Pharmaceutical Research

, Volume 30, Issue 8, pp 1956–1967 | Cite as

Polydopamine-Based Surface Modification for the Development of Peritumorally Activatable Nanoparticles

Research Paper

Abstract

Purpose

To create poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), where a drug-encapsulating NP core is covered with polyethylene glycol (PEG) in a normal condition but exposes a cell-interactive TAT-modified surface in an environment rich in matrix metalloproteinases (MMPs).

Methods

PLGA NPs were modified with TAT peptide (PLGA-pDA-TAT NPs) or dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate peptide (peritumorally activatable NPs, PANPs) via dopamine polymerization. Cellular uptake of fluorescently labeled NPs was observed with or without a pre-treatment of MMP-2 by confocal microscopy and flow cytometry. NPs loaded with paclitaxel (PTX) were tested against SKOV-3 ovarian cancer cells to evaluate the contribution of surface modification to cellular delivery of PTX.

Results

While the size and morphology did not significantly change due to the modification, NPs modified with dopamine polymerization were recognized by their dark color. TAT-containing NPs (PLGA-pDA-TAT NPs and PANPs) showed changes in surface charge, indicative of effective conjugation of TAT peptide on the surface. PLGA-pDA-TAT NPs and MMP-2-pre-treated PANPs showed relatively good cellular uptake compared to PLGA NPs, MMP-2-non-treated PANPs, and NPs with non-cleavable PEG. After 3 h treatment with cells, PTX loaded in cell-interactive NPs showed greater toxicity than non-interactive ones as the former could enter cells during the incubation period. However, due to the initial burst drug release, the difference was not as clear as microscopic observation.

Conclusions

PEGylated polymeric NPs that could expose cell-interactive surface in response to MMP-2 were successfully created by dual modification of PLGA NPs using dopamine polymerization.

Key words

dopamine polymerization PEG cleavage polymeric nanoparticles surface modification TAT peptide 

Abbreviations

MMPs

Matrix metalloproteinases

NPs

Nanoparticles

PANPs

Peritumorally activatable nanoparticles, PLGA NPs dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate via dopamine polymerization (PLGA-pDA-TAT/MMP-substrate PEG NPs)

pDA

Polymerized dopamine

PEG

Polyethylene glycol

PLGA

Poly(lactic-co-glycolic acid)

PLGA-pDA NPs

PLGA NPs with pDA coating

PLGA-pDA-TAT NPs

PLGA NPs modified with TAT peptide via dopamine polymerization

PLGA-PEG NPs

NPs prepared with a PLGA-PEG conjugate

PTX

Paclitaxel

Supplementary material

11095_2013_1039_MOESM1_ESM.docx (1.8 mb)
ESM 1(DOCX 1799 kb)

