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Fine-tuning the electronic structure of heavy-atom-free BODIPY photosensitizers for fluorescence imaging and mitochondria-targeted photodynamic therapy.

ABSTRACT: Theranostics that combines both diagnosis and therapy into a single platform has recently emerged as a promising biomedical approach for cancer treatment; however, the development of efficient theranostic agents with excellent optical properties remains a challenge. Here, we report novel mitochondria-targeting BODIPY photosensitizers (R-BODs) that possess considerable singlet oxygen generation capabilities and good fluorescence properties for imaging-guided photodynamic therapy (PDT). The incorporation of sulfur atoms into the π-conjugated skeleton of BODIPY along with the introduction of different functional groups at the meso-position of the BODIPY core is essential for tuning the photophysical and photosensitizing properties. Notably, the MeOPh-substituted thiophene-fused BODIPY (MeO-BOD, R = p-methoxyphenyl) displayed the highest singlet oxygen generation capability (Φ _Δ ≈ 0.85 in air-saturated acetonitrile) and a moderate fluorescence quantum yield (Φ _f = 17.11). Furthermore, MeO-BOD showed good biocompatibility, low dark toxicity and superior fluorescence imaging properties in living cells. More importantly, the PDT efficacy of mitochondria-specific anchoring of MeO-BOD was remarkably amplified with an extremely low half-maximal inhibitory concentration (IC₅₀) value of 95 nM. We believe that the incorporation of an electron-donating group at the meso-position of the thiophene-fused BODIPY platform may be an effective approach for developing theranostic agents for precision cancer therapy.

SUBMITTER: Qi S

PROVIDER: S-EPMC8152625 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heavy-atom-free sensitizers forming long-living triplet excited states via the spin-orbit charge transfer intersystem crossing (SOCT-ISC) process have recently attracted attention due to their potential to replace costly transition metal complexes in photonic applications. The efficiency of SOCT-ISC in BODIPY donor-acceptor dyads, so far the most thoroughly investigated class of such sensitizers, can be finely tuned by structural modification. However, predicting the triplet state yields and reactive oxygen species (ROS) generation quantum yields for such compounds in a particular solvent is still very challenging due to a lack of established quantitative structure-property relationship (QSPR) models. In this work, the available data on singlet oxygen generation quantum yields (ΦΔ ) for a dataset containing >70 heavy-atom-free BODIPY in three different solvents (toluene, acetonitrile, and tetrahydrofuran) were analyzed. In order to build reliable QSPR model, a series of new BODIPYs were synthesized that bear different electron donating aryl groups in the meso position, their optical and structural properties were studied along with the solvent dependence of singlet oxygen generation, which confirmed the formation of triplet states via the SOCT-ISC mechanism. For the combined dataset of BODIPY structures, a total of more than 5000 quantum-chemical descriptors was calculated including quantum-chemical descriptors using density functional theory (DFT), namely M06-2X functional. QSPR models predicting ΦΔ values were developed using multiple linear regression (MLR), which perform significantly better than other machine learning methods and show sufficient statistical parameters (R=0.88-0.91 and q2 =0.62-0.69) for all three solvents. A small root mean squared error of 8.2 % was obtained for ΦΔ values predicted using MLR model in toluene. As a result, we proved that QSPR and machine learning techniques can be useful for predicting ΦΔ values in different media and virtual screening of new heavy-atom-free BODIPYs with improved photosensitizing ability.

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Fine-tuning the electronic structure of heavy-atom-free BODIPY photosensitizers for fluorescence imaging and mitochondria-targeted photodynamic therapy.

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