Pharmaceutical Research

, 35:59 | Cite as

Carbon Dioxide-Generating PLG Nanoparticles for Controlled Anti-Cancer Drug Delivery

Research Paper
  • 49 Downloads

Abstract

Purpose

Poly(D,L-lactide-co-glycolide) (PLG) nanoparticles containing doxorubicin and mineralized calcium carbonate were fabricated and their anti-tumor efficacy was tested using a neuroblastoma-bearing mouse model.

Methods

PLG nanoparticles were prepared by a double emulsion (water-in-oil-in-water; W/O/W) method. Calcium carbonate was mineralized within the PLG nanoparticles during the emulsion process. Rabies virus glycoprotein (RVG) peptide was chemically introduced to the surface of the PLG nanoparticles as a targeting moiety against neuroblastoma. The cytotoxicity and cellular uptake characteristics of these nanoparticles were investigated in vitro. Moreover, their therapeutic efficacy was evaluated using a tumor-bearing mouse model.

Results

Mineralized calcium carbonate in PLG nanoparticles was ionized at acidic pH and generated carbon dioxide gas, which resultantly accelerated the release of doxorubicin from the nanoparticles. RVG peptide-modified, gas-generating PLG nanoparticles showed a significantly enhanced targeting ability to neuroblastoma and an increased therapeutic efficacy in vivo as compared with free doxorubicin.

Conclusions

Targeting ligand-modified polymer nanoparticles containing both anti-cancer drug and mineralized calcium carbonate could be useful for cancer treatment.

Key Words

cancer drug delivery gas-generation polymer nanoparticle 

Abbreviations

DOX

Doxorubicin

EDC

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide

mCNP

PLG nanoparticle containing mineralized calcium carbonate

MES

2-(N-Morpholino)ethanesulfonic acid

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

N2a

Neuro-2a

NHS

N-Hydroxysulfosuccinimide

PBS

Phosphate-buffered saline

PLG

Poly(D,L-lactide-co-glycolide)

PNP

Non-gas-generating PLG nanoparticle

PVA

Poly(vinyl alcohol)

RVG

Rabies virus glycoprotein

Notes

Acknowledgments and Disclosures

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (MSIP) (NRF-2016R1A2A2A10005086). The authors have declared no conflict of interest.

