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Design and Characterization of Metformin-Loaded Solid Lipid Nanoparticles for Colon Cancer

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ABSTRACT

Colorectal cancer is a global concern, and its treatment is fraught with non-selective effects including adverse side effects requiring hospital visits and palliative care. A relatively safe drug formulated in a bioavailability enhancing and targeting delivery platform will be of significance. Metformin-loaded solid lipid nanoparticles (SLN) were designed, optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release. Optimized SLN were 195.01 ± 6.03 nm in size, −17.08 ± 0.95 mV with regard to surface charge, fibrous in shape, largely amorphous, and release of metformin was controlled. The optimized size, charge, and shape suggest the solid lipid nanoparticles will migrate and accumulate in the colon tumor preventing its proliferation and subsequently leading to tumor shrinkage and cell death.

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References

  1. GLOBACON. Estimated Cancer incidence, mortality and prevalence worldwide in 2012. 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx Accessed 14 Feb 2015.

  2. Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. 2010;375:1624–33.

    Article  PubMed  Google Scholar 

  3. Truong NP, Whittaker MR, Mak CW, Davis TP. The importance of nanoparticle shape in cancer drug delivery. Expert Opin Drug Deliv. 2015;12:129–42.

    Article  CAS  PubMed  Google Scholar 

  4. Wen A, Rambhia P, French R, Steinmetz N. Design rules for nanomedical engineering: from physical virology to the applications of virus-based materials in medicine. J Biol Phys. 2013;39:301–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33:322–6.

    Article  CAS  PubMed  Google Scholar 

  6. Sahra IB, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576–86.

    Article  PubMed  Google Scholar 

  7. Luo Q, Hu D, Hu S, Yan M, Sun Z, Chen F. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 2012;12:517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011;34:2323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Currie C, Poole C, Gale E. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766–77.

    Article  CAS  PubMed  Google Scholar 

  10. Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila). 2008;1:369–75.

    Article  CAS  Google Scholar 

  11. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:6745–52.

    Article  CAS  PubMed  Google Scholar 

  12. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–60.

    Article  CAS  PubMed  Google Scholar 

  13. Joshi SR. Metformin: old wine in new bottle-evolving technology and therapy in diabetes. JAPI. 2005;53:963–72.

    PubMed  Google Scholar 

  14. Cheng C, Yu LX, Lee H, Yang C, Lue C, Chou C. Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur J Pharm Sci. 2004;22:297–304.

    Article  CAS  PubMed  Google Scholar 

  15. Yuan H, Jiang S, Du Y, Miao J, Zhang X, Hu F. Strategic approaches for improving entrapment of hydrophilic peptide drugs by lipid nanoparticles. Colloids Surf B: Biointerfaces. 2009;70:248–53.

    Article  CAS  PubMed  Google Scholar 

  16. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001;47:165–96.

    Article  CAS  PubMed  Google Scholar 

  17. Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.

    Article  PubMed  Google Scholar 

  18. Gupta R. Solid lipid nanoparticles for hydrophilic drug delivery system. Novel Sci Int J Pharm Sci. 2013;2:21–5.

    Google Scholar 

  19. Solanki A, Parikh J, Parikh R. Formulation and optimization of piroxicam proniosomes by 3-factor, 3-level box-behnken design. AAPS PharmSciTech. 2007;8:43–9.

    Article  PubMed Central  Google Scholar 

  20. Chopra S, Motwani SK, Iqbal Z, Talegaonkar S, Ahmad FJ, Khar RK. Optimisation of polyherbal gels for vaginal drug delivery by Box-Behnken statistical design. Eur J Pharm Biopharm. 2007;67:120–31.

    Article  CAS  PubMed  Google Scholar 

  21. Kramar A, Turk S, Vrecer F. Statistical optimisation of diclofenac sustained release pellets coated with polymethacrylic films. Int J Pharm. 2003;256:43–52.

    Article  CAS  PubMed  Google Scholar 

  22. Ficarra R, Cutroneo P, Aturki Z, Tommasini S, Calabrò ML, Phan-Tan-Luu R, et al. An experimental design methodology applied to the enantioseparation of a non-steroidal anti-inflammatory drug candidate. J Pharm Biomed Anal. 2002;29:989–97.

    Article  CAS  PubMed  Google Scholar 

  23. Pizarro C, González-Sáiz JM, Pérez-del-Notario N. Multiple response optimisation based on desirability functions of a microwave-assisted extraction method for the simultaneous determination of chloroanisoles and chlorophenols in oak barrel sawdust. J Chromatogr A. 2006;1132:8–14.

    Article  CAS  PubMed  Google Scholar 

  24. Sáiz-Abajo MJ, González-Sáiz JM, Pizarro C. Multi-objective optimisation strategy based on desirability functions used for chromatographic separation and quantification of proline and organic acids in vinegar. Anal Chim Acta. 2005;528:63–76.

    Article  Google Scholar 

  25. Gupta VK, Assmus MW, Beckert TE, Price JC. A novel pH- and time-based multi-unit potential colonic drug delivery system. II. Optimization of multiple response variables. Int J Pharm. 2001;213:93–102.

    Article  CAS  PubMed  Google Scholar 

  26. Hu S, Zhang Y. Endostar-loaded PEG-PLGA nanoparticles: in vitro and in vivo evaluation. Int J Nanomedicine. 2010;5:1039–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y, Yang M, Portney NG, Cui D, Budak G, Ozbay E, et al. Zeta potential: a surface electrical characteristic to probe the interaction of nanoparticles with normal and cancer human breast epithelial cells. Biomed Microdevices. 2008;10:321–8.

    Article  CAS  PubMed  Google Scholar 

  28. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems—a review (Part 1). Trop J Pharm Res. 2013;12:255–64.