References

  1. 1.
    Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12):6387–92.Google Scholar
  2. 2.
    Gabizon AA, Shmeeda H, Zalipsky S. Pros and cons of the liposome platform in cancer drug targeting. J Liposome Res. 2006;16(3):175–83.CrossRefGoogle Scholar
  3. 3.
    Yokoyama M. Drug targeting with nano-sized carrier systems. J Artif Organs. 2005;8(2):77–84.CrossRefGoogle Scholar
  4. 4.
    Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2(12):751–60.CrossRefGoogle Scholar
  5. 5.
    Wang M, Thanou M. Targeting nanoparticles to cancer. Pharmacol Res. (2010) 62(2):90–9Google Scholar
  6. 6.
    Gullotti E, Yeo Y. Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm. 2009;6(4):1041–51.CrossRefGoogle Scholar
  7. 7.
    Yu B, Tai HC, Xue W, Lee LJ, Lee RJ. Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol. 2010;27(7):286–98.CrossRefGoogle Scholar
  8. 8.
    Gu F, Zhang L, Teply BA, Mann N, Wang A, Radovic-Moreno AF, et al. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci U S A. 2008;105(7):2586–91.CrossRefGoogle Scholar
  9. 9.
    Cheng J, Teply BA, Sherifi I, Sung J, Luther G, Gu FX, et al. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials. 2007;28(5):869–76.CrossRefGoogle Scholar
  10. 10.
    Montcourrier P, Silver I, Farnoud R, Bird I, Rochefort H. Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism. Clin Exp Metastasis. 1997;15(4):382–92.CrossRefGoogle Scholar
  11. 11.
    Swallow CJ, Grinstein S, Rotstein OD. A vacuolar type h(+)-atpase regulates cytoplasmic ph in murine macrophages. J Biol Chem. 1990;265(13):7645–54.Google Scholar
  12. 12.
    Niidome T, Ohga A, Akiyama Y, Watanabe K, Niidome Y, Mori T, et al. Controlled release of peg chain from gold nanorods: targeted delivery to tumor. Bioorg Med Chem. 2010;18(12):4453–8.CrossRefGoogle Scholar
  13. 13.
    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.CrossRefGoogle Scholar
  14. 14.
    Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M. Inhibition of matrix metalloproteinase-2 secretion and invasion by human ovarian cancer cell line sk-ov-3 with lysine, proline, arginine, ascorbic acid and green tea extract. J Obstet Gynaecol Res. 2006;32(2):148–54.CrossRefGoogle Scholar
  15. 15.
    Rabinovich A, Medina L, Piura B, Segal S, Huleihel M. Regulation of ovarian carcinoma SKOV-3 cell proliferation and secretion of mmps by autocrine IL-6. Anticancer Res. 2007;27(1A):267–72.Google Scholar
  16. 16.
    Terada T, Iwai M, Kawakami S, Yamashita F, Hashida M. Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting. J Control Release. 2006;111(3):333–42.CrossRefGoogle Scholar
  17. 17.
    Hatakeyama H, Akita H, Kogure K, Oishi M, Nagasaki Y, Kihira Y, et al. Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene Ther. 2007;14(1):68–77.CrossRefGoogle Scholar
  18. 18.
    Hatakeyama H, Akita H, Ito E, Hayashi Y, Oishi M, Nagasaki Y, et al. Systemic delivery of sirna to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid. Biomaterials. 2011;32(18):4306–16.CrossRefGoogle Scholar
  19. 19.
    Mok H, Bae KH, Ahn C-H, Park TG. PEGylated and mmp-2 specifically depegylated quantum dots: comparative evaluation of cellular uptake. Langmuir. 2009;25(3):1645–50.CrossRefGoogle Scholar
  20. 20.
    Narayanan S, Binulal NS, Mony U, Manzoor K, Nair S, Menon D. Folate targeted polymeric ‘green’ nanotherapy for cancer. Nanotechnology. 2010;21(28):285107.CrossRefGoogle Scholar
  21. 21.
    Rao KS, Reddy MK, Horning JL, Labhasetwar V. TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs. Biomaterials. 2008;29(33):4429–38.CrossRefGoogle Scholar
  22. 22.
    Gullotti E, Yeo Y. Beyond the imaging: limitations of cellular uptake study in the evaluation of nanoparticles. J Control Release. 2012;164(2):170–6.CrossRefGoogle Scholar
  23. 23.
    Lee H, Rho J, Messersmith PB. Facile conjugation of biomolecules onto surfaces via mussel adhesive protein inspired coatings. Adv Mater. 2009;21(4):431–4.CrossRefGoogle Scholar
