Nothing Special   »   [go: up one dir, main page]
Skip to main content
Springer Nature Link
Log in

Effect of Chemical Binding of Doxorubicin Hydrochloride to Gold Nanoparticles, Versus Electrostatic Adsorption, on the In Vitro Drug Release and Cytotoxicity to Breast Cancer Cells

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The selective delivery of chemotherapeutic agent to the affected area is mainly dependent on the mode of drug loading within the delivery system. This study aims to compare the physical method to the chemical method on the efficiency of loading DOX.HCl to GNPs and the specific release of the loaded drug at certain tissue.

Method

Bifunctional polyethylene glycol with two different functionalities, the alkanethiol and the carboxyl group terminals, was synthesized. Then, DOX·HCl was covalently linked via hydrazone bond, a pH sensitive bond, to the carboxyl functional group and the produced polymer was used to prepare drug functionalized nanoparticles. Another group of GNPs was coated with carboxyl containing polymer; loading the drug into this system by the means of electrostatic adsorption. Finally, the prepared system were characterized with respect to size, shape and drug release in acetate buffer pH 5 and PBS pH 7.4 Also, the effect of DOX.HCl loaded systems on cell viability was assessed using MCF-7 breast cancer cell line.

Results

The prepared nanoparticles were spherical in shape, small in size and monodisperse. The release rate of the chemically bound drug in the acidic pH was higher than the electrostatically adsorbed one. Moreover, both systems show little release at pH 7.4. Finally, cytotoxicity profiles against human breast adenocarcinoma cell line (MCF-7) exhibited greater cytotoxicity of the chemically bound drug over the electrostatically adsorbed one.

Conclusion

Chemical binding of DOX·HCl to the carboxyl group of PEG coating GNPs selectively delivers high amount of drug to tumour-affected tissue which leads to reducing the unwanted effects of the drug in the non-affected ones.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AIBN:

Azobisisobutronitrile

ANOVA:

Analysis of variance

DCM:

Dichloromethane

DOX·HCl :

Doxorubicin HCl

DMSO:

Dimethyl sulfoxide

EPR:

Enhanced permeability and retention

GNPs:

Gold nanoparticles

HAuCl4.3 H3O:

Hydrogen tetrachloroauric acid trihydrate

IC50 :

The concentration of substance required for 50% growth inhibition

MCF-7:

Breast cancer cell line

MDR:

Multi-drug resistance

MWCO:

Molecular weight cut off

PCS:

Photon correlation spectroscopy

PDI:

Polydispersity index

P-gp:

P-glycoprotein

PBS:

Phosphate buffered saline

PEG:

Polyethylene glycol

RES:

Reticulo-endothelial system

SPR:

Surface plasmon resonance

TEM:

Transmission electron microscope

References

  1. Clarke R, Leonessa F, Multidrug TB. Resistance/P-glycoprotein and breast Cancer: Review and meta-analysis. Semin Oncol. 2005;32(Supplement 7):9–15.

    Article  CAS  Google Scholar 

  2. Wang J, Wu L, Kou L, Xu M, Sun J, Wang Y, et al. Novel nanostructured enoxaparin sodium-PLGA hybrid carriers overcome tumor multidrug resistance of doxorubicin hydrochloride. Int J Pharm. 2016;513(1):218–26.

    Article  PubMed  CAS  Google Scholar 

  3. Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev. 2002;54(5):631–51.

    Article  PubMed  CAS  Google Scholar 

  4. Connor EE, Mwamuka J, Gole A, Murphy CJ, Wyatt MD. Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small. 2005;1(3):325–7.

    Article  PubMed  CAS  Google Scholar 

  5. Ruan S, Yuan M, Zhang L, Hu G, Chen J, Cun X, et al. Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles. Biomaterials. 2015;37:425–35.

    Article  PubMed  CAS  Google Scholar 

  6. Choi SH, Byeon HJ, Choi JS, Thao L, Kim I, Lee ES, et al. Inhalable self-assembled albumin nanoparticles for treating drug-resistant lung cancer. J Control Release. 2015;197:199–207.

