One-Step Formulation of Targeted Aggregation-Induced Emission Dots for Image-Guided Photodynamic Therapy of Cholangiocarcinoma

Abstract

Photodynamic therapy (PDT) is a palliative technique that can improve median survival with minimal invasion for cholangiocarcinoma (CC) patients. An ideal photosensitizer (PS) is critical to guarantee the efficacy of PDT. However, conventional PSs have some obvious drawbacks, such as lack of specificity and easy aggregation in aqueous media that limit their further application in the clinic. We herein fully take advantage of a red emissive aggregation-induced emission (AIE) PS to fabricate integrin αβ targeted organic AIE dots for image-guided PDT via a simple and straightforward one-step strategy. The obtained AIE dots exhibit high specificity to CC as well as excellent antitumor effect both in vitro and in vivo. Different from conventional PSs and previously reported PS-loaded nanostructures, the AIE dots do not suffer from aggregation-caused fluorescence quenching and reduction in reactive oxygen species production when the AIE PS molecules are in an aggregated state. The significant antitumor effect, as well as good biocompatibility and negligible toxicity, makes the AIE dots promising for future translational research in CC diagnosis and therapy.

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“…This aggregation may increase photothermal effects in acidic tumor microenvironments and enhance therapeutic efficacy. 78 …”

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“…Photo-toxicity was performed by 480 nm light irradiating cells after internalizing different dose of samples.A ss hown in the Supporting Information, Figure S9, both deoxy-BP@RB-Hb and BP@RB-Hb presented obvious photo-toxicity with increasing doses.U nder the same conditions,B P@RB-Hb presented more serious photo-toxicity than deoxy-BP@RB-Hb,w hich indicated BP@RB-Hb could improve PDT efficiency.I tw as attributed to BP@RB-Hb provided more O 2 and produced more cytotoxic ROSi nt he PDT process.W ith 480 nm light irradiation, BP species transferred their energy to acceptor (RB) based on intraparticle FRET mechanism. [21] As shown in the Supporting Information, Figure S11, compared with control experiments,B P@RB-Hb showed good hemocompatibility, which was meaningful for their tests in vivo administration. Calcein-AM and propidium iodide (PI) were added to identify live and dead cells,r espectively.A ss hown in the Supporting Information, Figure S10, cells treated with BP@RB-Hb presented strong red fluorescence from PI in two-photon irradiation area and strong green fluorescence from Calcein-AM in non-irradiation area.…”

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“…Comparatively, small particles within 5.5 nm that can be rapidly cleared by renal and organic molecules are preferable, but they are limited by their short tumor retention and low QY. [40,41] Similarly, AIE phenomenon can be applied to NIR-II fluorophores ( Figure 2d) and PA nanoprobes (Figure 2e) with an ultrabright signal, high T/NT ratio, and enhanced QY. Application of aggregation-induced emission (AIE) phenomenon is an effective strategy to design and synthesize bright probes with high QY; AIE is the opposite of aggregation-caused quenching.…”

“…Traditional LN mapping techniques in clinical applications include radionuclide, blue dyes, and fluorescence imaging. 2019, 31,1904329 Passive targeting via EPR effect -PDFT1032 LN mapping and biopsy, osteosarcoma imaging and IGS [31] -SNPs LN mapping [32] -PDI NPs LN mapping and biopsy, glioblastoma imaging and PTT guidance [33] -AGL AIE dots Peritoneal carcinomatosis imaging and IGS [34] -HLZ-BTED dots Breast tumor imaging and visualizing tumor feeding blood vessels [35] -L897 NPs LN and glioblastoma imaging [36] -BPN-BBTD NPs Bladder tumor imaging and PTT guidance [37] Active targeting via ligands Peptide FSH β receptor DCNP-L 1 -FSH β Ovarian cancer imaging and IGS [38] Integrin α v β 3 IR-BEMC6P@RGD Gastroenteropancreatic neuroendocrine tumor imaging and IGS [39] T-TTD dots a) Cholangiocarcinoma imaging and PDT guidance [40] T-TPETS nanodots b) Hepatocellular carcinoma, imaging and PDT guidance [41] 68 Indocyanine green (ICG) is the only near-infrared fluorescence (NIRF) agent approved for clinical application by the Food and Drug Administration (FDA); it is widely used in ophthalmic angiography, the measurement of circulatory system and liver functions, and studies on intraoperative tumor imaging and LN mapping for various cancers, such as head and neck, [59] breast, [60] lung, gastrointestinal, [61] and urologic cancer. [55,56] The combination of two methods with a radionuclide and a dye has been the gold standard for SLN detection.…”