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

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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

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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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Correspondence to Yoon Yeo.

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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

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