Smart Aza-BODIPY Photosensitizer for Tumor Microenvironment-Enhanced Cancer Phototherapy

Abstract

Photoactivated cancer therapeutic methods emerging in recent decades, such as photothermal therapy (PTT) and photodynamic therapy (PDT), have drawn worldwide research interest. Herein, a smart near-infrared (NIR) photosensitizer 4-(4-(7-(4-Bromophenyl)-1,9-bis­(3,4-di­methoxy­phenyl)-5,5-di­fluoro-5H-5l4,6l4-di­pyrrolo­[1,2-c:2′,1′-f]­[1,3,5,2]­triaza­borinin-3-yl)­phenyl)­morpholine (MAB) with morpholine decorating on the aza-BODIPY core is synthesized to achieve dual-modal imaging-guided synergistic PDT/PTT, exhibiting a tumor microenvironment (TME) enhanced cancer theranostic performance. The introduction of electron-donating morpholine offers MAB-enhanced intramolecular charge transfer (ICT) and a pronounced red-shift with maximum absorption peak (λmax) at 730 nm. After encapsulating with amphiphilic polymer DSPE-mPEG2000, as-obtained MAB nanoparticles (NPs) with good biocompatibility can enrich targeting in the lysosomes of tumor cells and afterward be activated under the acidic microenvironment inside the lysosome (pH 5.0) to generate intracellular reactive oxygen species (ROS) for enhanced PDT through interruption of photoinduced electron transfer (PET). Through in vitro cytotoxicity assay studies, the half-maximal inhibitory concentration (IC50) of MAB NPs under irradiation with the 730 nm laser is ∼10 μg/mL, indicating an excellent phototherapy effect. Furthermore, an in vivo study illustrates a prominent PDT/PTT synergistic therapeutic effect, and MAB NPs can be rapidly metabolized.

Aza-BODIPY-Based Nanomedicines in Cancer Phototheranostics

“…In fact, phototherapeutic agents based on aza-BODIPY 1 – 8 all exhibited a photothermal effect in different degrees, which promoted better treatment outcomes of phototherapy along with photodynamic therapy. For example, based on aza-BODIPY 7 , we obtained a phototheranostic nanoagent with pHe-enhanced phototheranostic performance (Figure a,b) . In addition to singlet oxygen, this nanoagent can also produce hyperthermia efficiently upon NIR irradiation (Figure c,d).…”

“…For example, based on aza-BODIPY 7, we obtained a phototheranostic nanoagent with pHe-enhanced phototheranostic performance (Figure 7a,b). 42 In addition to singlet oxygen, this nanoagent can also produce hyperthermia efficiently upon NIR irradiation (Figure 7c,d). In particular, the photothermal effect was enhanced more at pH 5.0 than at pH 7.4, due to the protonation of the morpholine unit.…”

“…Based on the above synthetic route, we have successfully synthesized a family of aza-BODIPY photosensitizers with diverse functionalities, and the molecular structures of these photosensitizers are listed in Figure b. − Notably, due to the π-conjugation of aromatic rings on the aza-dipyrromethene core, most of these aza-BODIPY photosensitizers exhibit absorption and fluorescence wavelength in the NIR region. With the attachment of heavy atoms (Br, I) or other functional groups, aza-BODIPYs possess various desired functionalities.…”

“…(f) In vivo photothermal images of HeLa tumor-bearing mice after different time of irradiation. Adapted with permission from ref . Copyright 2019 American Chemical Society.…”

Balanced Intersystem Crossing in Iodinated Silicon-Fluoresceins Allows New Class of Red Shifted Theranostic Agents

“…Photodynamic therapy (PDT), which involves the generation of cytotoxic reactive oxygen species (ROS) through interaction of a photosensitizer (PS), light, and molecular oxygen ( 3 O 2 ), is a developing treatment methodology for a wide variety of cancer types. , PDT has remarkable advantages over conventional therapies such as activation of the immune system, minimal invasiveness, opportunities for repeated application without initiating drug resistance, and a fast healing process with little or no scar formation. − Additionally, the technique offers localized treatment as singlet oxygen ( 1 O 2 ) has a short lifetime in aqueous medium and the excitation light can be precisely delivered to the tumor region, leaving most of the healthy cells unaffected. ,, However, there is a major obstacle that PDT agents have to overcome to receive widespread acceptance in clinical studies, which is the limited penetration depth of irradiation light through tissues. , It is a known fact that red/near-IR excitation light has the ability to penetrate more deeply into the target tissue while being less harmful to cells. − This basically extends the scope of PDT by enabling the treatment of deep tumors. In this direction, a large amount of effort has been devoted to design red-shifted PSs. − Nevertheless, most of the current examples are either based on the first-generation hydrophobic PSs, which require significant synthetic efforts to implement water solubility, or some other hydrophilic PSs having dark toxicity and photostability issues. ,, …”