NIR-II Aza-BODIPY Dyes Bioconjugated to Monoclonal Antibody Trastuzumab for Selective Imaging of HER2-Positive Ovarian Cancer.

Using fluorescence-guided surgery (FGS) to cytoreductive surgery helps achieving complete resection of microscopic ovarian tumors. The use of visible and NIR-I fluorophores has led to beneficial results in clinical trials; however, involving NIR-II dyes seems to outperform those benefits due to the deeper tissue imaging and higher signal/noise ratio attained within the NIR-II optical window. In this context, we developed NIR-II emitting dyes targeting human epidermal growth factor receptor 2 (HER2)-positive ovarian tumors by coupling water-soluble NIR-II aza-BODIPY dyes to the FDA-approved anti-HER2 antibody, namely, trastuzumab. These bioconjugated NIR-II-emitting dyes displayed a prolonged stability in serum and a maintained affinity toward HER2 in vitro. We obtained selective targeting of HER2 positive tumors (SKOV-3) in vivo, with a favorable tumor accumulation. We demonstrated the fluorescence properties and the specific HER2 binding of the bioconjugated dyes in vivo and thus their potential for NIR-II FGS in the cancer setting.

Al(III) and Ga(III) Bisphenolate Azadipyrromethene-Based "N2O2" Complexes as Efficient NIR-Fluorophores.

Aza-boron-dipyrromethenes (Aza-BODIPYs) are an increasingly studied class of fluorophores. They can be seen as an azadipyrromethene ("aza-DIPY") ligand rigidified by a metalloid, a boron atom. Based on this idea, a series of complexes of group 13 metals (aluminum and gallium) have been synthesized and characterized. The impact of the metal and of the nature of the substituents of aza-DIPY core were investigated. The photophysical and electrochemical properties were determined, and an X-ray structure of an azaGaDIPY was obtained. These data reveal that azaGaDIPY and azaAlDIPY exhibit significant red-shifted fluorescence compared to their analogue aza-BODIPY. Their emission can go up to 800 nm for the maximum emission length and up to NIR-II for the emission tail. This, associated with their electrochemical stability (no metal release whether oxidized or reduced) makes them a promising class of fluorophores for optical medical imaging. Moreover, X-ray structure and molecular modeling studies have shown that this redshift seems to be more due to the geometry around the boron/metal than to the nature of the metal.

Lipoprotein interactions with water-soluble NIR-II emitting aza-BODIPYs boost the fluorescence signal and favor selective tumor targeting.

Following intravenous administration, the interaction of fluorescent exogenous molecules with circulating endogenous transporters can influence their photophysical properties as well as their fate and distribution, and possibly their recognition by different cell types. This type of interaction can be used to optimize the drug delivery but also the imaging properties of a compound of interest. In this study, we investigated the behavior of SWIR-WAZABY-01 fluorophore, a water-soluble aza-BODIPY dye emitting in the NIR-II region, both in vitro and in vivo. While the fluorescence emission of SWIR-WAZABY-01 was weak in aqueous solutions, it was intensely magnified in plasma (∼ ×30). Further analyses using lipoprotein gel electrophoresis and ultracentrifugation revealed interactions between SWIR-WAZABY-01 and plasma lipoproteins in vitro and ex vivo, in particular with LDL. The tumor uptake mechanism of SWIR-WAZABY-01 was investigated based on the presence of low-density lipoprotein (LDL) receptors and passive tumor uptake. Overall, we found that SWIR-WAZABY-01 interacts with lipoproteins enhancing their NIR-II fluorescence emission, and driving the tumor accumulation with regards to the expression of lipoprotein receptors (LDLR, SR-BI). Moreover, SWIR-WAZABY-01, by exploiting endogenous lipoproteins, arises as a new, potent and relevant tool to efficiently label LDL involved in pathologies.