    Article  PubMed  CAS  Google Scholar 

  7. Zhang G, Yang Z, Lu W, Zhang R, Huang Q, Tian M, et al. Influence of anchoring ligands and particle size on the colloidal stability and in vivo biodistribution of polyethylene glycol-coated gold nanoparticles in tumor-xenografted mice. Biomaterials. 2009;30(10):1928–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Gao J, Huang X, Liu H, Zan F, Ren J. Colloidal stability of gold nanoparticles modified with thiol compounds: Bioconjugation and application in Cancer cell imaging. Langmuir. 2012;28(9):4464–71.

    Article  PubMed  CAS  Google Scholar 

  9. Liu X, Huang N, Wang H, Li H, Jin Q, Ji J. The effect of ligand composition on the in vivo fate of multidentate poly(ethylene glycol) modified gold nanoparticles. Biomaterials. 2013;34(33):8370–81.

    Article  PubMed  CAS  Google Scholar 

  10. Bednarski M, Dudek M, Knutelska J, Nowiński L, Sapa J, Zygmunt M, et al. The influence of the route of administration of gold nanoparticles on their tissue distribution and basic biochemical parameters: in vivo studies. Pharmacol Rep. 2015;67(3):405–9.

    Article  PubMed  CAS  Google Scholar 

  11. Carvalho C, Santos RX, Cardoso S, Correia S, Oliveira PJ, Santos MS, et al. Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. 2009;16(25):3267–85.

    Article  PubMed  CAS  Google Scholar 

  12. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharmacol Rep. 2012;64(5):1020–37.

    Article  PubMed  CAS  Google Scholar 

  14. del Rosario LS, Demirdirek B, Harmon A, Orban D, Uhrich KE. Micellar Nanocarriers assembled from doxorubicin-conjugated amphiphilic macromolecules (DOX–AM). Macromol Biosci. 2010;10(4):415–23.

    Article  PubMed  CAS  Google Scholar 

  15. Guerzoni LPB, Nicolas V, Angelova A. In vitro modulation of TrkB receptor signaling upon sequential delivery of curcumin-DHA loaded carriers towards promoting neuronal survival. Pharm Res. 2017;34(2):492–505.

    Article  PubMed  CAS  Google Scholar 

  16. Angelova A, Garamus VM, Angelov B, Tian Z, Li Y, Zou A. Advances in structural design of lipid-based nanoparticle carriers for delivery of macromolecular drugs, phytochemicals and anti-tumor agents. Adv Colloid Interf Sci. 2017;249:331–45.

    Article  CAS  Google Scholar 

  17. Angelova A, Angelov B, Drechsler M, Lesieur S. Neurotrophin delivery using nanotechnology. Drug Discov Today. 2013;18(23):1263–71.

    Article  PubMed  CAS  Google Scholar 

  18. Chen Y, Angelova A, Angelov B, Drechsler M, Garamus VM, Willumeit-Romer R, et al. Sterically stabilized spongosomes for multidrug delivery of anticancer nanomedicines. J Mater Chem B. 2015;3(39):7734–44.

    Article  CAS  Google Scholar 

  19. Zerkoune L, Lesieur S, Putaux J-L, Choisnard L, Geze A, Wouessidjewe D, et al. Mesoporous self-assembled nanoparticles of biotransesterified cyclodextrins and nonlamellar lipids as carriers of water-insoluble substances. Soft Matter. 2016;12(36):7539–50.

    Article  PubMed  CAS  Google Scholar 

  20. Paciotti GF, Myer L, Weinreich D, Goia D, Pavel N, McLaughlin RE, et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Delivery. 2004;11(3):169–83.

    Article  PubMed  CAS  Google Scholar 

  21. El-Sayed IH, Huang X, El-Sayed MA. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett. 2006;239(1):129–35.

    Article  PubMed  CAS  Google Scholar 

  22. Turkevich J, Stevenson PC, Hillier J. A study of the nucleation and growth processes in the synthesis of colloidal gold. Discuss Faraday Soc. 1951;11(0):55–75.

