Clickable albumin nanoparticles for pretargeted drug deliv-ery towards PD-L1 overexpressing tumors in combination immunotherapy

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We present a simple methodology to design a pretargeted drug delivery system, based on clickable anti-PD-L1 antibodies and clickable BSA nanoparticles (NPs). In this work, BSA NPs were produced using the solvent pre-cipitation methodology that renders colloidally stable NPs which were subsequently functionalized with a clickable moiety based on chlorosydnone (Cl-Syd). Those reactive groups are able to specifically react with dibenzocyclooctyne (DBCO) groups in a click-type fashion, reaching second order reaction rate constants as high as 1.9 M-1·s-1 which makes this reaction highly suitable for in vivo applications. The presence of reactive Cl-Syd was demonstrated by re-acting the functionalized NPs with a DBCO modified sulfo-cyanine-5 dye (sCy5). With this reaction, it was possible to infer the number of reactive moieties per NPs. Finally, and with the aim of demonstrating the suitability of this system to be used in pretargeted strategies, functionalized fluorescent NPs were used to label H358 cells with a clickable anti-PD-L1 antibody, applying the reaction between Cl-Syd and DBCO as corresponding clickable groups. The results of these experiments demonstrate the biorthogonality of the system to perform the reaction in vitro, in a period as short as 15 minutes.