauludin, R.; Müller, R.H.; Keck, C.M. Kinetic solubility and dissolution velocity of rutin nanocrystals. Eur. J. Pharm. Sci., 2009, 36(4-5), 502-510.
[] [PMID: 19130880]
Kunjiappan, S.; Chowdhury, A.; Somasundaram, B.; Bhattacharjee, C.; Periyasamy, S. Optimization, preparation and characterization of rutin-quercetin dual drug loaded keratin nanoparticles for biological applications. Nanomed. J., 2016, 3(4), 253-267.
Liu, G.; Pang, J.; Huang, Y.; Xie, Q.; Guan, G.; Jiang, Y. Self-assembled nanospheres of folate-decorated zein for the targeted delivery of 10-hydroxycamptothecin. Ind. Eng. Chem. Res., 2017, 56(30), 8517-8527.
Ranjha, N.M.; Qureshi, U.F. Preparation and characterization of crosslinked acrylic acid/hydroxypropyl methyl cellulose hydrogels for drug delivery. Int. J. Pharm. Pharm. Sci., 2014, 6(4), 400-410.
Saravanan, G.; Panneerselvam, T.; Alagarsamy, V.; Kunjiappan, S.; Parasuraman, P.; Murugan, I.; Dinesh Kumar, P. Design, graph theoretical analysis, density functionality theories, in silico modeling, synthesis, characterization and biological activities of novel thiazole fused quinazolinone derivatives. Drug Dev. Res., 2018, 79(6), 260-274.
[] [PMID: 30244475]
İnkaya, E.; Dinçer, M.; Ekici, Ö.; Cukurovali, A.N. ′-(2-methoxy-benzylidene)-N-[4-(3-methyl-3-phenyl-cyclobutyl)-thiazol-2-yl]-chloro-acetic hydrazide: X-ray structure, spectroscopic characterization and DFT studies. J. Mol. Struct., 2012, 1026, 117-126.
Güntepe, F.; Saraçoğlu, H.; Çalışkan, N.; Yüksektepe, Ç.; Cukurovali, A. Synthesis, molecular and crystal structure analysis of 2-bromo-4-chloro-6-[4-(3-methyl-3-phenyl-cyclobutyl)-thiazol-2-yl]-hydrazonomethyl-phenol by experimental methods and theoretical calculations. J. Mol. Struct., 2012, 1022, 204-210.
Kunjiappan, S.; Panneerselvam, T.; Somasundaram, B.; Sankaranarayanan, M.; Parasuraman, P.; Joshi, S.D.; Arunachalam, S.; Murugan, I. Design, graph theoretical analysis and in silico modeling of dunaliella bardawil biomass encapsulated n-succinyl chitosan nanoparticles for enhanced anticancer activity. Anticancer. Agents Med. Chem., 2018, 18(13), 1900-1918.
[] [PMID: 29956638]
Kunjiappan, S.; Panneerselvam, T.; Somasundaram, B.; Arunachalam, S.; Sankaranarayanan, M.; Parasuraman, P. Preparation of liposomes encapsulated Epirubicin-gold nanoparticles for tumor specific delivery and release. Biomed. Phys. Eng. Express, 2018, 4(4)045027
Zamzami, N.; Marchetti, P.; Castedo, M.; Decaudin, D.; Macho, A.; Hirsch, T.; Susin, S.A.; Petit, P.X.; Mignotte, B.; Kroemer, G. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J. Exp. Med., 1995, 182(2), 367-377.
[] [PMID: 7629499]
Anitha, A.; Maya, S.; Deepa, N.; Chennazhi, K.; Nair, S.; Tamura, H.; Jayakumar, R. Efficient water soluble O-carboxymethyl chitosan nanocarrier for the delivery of curcumin to cancer cells. Carbohydr. Polym., 2011, 83(2), 452-461.
Shaw, L.M. In Cell Migration; Springer, 2005, pp. 97-105.
Kunjiappan, S.; Bhattacharjee, C.; Chowdhury, R. In vitro antioxidant and hepatoprotective potential of Azolla microphylla phytochemically synthesized gold nanoparticles on acetaminophen - induced hepatocyte damage in Cyprinus carpio L. In Vitro Cell. Dev. Biol. Anim., 2015, 51(6), 630-643.
[] [PMID: 25862331]
Chowdhury, A.; Kunjiappan, S.; Panneerselvam, T.; Somasundaram, B.; Bhattacharjee, C. Nanotechnology and nanocarrier-based approaches on treatment of degenerative diseases. Int. Nano Lett., 2017, 7(2), 91-122.
Nikalje, A.P. Nanotechnology and its applications in medicine. Med. Chem., 2015, 5(2), 081-089.
Meng, H.; Xue, M.; Xia, T.; Ji, Z.; Tarn, D.Y.; Zink, J.I.; Nel, A.E. Use of size and a copolymer design feature to improve the biodistribution and the enhanced permeability and retention effect of doxorubicin-loaded mesoporous silica nanoparticles in a murine xenograft tumor model. ACS Nano, 2011, 5(5), 4131-4144.
[] [PMID: 21524062]
Ji, Z.; Jin, X.; George, S.; Xia, T.; Meng, H.; Wang, X.; Suarez, E.; Zhang, H.; Hoek, E.M.; Godwin, H.; Nel, A.E.; Zink, J.I. Dispersion and stability optimization of TiO2 nanoparticles in cell culture media. Environ. Sci. Technol., 2010, 44(19), 7309-7314.
[] [PMID: 20536146]
Pfeiffer, C.; Rehbock, C.; Hühn, D.; Carrillo-Carrion, C.; de Aberasturi, D.J.; Merk, V.; Barcikowski, S.; Parak, W.J. Interaction of colloidal nanoparticles with their local environment: the (ionic) nanoenvironment around nanoparticles is different from bulk and determines the physico-chemical properties of the nanoparticles. J. R. Soc. Interface, 2014, 11(96)20130931
[] [PMID: 24759541]
Honary, S.; Zahir, F. Effect of zeta potential on the properties of nano-drug delivery systems-A review (Part 2). Trop. J. Pharm. Res., 2013, 12(2), 265-273.
Sun, Y.; Zhao, Y.; Teng, S.; Hao, F.; Zhang, H.; Meng, F.; Zhao, X.; Zheng, X.; Bi, Y.; Yao, Y.; Lee, R.J.; Teng, L. Folic acid receptor-targeted human serum albumin nanoparticle formulation of cabazitaxel for tumor therapy. Int. J. Nanomedicine, 2018, 14, 135-148.
[] [PMID: 30613142]
Nita, M.; Grzybowski, A. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid. Med. Cell. Longev., 2016, 20163164734
[] [PMID: 26881021]
Chowdhury, A.; Panneerselvam, T.; Suthendran, K.; Bhattachejee, C.; Balasubramanian, S.; Murugesan, S.; Suraj, B.; Selvaraj, K. Optimization of microwave-assisted extraction of bioactive polyphenolic compounds from Marsilea quadrifolia L. using RSM and ANFIS modelling. Indian J. Nat. Prod. Resour., 2018, 9(3), 204-221.

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