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. 2022 Jul 26;13:4318. doi: 10.1038/s41467-022-32050-4

Fig. 5. An in situ click reaction amplified the tumour accumulation of the bioorthogonal POLY-PROTAC NPs in vivo.

Fig. 5

a Diagrammatic illustration of the tumour-specific delivery of the POLY-PROTAC NPs via a bioorthogonal click reaction with the extracellular tumour acidity-activatable pretargeted NPs. b–d DLS and TEM examinations of the pretargeted NPs at b pH 7.4 and c pH 6.5 (scale bar = 50 μm). The PED pretargeted NPs dissociated in the acidic extracellular tumour environment and exposed DBCO in vitro. d Normalised fluorescence plots of the pretargeted NPs versus pH value (inset: fluorescence image of the PEA NPs under different pH conditions). e, f DLS and TEM examinations of the particle distribution and morphology of the mixture of PED + N3@PGD7 NPs ate pH 7.4 and f 6.5 (scale bar = 50 μm). The bioorthogonal click reaction occurred between the PED pretargeted NPs and the N3@PGD7 POLY-PROTAC NPs at pH 6.5. g, h The pretargeted NPs specifically accumulated at the tumour site and were activated by the acidic tumour pH. g Fluorescence images of the biodistribution of PED NPs in the MDA-MB-231 tumour-bearing nude mice in vivo and h ex vivo CLSM examination of tumour sections (scale bar = 50 μm). The experiment was repeated independently 3 times with similar results. i–m PED NPs increased the tumour distribution of N3@PGD7 NPs after the bioorthogonal click reaction in vivo. i Fluorescence imaging of MDA-MB-231 tumour-bearing BALB/c nude mice and j CLSM images of the tumour sections at 48 h post-injection (scale bar = 50 μm) (the mice were i.v. injected with the PED pretargeted NPs at a DBCO dose of 1.0 mg/kg and subsequently i.v. injected with the N3@PGDA7 NPs at an azide dose of 0.055 mg/kg at 2 h after PED injection). The in situ bioorthogonal click reaction markedly increased ARV771 distribution in the tumour. k Intratumoural fluorescence intensity in N3@PGDA7 NP-injected mice (n = 3 biologically independent mice). l Fluorescence images of the major organs 48 h post-injection. m HPLC-determined intratumoural ARV771 distribution (n = 3 biologically independent mice). All data are presented as mean ± SD.