An Azide-Tethered Cremophor® ELP Surfactant Allowing Facile Post-Surface Functionalization of Nanoemulsions

Abstract

Abstract Nanoemulsions (NEs) comprising Labrafac WC® as an inner oil and Cremophor® ELP as an outer surfactant are promising organic nanoparticles for biomedical applications due to their characteristics, such as a low toxicity, good structural robustness, and a high capacity to encapsulate hydrophobic contrasting agents or drugs. However, NEs present a limited ability to undertake surface functionalization, resulting in uncontrollable cellular uptake or the poor targeting of specific biomolecules and cells. To address this drawback, we herein developed the Cremophor® ELP-derivative (Crem-N3), which possesses multiple azides. Remarkably, the surfaces of NEs formulated from Crem-N3 were easily modified with dibenzocyclooctyne derivatives through a copper-free azide–alkyne cycloaddition reaction known as a bioorthogonal click reaction. Förster resonance energy transfer analysis revealed that these surface-modified NEs possess the desired dispersibility and integrity. Furthermore, NEs that were functionalized with a cell-penetrating peptide, namely octaalginine (R8), were rapidly internalized into cancer cells, unlike NEs containing no R8. Based on our results, we believe that NEs composed of Crem-N3 as a co-surfactant are advanced NEs that allow flexible functionalization in response to targeted applications, such as vivo diagnostic applications that require a probe with minimum toxicity and specificity toward biological substances.