    Article  Google Scholar 

  23. Che E, Wan L, Zhang Y, Zhao Q, Han X, Li J, et al. Development of phosphonate-terminated magnetic mesoporous silica nanoparticles for pH-controlled release of doxorubicin and improved tumor accumulation. Asian J Pharm Sci. 2014;9(6):317–23.

    Article  Google Scholar 

  24. Mahou R, Wandrey C. Versatile route to synthesize heterobifunctional poly (ethylene glycol) of variable functionality for subsequent pegylation. Polymers. 2012;4(1):561–89.

    Article  CAS  Google Scholar 

  25. Shenoy D, Fu W, Li J, Crasto C, Jones G, DiMarzio C, et al. Surface functionalization of gold nanoparticles using hetero-bifunctional poly (ethylene glycol) spacer for intracellular tracking and delivery. Int J Nanomedicine. 2006;1(1):51–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Woghiren C, Sharma B, Stein S. Protected thiol-polyethylene glycol: a new activated polymer for reversible protein modification. Bioconjug Chem. 1993;4(5):314–8.

    Article  PubMed  CAS  Google Scholar 

  27. Napoli A, Tirelli N, Kilcher G, Hubbell A. New synthetic methodologies for amphiphilic multiblock copolymers of ethylene glycol and propylene sulfide. Macromolecules. 2001;34(26):8913–7.

    Article  CAS  Google Scholar 

  28. Volcker N, Klee D, Hanna M, Hocker H, Bou JJ, Ilarduya Ad, et al. Synthesis of heterotelechelic poly (ethylene glycol) s and their characterization by MALDI-TOF-MS. Macromol Chem Phys 1999;200(6):1363–1373.

  29. Bogdanov AA. Graft-copolymer stabilized metal nanoparticles. US patent. 2015;

  30. Moldt T, Brete D, Przyrembel D, Das S, Goldman JR, Kundu PK, et al. Tailoring the properties of surface-immobilized Azobenzenes by monolayer dilution and surface curvature. Langmuir. 2015;31(3):1048–57.

    Article  PubMed  CAS  Google Scholar 

  31. Overberger C, O'shaughnessy M, Shalit H. The preparation of some aliphatic azo nitriles and their decomposition in solution. J Am Chem Soc. 1949;71(8):2661–6.

    Article  Google Scholar 

  32. Herrwerth S, Rosendahl T, Feng C, Fick J, Eck W, Himmelhaus M, et al. Covalent coupling of antibodies to self-assembled monolayers of Carboxy-functionalized poly(ethylene glycol): protein resistance and specific binding of biomolecules. Langmuir. 2003;19(5):1880–7.

    Article  CAS  Google Scholar 

  33. Zayed G, Tessmar JK. Heterobifunctional poly (ethylene glycol) derivatives for the surface modification of gold nanoparticles toward bone mineral targeting. Macromol Biosci. 2012;12(8):1124–36.

    Article  PubMed  CAS  Google Scholar 

  34. Prime KL, Whitesides GM. Adsorption of proteins onto surfaces containing end-attached oligo(ethylene oxide): a model system using self-assembled monolayers. J Am Chem Soc. 1993;115(23):10714–21.

    Article  CAS  Google Scholar 

  35. Li JJ. Williamson ether synthesis. Name Reactions: Springer; 2014. p. 628-.

  36. Witt D, Klajn R, Barski P, Grzybowski BA. Applications, properties and synthesis of Ѡ-functionalized n-Alkanethiols and disulfides - the building blocks of self-assembled monolayers. Curr Org Chem. 2004;8(18):1763–97.

    Article  CAS  Google Scholar 

  37. Nudelman A, Bechor Y, Falb E, Fischer B, Wexler BA, Nudelman A. Acetyl chloride-methanol as a convenient reagent for: A) quantitative formation of amine hydrochlorides B) carboxylate Ester formation C) mild removal of N-t-Boc-protective group. Synth Commun. 1998;28(3):471–474.

