Degradation and Bio-Safety Evaluation of mPEG-PLGA-PLL Copolymer-Prepared Nanoparticles

Abstract

Studies have shown that monomethoxy(polyethylene glycol)−poly(D,Llactic-co-glycolic acid)−poly(L-lysine) (mPEG-PLGA-PLL)-prepared nanoparticles (NPs) are promising drugs carriers, with good drug loading and delivery performance. To further promote the use of this material in clinical applications, its degradation and biosafety were evaluated. This paper describes degradation studies and biosafety evaluations of different block composition ratios (LA/GA = 60/40, 70/30, and 80/20) of the main material, PLGA, for mPEG-PLGA-PLL (PEAL) NPs. The degradation of PEAL NPs was studied by characterizing the change in molecular weight, the chemical composition, and the degradation rate in addition to the pH value, the particle size, the zeta potential, and the lactic acid and lysine contents in degradation solutions by transmission electron microscopy (TEM), gel permeation chromatography (GPC), and 1 H NMR. The results show that with prolonged degradation time, the pH, particle size, zeta potential, and molecular weight were reduced and that the lactic acid and lysine contents and the molecular weight distribution were increased. 1 H NMR demonstrated that the hydrolysis rate for glycolic units was faster than those for lactic acid and lysine units. The degradation rate of NPs in pH 7.4 PBS was faster than that in pH 5.0 PBS. The degradation rate of PEAL NPs increased as the LA/GA increased from LA/GA = 60/40 to 80/20. Investigations of intracellular protein synthesis, lactate dehydrogenase (LDH) release, 4′,6-diamidino-2-phenylindole (DAPI) nuclear staining and reactive oxygen species (ROS) content in Huh7, L02, and RAW 264.7 cells showed that the PEAL NPs had no effect on protein synthesis or cell membrane integrity and did not induce chromatin agglutination. Although the ROS content was slightly concentration-dependent and time-dependent, the change in content was minimal and diffusely distributed within the cell. After THP-1 cells were induced to differentiate into macrophages, a subsequent incubation with 5 mM PEAL NPs for 24 h did not significantly induce the macrophage release of IL-1β, TNF-α, and TGF-β1 compared with the negative control. Embryos that had their chorion removed were coincubated with PEAL NPs to determine if there were any effects on embryonic development. It is known that zebrafish embryos at 10−24 h post-fertilization (hpf) are most sensitive to PEAL NPs. Zebrafish embryos treated with different concentrations of PEAL NPs within this sensitive time frame demonstrated that PEAL NPs have a high level of biosafety. Our work demonstrates that PEAL NPs are safe candidates for use as biodegradable carriers for drug and gene delivery.

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