  24. 24.
    Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science. 2007;318(5849):426–30.CrossRefGoogle Scholar
  25. 25.
    Zhang M, Zhang X, He X, Chen L, Zhang Y. A self-assembled polydopamine film on the surface of magnetic nanoparticles for specific capture of protein. Nanoscale. 2012;4(10):3141–7.CrossRefGoogle Scholar
  26. 26.
    Ni K, Lu H, Wang C, Black KCL, Wei D, Ren Y, et al. A novel technique for in situ aggregation of gluconobacter oxydans using bio-adhesive magnetic nanoparticles. Biotechnol Bioeng. 2012;109(12):2970–7.CrossRefGoogle Scholar
  27. 27.
    Tsai WB, Chen WT, Chien HW, Kuo WH, Wang MJ. Poly(dopamine) coating of scaffolds for articular cartilage tissue engineering. Acta Biomater. 2011;7(12):4187–94.CrossRefGoogle Scholar
  28. 28.
    Ryou MH, Lee YM, Park JK, Choi JW. Mussel-inspired polydopamine-treated polyethylene separators for high-power li-ion batteries. Adv Mater. 2011;23(27):3066–70.CrossRefGoogle Scholar
  29. 29.
    Lu L, Li QL, Maitz MF, Chen JL, Huang N. Immobilization of the direct thrombin inhibitor-bivalirudin on 316l stainless steel via polydopamine and the resulting effects on hemocompatibility in vitro. J Biomed Mater Res A. 2012;100(9):2421–30.Google Scholar
  30. 30.
    Kang K, Choi IS, Nam Y. A biofunctionalization scheme for neural interfaces using polydopamine polymer. Biomaterials. 2011;32(27):6374–80.CrossRefGoogle Scholar
  31. 31.
    Xu P, Gullotti E, Tong L, Highley CB, Errabelli DR, Hasan T, et al. Intracellular drug delivery by poly(lactic-co-glycolic acid) nanoparticles, revisited. Mol Pharm. 2009;6(1):190–201.CrossRefGoogle Scholar
  32. 32.
    Zhang Y, So MK, Rao J. Protease-modulated cellular uptake of quantum dots. Nano Lett. 2006;6(9):1988–92.CrossRefGoogle Scholar
  33. 33.
    Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med. 2001;7(6):743–8.CrossRefGoogle Scholar
  34. 34.
    Lee S, Cha EJ, Park K, Lee SY, Hong JK, Sun IC, et al. A near-infrared-fluorescence-quenched gold-nanoparticle imaging probe for in vivo drug screening and protease activity determination. Angew Chem Int Ed Engl. 2008;47(15):2804–7.CrossRefGoogle Scholar
  35. 35.
    Amoozgar Z, Park J, Lin Q, Yeo Y. Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor-specific drug delivery. Mol Pharm. 2012;9(5):1262–70.Google Scholar
  36. 36.
    Berry CC. Intracellular delivery of nanopartides via the HIV-1 tat pepticle. Nanomedicine. 2008;3(3):357–65.CrossRefGoogle Scholar
  37. 37.
    Sood AK, Fletcher MS, Coffin JE, Yang M, Seftor EA, Gruman LM, et al. Functional role of matrix metalloproteinases in ovarian tumor cell plasticity. Am J Obstet Gynecol. 2004;190(4):899–909.CrossRefGoogle Scholar
  38. 38.
    Torchilin VP. Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers. Adv Drug Deliv Rev. 2008;60(4–5):548–58.CrossRefGoogle Scholar
  39. 39.
    Nam YS, Park JY, Han SH, Chang IS. Intracellular drug delivery using poly(d, l-lactide-co-glycolide) nano- particles derivatized with a peptide from a transcriptional activator protein of HIV-1. Biotechnol Lett. 2002;24(24):2093–8.CrossRefGoogle Scholar
  40. 40.
    Torchilin VP, Rammohan R, Weissig V, Levchenko TS. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc Natl Acad Sci U S A. 2001;98(15):8786–91.CrossRefGoogle Scholar
  41. 41.
    Koch AM, Reynolds F, Merkle HP, Weissleder R, Josephson L. Transport of surface-modified nanoparticles through cell monolayers. ChemBioChem. 2005;6(2):337–45.CrossRefGoogle Scholar
  42. 42.
    Tong R, Cheng J. Paclitaxel-initiated, controlled polymerization of lactide for the formulation of polymeric nanoparticulate delivery vehicles. Angew Chem Int Ed Engl. 2008;47(26):4830–4.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteUSA
  2. 2.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  3. 3.Biomedical Research InstituteKorea Institute of Science and TechnologySeoulRepublic of Korea

Personalised recommendations