  38. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70–7.

    Article  PubMed  CAS  Google Scholar 

  39. Tyuftin AA, Solovieva SE, Murav’ev AA, Polyantsev FM, Latypov SK, Antipina IS. Thiacalix[4] arenes with terminal thiol groups at the lower rim: synthesis and structure. Russ Chem Bull. 2009;58(1):145–51.

    Article  CAS  Google Scholar 

  40. Patil R, Portilla-Arias J, Ding H, Konda B, Rekechenetskiy A, Inoue S, et al. Cellular delivery of doxorubicin via pH-controlled hydrazone linkage using multifunctional nano vehicle based on poly (β-L-malic acid). Int J Mol Sci. 2012;13(9):11681–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Wang F, Wang Y-C, Dou S, Xiong M-H, Sun T-M, Wang J. Doxorubicin-tethered responsive gold nanoparticles facilitate intracellular drug delivery for overcoming multidrug resistance in Cancer cells. ACS Nano. 2011;5(5):3679–92.

    Article  PubMed  CAS  Google Scholar 

  42. Etrych T, Mrkvan T, Chytil P, Koňák Č, Říhová B, Ulbrich K. N-(2-hydroxypropyl)methacrylamide-based polymer conjugates with pH-controlled activation of doxorubicin. I. New synthesis, physicochemical characterization and preliminary biological evaluation. J Appl Polym Sci. 2008;109(5):3050–61.

    Article  CAS  Google Scholar 

  43. Frens G. Controlled nucleation for the regulation of the particle size in monodisperse gold suspensions. Nature. 1973;241(105):20–2.

    CAS  Google Scholar 

  44. Madhusudhan A, Reddy GB, Venkatesham M, Veerabhadram G, Kumar DA, Natarajan S, et al. Efficient pH dependent drug delivery to target cancer cells by gold nanoparticles capped with carboxymethyl chitosan. Int J Mol Sci. 2014;15(5):8216–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Gu Y-J, Cheng J, Man CW-Y, Wong W-T, Cheng SH. Gold-doxorubicin nanoconjugates for overcoming multidrug resistance. Nanomedicine. 2012;8(2):204–11.

    Article  PubMed  CAS  Google Scholar 

  46. Corbierre MK, Cameron NS, Lennox RB. Polymer-stabilized gold nanoparticles with high grafting densities. Langmuir. 2004;20(7):2867–73.

    Article  PubMed  CAS  Google Scholar 

  47. Vigevani A, Doxorubicin WMJ. Doxorubicin. In: Klaus F, editor. Analytical profiles of drug substances. Volume 9: academic press; 1981. p. 245–74.

    Chapter  Google Scholar 

  48. Norman TJ, Grant CD, Magana D, Zhang JZ, Liu J, Cao D, et al. Near infrared optical absorption of gold nanoparticle aggregates. J Phys Chem B. 2002;106(28):7005–12.

    Article  CAS  Google Scholar 

  49. Chah S, Hammond MR, Zare RN. Gold nanoparticles as a colorimetric sensor for protein conformational changes. Chem Biol. 12(3):323–8.

  50. Burns C, Spendel WU, Puckett S, Pacey GE. Solution ionic strength effect on gold nanoparticle solution color transition. Talanta. 2006;69(4):873–6.

    Article  PubMed  CAS  Google Scholar 

  51. Nam J, Won N, Jin H, Chung H, Kim S. pH-induced aggregation of gold nanoparticles for Photothermal Cancer therapy. J Am Chem Soc. 2009;131(38):13639–45.

    Article  PubMed  CAS  Google Scholar 

  52. Aryal S, RB KC, Bhattarai N, Kim CK, Kim HY. Study of electrolyte induced aggregation of gold nanoparticles capped by amino acids. J Colloid Interface Sci. 2006;299(1):191–7.

    Article  PubMed  CAS  Google Scholar 

  53. Wang G, Sun W. Optical limiting of gold nanoparticle aggregates induced by electrolytes. J Phys Chem B. 2006;110(42):20901–5.