    Google Scholar 

  29. Dobrzyska I, Szachowicz-petelska B, Sulkowski S, Figaszewski Z. Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol Cell Biochem. 2005;276:113–9.

    Article  Google Scholar 

  30. Fadnes B, Uhlin-Hansen L, Lindin I, Rekdal O. Small lytic peptides escape the inhibitory effect of heparan sulfate on the surface of cancer cells. BMC Cancer. 2011;11:116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gaspar D, Veiga AS, Castanho MA. From antimicrobial to anticancer peptides. A review. Front Microbiol. 2013;4:294.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Davis ME, Chen Z, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7:771–82.

    Article  CAS  PubMed  Google Scholar 

  33. Cheng C, Lawrence XY, Lee H, Yang C, Lue C, Chou C. Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur J Pharm Sci. 2004;22:297–304.

    Article  CAS  PubMed  Google Scholar 

  34. Mukherjee S, Ray S, Thakur RS. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci. 2009;71:349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Manjunath K, Reddy JS, Venkateswarlu V. Solid lipid nanoparticles as drug delivery systems. Methods Find Exp Clin Pharmacol. 2005;27:127–44.

    Article  CAS  PubMed  Google Scholar 

  36. Patel KD, Patel NK. Formulation and evaluation of metformin hydrochloride microparticles by emulsion solvent evaporation technique. J Drug Deliv Ther. 2013;3:125–30.

    CAS  Google Scholar 

  37. Champion JA, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 2009;26:244–9.

    Article  CAS  PubMed  Google Scholar 

  38. Yan Y, Such GK, Johnston AP, Best JP, Caruso F. Engineering particles for therapeutic delivery: prospects and challenges. ACS Nano. 2012;6:3663–9.

    Article  CAS  PubMed  Google Scholar 

  39. Oh N, Park J. Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomedicine. 2014;9:51–63.

    PubMed  PubMed Central  Google Scholar 

  40. Sharma G, Valenta DT, Altman Y, Harvey S, Xie H, Mitragotri S, et al. Polymer particle shape independently influences binding and internalization by macrophages. J Control Release. 2010;147:408–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caldorera-Moore M, Guimard N, Shi L, Roy K. Designer nanoparticles: incorporating size, shape and triggered release into nanoscale drug carriers. Expert Opin Drug Deliv. 2010;7:479–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Christian DA, Cai S, Garbuzenko OB, Harada T, Zajac AL, Minko T, et al. Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. Mol Pharm. 2009;6:1343–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim Y, Dalhaimer P, Christian DA, Discher DE. Polymeric worm micelles as nano-carriers for drug delivery. Nanotechnology. 2005;16:S1–8.

    Article  Google Scholar 

  44. Lee KL, Hubbard LC, Hern S, Yildiz I, Gratzl M, Steinmetz NF. Shape matters: the diffusion rates of TMV rods and CPMV icosahedrons in a spheroid model of extracellular matrix are distinct. Biomater Sci. 2013;1:581–8.

    Article  CAS  Google Scholar 

  45. Daum N, Tscheka C, Neumeyer A, Schneider M. Novel approaches for drug delivery systems in nanomedicine: effects of particle design and shape. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4:52–65.

    Article  CAS  PubMed  Google Scholar 

  46. Geng Y, Dalhaimer P, Cai S, Tsai R, Tewari M, Minko T, et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol. 2007;2:249–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vivek K, Reddy H, Murthy RS. Investigations of the effect of the lipid matrix on drug entrapment, in vitro release, and physical stability of olanzapine-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2007;8:16–24.

    Article  PubMed Central  Google Scholar 

  48. Ibrahim WM, AlOmrani AH, Yassin AE. Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability. Int J Nanomedicine. 2014;9:129–44.

    PubMed  Google Scholar 

  49. zur Mühlen A, Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery–drug release and release mechanism. Eur J Pharm Biopharm. 1998;45:149–55.

    Article  PubMed  Google Scholar 

  50. Tiyaboonchai W, Tungpradit W, Plianbangchang P. Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. Int J Pharm. 2007;337:299–306.

    Article  CAS  PubMed  Google Scholar 

  51. Wang R, Li L, Wang B, Zhang T, Sun L. FK506-loaded solid lipid nanoparticles: preparation, characterization and in vitro transdermal drug delivery. Afr J Pharm Pharmacol. 2012;6:904–13.

    Google Scholar 

  52. Wilson B, Ambika T, Patel RDK, Jenita JL, Priyadarshini S. Nanoparticles based on albumin: preparation, characterization and the use for 5-flurouracil delivery. Int J Biol Macromol. 2012;51:874–8.

    Article  CAS  PubMed  Google Scholar 

  53. Garg A, Singh S. Enhancement in antifungal activity of eugenol in immunosuppressed rats through lipid nanocarriers. Colloids Surf B: Biointerfaces. 2011;87:280–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Biomaterials and Drug Delivery Unit, Faculty of Pharmaceutical Sciences, University of Jos, Jos, 930001, Nigeria

    Ndidi C. Ngwuluka

  2. Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P. Marg, Matunga (E), Mumbai, 400019, Maharashtra, India

    Darsheen J. Kotak & Padma V. Devarajan

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  1. Ndidi C. Ngwuluka
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  3. Padma V. Devarajan
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Correspondence to Ndidi C. Ngwuluka.

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Ngwuluka, N.C., Kotak, D.J. & Devarajan, P.V. Design and Characterization of Metformin-Loaded Solid Lipid Nanoparticles for Colon Cancer. AAPS PharmSciTech 18, 358–368 (2017). https://doi.org/10.1208/s12249-016-0505-3

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