Abstract
Dye-loaded polymer nanoparticles (NPs) emerge as a powerful tool for bioimaging applications, owing to their exceptional brightness and controlled small size. However, aggregation-caused quenching (ACQ) and leakage of dyes at high loading remain important challenges of these nanomaterials. The use of bulky hydrophobic counterions has been recently proposed as an effective approach to minimize ACQ and dye leakage, but the role of counterion structure is still poorly understood. Here, a systematic study based on ten counterions, ranging from small hydrophilic perchlorate up to large hydrophobic tetraphenylborate derivatives, reveals how counterion nature can control encapsulation and emission of a cationic dye (rhodamine B octadecyl ester) in NPs prepared by nanoprecipitation of a biodegradable polymer, poly-lactide-co-glycolide (PLGA). We found that increase in counterion hydrophobicity enhances dye encapsulation efficiency and prevents dye adsorption at the particle surface. Cellular imaging studies revealed that ≥95 % encapsulation efficiency, achieved with most hydrophobic counterions (fluorinated tetraphenylborates), is absolutely required because non-encapsulated dye species at the surface of NPs are the origin of dye leakage and strong fluorescence background in cells. The size of counterions is found to be essential to prevent ACQ, where the largest species, serving as effective spacer between dyes, provide the highest fluorescence quantum yield. Moreover, we found that the most hydrophobic counterions favor dye-dye coupling inside NPs, leading to ON/OFF fluorescence switching of single particles. By contrast, less hydrophobic counterions tend to disperse dyes in the polymer matrix favoring stable emission of NPs. The obtained structure-property relationships validate the counterion-based approach as a mature concept to fight ACQ and dye leakage in the development of advanced polymeric nanomaterials with controlled optical properties.
Highlights
In the last decades, fluorescent nanoparticles (NPs) have grown from a scientific curiosity to a reliable tool in bioimaging[1] and theranostics.[2]
Intensive work in the field generated a number of families of fluorescent organic NPs, such as conjugated polymer NPs,[1c] dye-loaded polymer[2h, 4a] and lipid[5] NPs as well as dye-based NPs,[6] notably using aggregation-induced emission (AIE) dyes.[2h, 7] Among these families, dye-loaded polymer NPs are of particular interest because they combine high stability, potential biodegradability and capacity to co-encapsulate other contrast agents and drugs.[2h, 8] this class of NPs still faces two major challenges – inefficient encapsulation of fluorophores and aggregation-caused quenching (ACQ) of these dyes
We have shown that the bulky counterion tetrakis(pentafluorophenyl)borate (F5-TPB) in the ion pair with rhodamine B octadecyl ester (R18) enables dye encapsulation with minimal ACQ, resulting in 40-nm polymer NPs that are 5-100-fold brighter than corresponding quantum dots.[8, 16,17]
Summary
Fluorescent nanoparticles (NPs) have grown from a scientific curiosity to a reliable tool in bioimaging[1] and theranostics.[2]. Several studies have shown that higher hydrophobicity of the dyes increases their encapsulation efficiency in hydrophobic matrices and stability towards dye leakage.[9] even the most hydrophobic dyes still suffer from incomplete encapsulation at loadings higher than 1% (w/w).[10] On the other hand, a fruitful direction to fight ACQ is to design fluorophores exhibiting efficient emission in the solid state.[7b, 11] The direct approach is introducing bulky groups[12] and polymer chains[13] to the fluorophore, which can prevent pi-pi stacking of dyes in the polymeric matrix. AIE has become a highly popular and efficient approach to prevent ACQ of dyes in the solid state,[7, 14] this method is focused on NPs presenting a core of pure AIE dyes.[2gi, 15]
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