    Article  PubMed  CAS  Google Scholar 

  54. Takae S, Akiyama Y, Otsuka H, Nakamura T, Nagasaki Y, Kataoka K. Ligand density effect on Biorecognition by PEGylated gold nanoparticles: regulated interaction of RCA120 lectin with lactose installed to the distal end of tethered PEG strands on gold surface. Biomacromolecules. 2005;6(2):818–24.

    Article  PubMed  CAS  Google Scholar 

  55. Jo DH, Kim JH, Lee TG, Kim JH. Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases. Nanomedicine. 2015;11(7):1603–11.

    Article  PubMed  CAS  Google Scholar 

  56. Chavanpatil MD, Khdair A, Patil Y, Handa H, Mao G, Panyam J. Polymer-surfactant nanoparticles for sustained release of water-soluble drugs. J Pharm Sci. 2007;96(12):3379–89.

    Article  PubMed  CAS  Google Scholar 

  57. Zayed G, Tessmar J, Gopferich A. Development of colloids for cell and tissue targeting: bisphosphonate-functionalized gold nanoparticles for the investigation of bone targeting. In: phD; 2010.

    Google Scholar 

  58. Miyamoto D, Oishi M, Kojima K, Yoshimoto K, Nagasaki Y. Completely dispersible PEGylated gold nanoparticles under physiological conditions: modification of gold nanoparticles with precisely controlled PEG-b-polyamine. Langmuir. 2008;24(9):5010–7.

    Article  PubMed  CAS  Google Scholar 

  59. Lu D, Wen X, Liang J, Gu Z, Zhang X, Fan Y. A pH-sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate. J Biomed Mater Res B Appl Biomater. 2009;89B(1):177–83.

    Article  CAS  Google Scholar 

  60. Sun T-M, Wang Y-C, Wang F, Du J-Z, Mao C-Q, Sun C-Y, et al. Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds. Biomaterials. 2014;35(2):836–45.

    Article  PubMed  CAS  Google Scholar 

  61. Zhang Z, Wang L, Wang J, Jiang X, Li X, Hu Z, et al. Mesoporous silica-coated gold Nanorods as a light-mediated multifunctional Theranostic platform for Cancer treatment. Adv Mater. 2012;24(11):1418–23.

    Article  PubMed  CAS  Google Scholar 

  62. François A, Laroche A, Pinaud N, Salmon L, Ruiz J, Robert J, et al. Encapsulation of docetaxel into PEGylated gold nanoparticles for vectorization to Cancer cells. ChemMedChem. 2011;6(11):2003–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt

    Gamal M. Zayed, Wael A. Abdelhafez, Fahd M. Alsharif & Ahmed M. Abdelsalam

  2. Al-Azhar Centre of Nanosceinecs and Applications (ACNA), Assiut, Egypt

    Gamal M. Zayed

  3. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Port Said University, Port Fouad, Egypt

    Islam Kamal

  4. Department of Pharmaceutics, Qassim University, Qassim, Kingdom of Saudi Arabia

    Mohamed A. Amin

  5. Department of Pharmaceutical Chemistry, Al-Azhar University, Assiut, Egypt

    Montaser Sh. A. Shaykoon

  6. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt

    Hatem A. Sarhan

Authors
  1. Gamal M. Zayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Islam Kamal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wael A. Abdelhafez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fahd M. Alsharif
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohamed A. Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Montaser Sh. A. Shaykoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hatem A. Sarhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ahmed M. Abdelsalam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gamal M. Zayed.

Electronic supplementary material

ESM 1

(DOCX 1034 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zayed, G.M., Kamal, I., Abdelhafez, W.A. et al. Effect of Chemical Binding of Doxorubicin Hydrochloride to Gold Nanoparticles, Versus Electrostatic Adsorption, on the In Vitro Drug Release and Cytotoxicity to Breast Cancer Cells. Pharm Res 35, 112 (2018). https://doi.org/10.1007/s11095-018-2393-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-018-2393-6

Key words

Search

Navigation