Delivery of Ursolic Acid by Polyhydroxybutyrate Nanoparticles for
                    Cancer Therapy: in silico and in vitro Studies

Sureshbabu Ram Kumar Pandian; Selvaraj Kunjiappan; Parasuraman Pavadai; Velmurugan Sundarapandian; Vivek Chandramohan; Krishnan Sundar

doi:10.1055/a-1640-0009

Drug Research, Inhaltsverzeichnis

Drug Res (Stuttg) 2022; 72(02): 72-81
DOI: 10.1055/a-1640-0009

Original Article

Delivery of Ursolic Acid by Polyhydroxybutyrate Nanoparticles for Cancer Therapy: in silico and in vitro Studies

Autor*innen

Sureshbabu Ram Kumar Pandian

¹Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
Selvaraj Kunjiappan

¹Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
Parasuraman Pavadai

²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, M S R Nagar, Bengaluru, Karnataka, India
Velmurugan Sundarapandian

¹Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
Vivek Chandramohan

³Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru, Karnataka, India
Krishnan Sundar

¹Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India

Abstract

Ursolic acid (UA), a pentacyclic triterpenoid and a phytochemical, is a potent inhibitory agent against proliferation of various tumors. Polyhydroxybutyrate nanoparticles (PHB NPs) are preferred in therapeutics due to their drug-stabilizing property and enhanced biological activity. In this study, PHB NPs were utilized to deliver and enhance the bioavailability of UA against cancer cells (HeLa). Further, molecular docking and dynamic studies were conducted to calculate the binding affinity and stability of UA at the active site of target protein (epidermal growth factor receptor-EGFR). The PHB NPs revealed the average size as 150–200 nm in TEM, which were used in subsequent experiments. The cytoplasmic uptake of nanoparticles was confirmed by florescent microscopy. The encapsulation potential of PHB NPs with UA was assessed by UV–visible spectrophotometer as 54%. Besides, the drug release behavior, cytotoxicity and the regulation of apoptosis were investigated in vitro. The cytotoxicity results revealed that the maximum efficiency of drug delivery was at 96^th hour.

