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.
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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
References
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.
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.
Yokoyama M. Drug targeting with nano-sized carrier systems. J Artif Organs. 2005;8(2):77–84.
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.
Wang M, Thanou M. Targeting nanoparticles to cancer. Pharmacol Res. (2010) 62(2):90–9
Gullotti E, Yeo Y. Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm. 2009;6(4):1041–51.
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.
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.
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.
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.
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.
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.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.
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.
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.
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.
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.
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.
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.
Narayanan S, Binulal NS, Mony U, Manzoor K, Nair S, Menon D. Folate targeted polymeric ‘green’ nanotherapy for cancer. Nanotechnology. 2010;21(28):285107.
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.
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.
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.
Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science. 2007;318(5849):426–30.
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.
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.
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.
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.
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.
Kang K, Choi IS, Nam Y. A biofunctionalization scheme for neural interfaces using polydopamine polymer. Biomaterials. 2011;32(27):6374–80.
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.
Zhang Y, So MK, Rao J. Protease-modulated cellular uptake of quantum dots. Nano Lett. 2006;6(9):1988–92.
Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med. 2001;7(6):743–8.
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.
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.
Berry CC. Intracellular delivery of nanopartides via the HIV-1 tat pepticle. Nanomedicine. 2008;3(3):357–65.
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.
Torchilin VP. Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers. Adv Drug Deliv Rev. 2008;60(4–5):548–58.
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.
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.
Koch AM, Reynolds F, Merkle HP, Weissleder R, Josephson L. Transport of surface-modified nanoparticles through cell monolayers. ChemBioChem. 2005;6(2):337–45.
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.
Acknowledgments And Disclosures
The authors thank Dr. Gaurav Bajaj for the help with quantitative RT-PCR. This work was supported by NIH R21 CA135130, NSF DMR-1056997, a Grant from the Lilly Endowment, Inc. to College of Pharmacy, Purdue University, Intramural Research Program (Global RNAi Carrier Initiative) of Korea Institute of Science and Technology, the P.E.O. Scholar Award (EG), and the Bilsland Dissertation Fellowship (EG).
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Gullotti, E., Park, J. & Yeo, Y. Polydopamine-Based Surface Modification for the Development of Peritumorally Activatable Nanoparticles. Pharm Res 30, 1956–1967 (2013). https://doi.org/10.1007/s11095-013-1039-y
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DOI: https://doi.org/10.1007/s11095-013-1039-y