Supplementary material

11095_2018_2359_MOESM1_ESM.docx (4.6 mb)
ESM 1 (DOCX 4730 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Parveen S, Sahoo SK. Polymeric nanoparticles for cancer therapy. J Drug Target. 2008;16(2):108–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Cho K, Wang X, Nie S, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clinical Cancer Res. 2008;14(5):1310–6.CrossRefGoogle Scholar
  4. 4.
    Sawant RM, Hurley J, Salmaso S, Kale A, Tolcheva E, Levchenko T, et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical Nanocarriers. Bioconjug Chem. 2006;17(4):943–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Schmaljohann D. Thermo-and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev. 2006;58(15):1655–70.CrossRefPubMedGoogle Scholar
  6. 6.
    Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nature Rev Cancer. 2004;4(11):891–9.CrossRefGoogle Scholar
  7. 7.
    Folkman J. Tumor angiogenesis: therapeutic implications. New Eng J Med. 1971;285(21):1182–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: passive and active tumor targeting of Nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Lee ES, Oh KT, Kim D, Youn YS, Bae YH. Tumor pH-responsive flower-like micelles of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine). J Control Release. 2007;123(1):19–26.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Liu J, Huang Y, Kumar A, Tan A, Jin S, Mozhi A, et al. pH-sensitive Nano-Systems for drug delivery in cancer therapy. Biotechnol Adv. 2014;32(4):693–710.CrossRefPubMedGoogle Scholar
  11. 11.
    Mundargi RC, Babu VR, Rangaswamy V, Patel P, Aminabhavi TM. Nano/micro Technologies for Delivering Macromolecular Therapeutics Using Poly(D, L-Lactide-co-Glycolide) and its derivatives. J Control Release. 2008;125(3):193–209.CrossRefPubMedGoogle Scholar
  12. 12.
    Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007;32(8):762–98.CrossRefGoogle Scholar
  13. 13.
    Bala I, Hariharan S, Kumar MR. PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carrier Sys. 2004;21(5):387–422.CrossRefGoogle Scholar
  14. 14.
    Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Son S, Jang J, Youn H, Lee S, Lee D, Lee YS, et al. Brain-targeted rabies virus glycoprotein-disulfide linked PEI Nanocarrier for delivery of neurogenic Microrna. Biomaterials. 2011;32(21):4968–75.CrossRefPubMedGoogle Scholar
  16. 16.
    Choi B, Park HJ, Hwang S, Park J. Preparation of alginate beads for floating drug delivery system: effects of CO2 gas-forming agents. Int J Pharm. 2002;239(1):81–91.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee J, Min HS, You DG, Kim K, Kwon IC, Rhim T, et al. Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma. J Controlled Release. 2016;223:197–206.CrossRefGoogle Scholar
  18. 18.
    Pakulska MM, Donaghue IE, Obermeyer JM, Tuladhar A, McLaughlin CK, Shendruk TN, et al. Encapsulation-free controlled release: electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles. Sci Adv. 2016;2(5):e1600519.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Min KH, Min HS, Lee HJ, Park DJ, Yhee JY, Kim K, et al. pH-controlled gas-generating mineralized nanoparticles: a Theranostic agent for ultrasound imaging and therapy of cancers. ACS Nano. 2015;9(1):134–45.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hirn S, Semmler-Behnke M, Schleh C, Wenk A, Lipka J, Schäffler M, et al. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur J Pharm Biopharm. 2011;77(3):407–16.CrossRefPubMedGoogle Scholar
  21. 21.
    Davis ME, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7(9):771–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Choi KY, Min KH, Na JH, Choi K, Kim K, Park JH, et al. Self-assembled hyaluronic acid nanoparticles as a potential drug carrier for cancer therapy: synthesis, characterization, and in vivo biodistribution. J Mater Chem. 2009;19(24):4102–7.CrossRefGoogle Scholar
  23. 23.
    Naka K, Tanaka Y, Chujo Y. Effect of anionic starburst dendrimers on the crystallization of CaCO3 in aqueous solution: size control of spherical Vaterite particles. Langmuir. 2002;18(9):3655–8.CrossRefGoogle Scholar
  24. 24.
    Xiao H, Wang L. Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery. Int J Nanomedicine. 2015;10:5309–25.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cho HJ, Yoon IS, Yoon HY, Koo H, Jin YJ, Ko SH, et al. Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin. Biomaterials. 2012;33(4):1190–200.CrossRefPubMedGoogle Scholar
  26. 26.
    Ma MG, Dong YY, Fu LH, Li SM, Sun RC. Cellulose/CaCO3 nanocomposites: microwave ionic liquid synthesis, characterization, and biological activity. Carbohydr Polym. 2013;92(2):1669–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Rim HP, Min KH, Lee HJ, Jeong SY, Lee SC. pH-tunable calcium phosphate covered mesoporous silica Nanocontainers for intracellular controlled release of guest drugs. Angew Chem Int Ed. 2011;50(38):8853–7.CrossRefGoogle Scholar
  28. 28.
    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):1959–73.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lee C, Hwang HS, Lee S, Kim B, Kim JO, Oh KT, et al. Rabies virus-inspired silica-coated gold Nanorods as a Photothermal therapeutic platform for treating brain tumors. Adv Mater. 2017;29(13):1605563.CrossRefGoogle Scholar
  30. 30.
    Kang E, Min HS, Lee J, Han MH, Ahn HJ, Yoon IC, et al. Nanobubbles from gas-generating polymeric nanoparticles: ultrasound imaging of living subjects. Angew Chem Int Ed. 2010;49(3):524–8.CrossRefGoogle Scholar
  31. 31.
    Zhou Y, Wang Z, Chen Y, Shen H, Luo Z, Li A, et al. Microbubbles from gas-generating Perfluorohexane Nanoemulsions for targeted temperature-sensitive ultrasonography and synergistic HIFU ablation of tumors. Adv Mater. 2013;25(30):4123–30.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hyeon Jin Jang
    • 1
  • Eun Ju Jeong
    • 1
  • Kuen Yong Lee
    • 1
    • 2
  1. 1.Department of BioengineeringHanyang UniversitySeoulRepublic of Korea
  2. 2.Institute of Nano Science and TechnologyHanyang UniversitySeoulRepublic of Korea

Personalised recommendations