Low molecular weight PEG–PLGA polymers provide a superior matrix for conjugated polymer nanoparticles in terms of physicochemical properties, biocompatibility and optical/photoacoustic performance

Abstract

The near-infrared absorbing conjugated polymer poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b′]-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT) has been investigated as a contrast agent for optical and photoacoustic imaging. Lipophilic π-conjugated polymers can be efficiently encapsulated within self-assembling diblock copolymer poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG–PLGA) nanoparticles, although the effect of variations in PEG and PLGA chain lengths on nanoparticle properties, performance and biocompatibility have not yet been investigated. In this study, PEG–PLGA with different block lengths (PEG_2kDa–PLGA_4kDa, PEG_2kDa–PLGA_15kDa and PEG_5kDa–PLGA_55kDa) were used to encapsulate PCPDTBT. Nanoparticle sizes were smallest (<100 nm) when using PEG_2kDa–PLGA_4kDa, with <5% PCPDTBT content and a reduction in the total solids concentration of the organic phase. All PEG–PLGA nanoparticles were colloidally stable in water and serum-supplemented cell culture medium over 24 h at 37 °C, with slight evidence of protein surface adsorption. PEG_2kDa–PLGA_4kDa systems showed a threefold lower cytotoxicity (IC₅₀ value) than the other two systems. Haemolytic activity was <2.5% for all systems and no platelet aggregation or inhibition of ADP-induced platelet aggregation was observed. Encapsulation of PCPDTBT within a PEG–PLGA matrix shifted fluorescence emission towards red wavelengths (760 nm in THF vs. 840 nm in nanoparticles) and reduced the quantum yield by 30–70-fold compared to THF. Nonetheless, PCPDTBT:PEG_2kDa–PLGA_4kDa systems had a marginally higher quantum yield and signal-to-background ratio in a phantom mouse compared with PEG_2kDa–PLGA_15kDa and PEG_5kDa–PLGA_55kDa systems. As a photoacoustic imaging probe, PCPDTBT:PEG_2kDa–PLGA_4kDa systems also showed a higher photoacoustic amplitude compared to higher molecular weight PEG–PLGA systems. Overall, the low molecular weight PEG_2kDa–PLGA_4kDa nanoparticle systems conferred the benefits of smaller sizes, reduced cytotoxicity and enhanced imaging performance compared to higher molecular weight matrix polymers.