Key words

PHB nanoparticles - plant metabolite - ursolic acid - drug delivery - EGFR

Volltext

Referenzen

References
1 Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids surfaces B biointerfaces 2010; 75: 1-18
2 Cohen H, Levy RJ, Gao J. et al. Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Ther 2000; 7: 1896-1905
3 Choi J, Lee SY. Process analysis and economic evaluation for poly (3-hydroxybutyrate) production by fermentation. Bioprocess Eng 1997; 17: 335-342
4 Woitiski CB, Veiga F, Ribeiro A. et al. Design for optimization of nanoparticles integrating biomaterials for orally dosed insulin. Eur J Pharm Biopharm 2009; 73: 25-33
5 Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 2004; 56: 1649-1659
6 Yao Y-C, Zhan X-Y, Zhang J. et al. A specific drug targeting system based on polyhydroxyalkanoate granule binding protein PhaP fused with targeted cell ligands. Biomaterials 2008; 29: 4823-4830
7 Pandian SR, Deepak V, Kalishwaralal K. et al. Optimization and fed-batch production of PHB utilizing dairy waste and sea water as nutrient sources by Bacillus megaterium SRKP-3. Bioresour Technol 2010; 101: 705-711
8 Redd WH, Montgomery GH, DuHamel KN. Behavioral intervention for cancer treatment side effects. J Natl Cancer Inst 2001; 93: 810-823
9 Cheong I, Huang X, Bettegowda C. et al. A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science (80- ) 2006; 314: 1308-1311
10 Hsu H-Y, Yang J-J, Lin C-C. Effects of oleanolic acid and ursolic acid on inhibiting tumor growth and enhancing the recovery of hematopoietic system postirradiation in mice. Cancer Lett 1997; 111: 7-13
11 Zhou XJ, Hu XM, Yi YM. et al. Preparation and body distribution of freeze-dried powder of ursolic acid phospholipid nanoparticles. Drug Dev Ind Pharm 2009; 35: 305-310
12 Liu J. Oleanolic acid and ursolic acid: research perspectives. J Ethnopharmacol 2005; 100: 92-94
13 Ovesna Z, Vachalkova A, Horvathova K. et al. Pentacyclic triterpenoic acids: new chemoprotective compounds Minireview. Neoplasma 2004; 51: 327-333
14 Badary OA, Abdel-Naim AB, Abdel-Wahab MH. et al. The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology 2000; 143: 219-226
15 Nagi MN, Mansour MA. Protective effect of thymoquinone against doxorubicin–induced cardiotoxicity in rats: A possible mechanism of protection. Pharmacol Res 2000; 41: 283-289
16 Pandian SRK, Deepak V, Kalishwaralal K. et al. Synthesis of PHB nanoparticles from optimized medium utilizing dairy industrial waste using Brevibacterium casei SRKP2: a green chemistry approach. Colloids Surfaces B Biointerfaces 2009; 74: 266-273
17 Theivendren SK and MS and BK and PP and EB and PM and EG-M and SA and SRKP and VR a. Capsaicin-loaded solid lipid nanoparticles: Design, biodistribution, in silico modeling and in vitro cytotoxicity evaluation. Nanotechnology 2020. Im Internet http://iopscience.iop.org/article/10.1088/1361-6528/abc57e
18 Pandian SRK, Pavadai P, Vellaisamy S. et al. Formulation and evaluation of rutin-loaded solid lipid nanoparticles for the treatment of brain tumor. Naunyn Schmiedebergs Arch Pharmacol 2020. doi: 10.1007/s00210-020-02015-9
19 Lee J, Jung S-G, Park C-S. et al. Tumor-specific hybrid polyhydroxybutyrate nanoparticle: Surface modification of nanoparticle by enzymatically synthesized functional block copolymer. Bioorg Med Chem Lett 2011; 21: 2941-2944
20 Yin Win K, Feng S-S. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 2005; 26: 2713-2722
21 Ram Kumar Pandian S, Anjanei D, Raja NRL. et al. PEGylated silver nanoparticles from Sesbania aegyptiaca exhibit immunomodulatory and anti-cancer activity. Mater Res Express 2018; 6: 35402
22 Pandian SRK, Deepak V, Nellaiah H. et al. PEG–PHB-glutaminase nanoparticle inhibits cancer cell proliferation in vitro through glutamine deprivation. Vitr Cell Dev Biol 2015; 51: 372-380
23 Schneider P, Hosseiny SS, Szczotka M. et al. Rapid solubility determination of the triterpenes oleanolic acid and ursolic acid by UV-spectroscopy in different solvents. Phytochem Lett 2009; 2: 85-87
24 Xiong Y-C, Yao Y-C, Zhan X-Y. et al. Application of polyhydroxyalkanoates nanoparticles as intracellular sustained drug-release vectors. J Biomater Sci Polym Ed 2010; 21: 127-140
25 Wiggam MI, O’Kane MJ, Harper R. et al. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management: a randomized controlled study. Diabetes Care 1997; 20: 1347-1352
26 Zinn M, Witholt B, Egli T. Occurrence, synthesis and medical application of bacterial polyhydroxyalkanoate. Adv Drug Deliv Rev 2001; 53: 5-21
27 Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorg Med Chem 2009; 17: 2950-2962
28 Fletcher RA, Brazin JA, Staymates ME. et al. Fabrication of polymer microsphere particle standards containing trace explosives using an oil/water emulsion solvent extraction piezoelectric printing process. Talanta 2008; 76: 949-955
29 Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature 2003; 422: 37-44
30 Woodrow KA, Cu Y, Booth CJ. et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat Mater 2009; 8: 526-533
31 Yuan F, Dellian M, Fukumura D. et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 1995; 55: 3752-3756
32 Kim S, Kim J-H, Jeon O. et al. Engineered polymers for advanced drug delivery. Eur J Pharm Biopharm 2009; 71: 420-430
33 Singh P, Bast F. In silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor. Med Chem Res 2014; 23: 5074-5085
34 Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol 2018; 12: 3-20
35 Lee T-Y, Tseng Y-H. The Potential of Phytochemicals in Oral Cancer Prevention and Therapy: A Review of the Evidence. Biomolecules 2020; 10: 1150
36 Sasaki T, Hiroki K, Yamashita Y. The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment. Biomed Res Int 2013; 2013: 546318
37 Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel) 2017; 9: 52
38 Zhang C, Zhao L, Dong Y. et al. Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery. Eur J Pharm Biopharm 2010; 76: 10-16
39 Cadee JA, Brouwer LA, Den Otter W. et al. A comparative biocompatibility study of microspheres based on crosslinked dextran or poly (lactic-co-glycolic) acid after subcutaneous injection in rats. J Biomed Mater Res An Off J Soc Biomater Japanese Soc Biomater Aust Soc Biomater Korean Soc Biomater 2001; 56: 600-609
40 Shikanov A, Vaisman B, Krasko MY. et al. Poly (sebacic acid-co-ricinoleic acid) biodegradable carrier for paclitaxel: In vitro release and in vivo toxicity. J Biomed Mater Res Part A An Off J Soc Biomater Japanese Soc Biomater Aust Soc Biomater Korean Soc Biomater 2004; 69: 47-54
41 Komiya T, Achiwa Y, Katsuzaki H. et al. Effect of oleanolic and ursolic acids isolated from Loquat (Eriobotrya) on the growth of human lymphoid leukemia cells. Food Sci Technol Int Tokyo 1998; 4: 282-284
42 Errico C, Bartoli C, Chiellini F. et al. Poly (hydroxyalkanoates)-based polymeric nanoparticles for drug delivery. J Biomed Biotechnol 2009; 2009
43 Qin L, Xue M, Wang W. et al. The in vitro and in vivo anti-tumor effect of layered double hydroxides nanoparticles as delivery for podophyllotoxin. Int J Pharm 2010; 388: 223-230
44 Mesri M, Wall NR, Li J. et al. Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 2001; 108: 981-990
45 Neto CC. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr 2007; 137: 186S-193S