Polydopamine-Based Surface Modification for the Development of Peritumorally Activatable Nanoparticles
- 1.6k Downloads
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).
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.
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.
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 wordsdopamine polymerization PEG cleavage polymeric nanoparticles surface modification TAT peptide
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)
- 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
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).
- 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
- 5.Wang M, Thanou M. Targeting nanoparticles to cancer. Pharmacol Res. (2010) 62(2):90–9Google Scholar
- 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
- 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
- 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
- 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