Acceptor Engineering Produces Ultrafast Nonradiative Decay in NIR-II Aza-BODIPY Nanoparticles for Efficient Osteosarcoma Photothermal Therapy via Concurrent Apoptosis and Pyroptosis.

Small-molecule photothermal agents (PTAs) with intense second near-infrared (NIR-II, 1,000 to 1,700 nm) absorption and high photothermal conversion efficiencies (PCEs) are promising candidates for treating deep-seated tumors such as osteosarcoma. To date, the development of small-molecule NIR-II PTAs has largely relied on fabricating donor-acceptor-donor (D-A-D/D') structures and limited success has been achieved. Herein, through acceptor engineering, a donor-acceptor-acceptor (D-A-A')-structured NIR-II aza-boron-dipyrromethene (aza-BODIPY) PTA (SW8) was readily developed for the 1,064-nm laser-mediated phototheranostic treatment of osteosarcoma. Changing the donor groups to acceptor groups produced remarkable red-shifts of absorption maximums from first near-infrared (NIR-I) regions (~808 nm) to NIR-II ones (~1,064 nm) for aza-BODIPYs (SW1 to SW8). Furthermore, SW8 self-assembled into nanoparticles (SW8@NPs) with intense NIR-II absorption and an ultrahigh PCE (75%, 1,064 nm). This ultrahigh PCE primarily originated from an additional nonradiative decay pathway, which showed a 100-fold enhanced decay rate compared to that shown by conventional pathways such as internal conversion and vibrational relaxation. Eventually, SW8@NPs performed highly efficient 1,064-nm laser-mediated NIR-II photothermal therapy of osteosarcoma via concurrent apoptosis and pyroptosis. This work not only illustrates a remote approach for treating deep-seated tumors with high spatiotemporal control but also provides a new strategy for building high-performance small-molecule NIR-II PTAs.

A Gas/phototheranostic Nanocomposite Integrates NIR-II-Peak Absorbing Aza-BODIPY with Thermal-Sensitive Nitric Oxide Donor for Atraumatic Osteosarcoma Therapy.

Photothermal therapy (PTT) has received increasing interest in cancer therapeutics owing to its excellent efficacy and controllability. However, there are two major limitations in PTT applications, which are the tissue penetration depth of lasers within the absorption range of photothermal agents and the unavoidable tissue empyrosis induced by high-energy lasers. Herein, a gas/phototheranostic nanocomposite (NA1020-NO@PLX) is engineered that integrates the second near-infrared-peak (NIR-II-peak) absorbing aza-boron-dipyrromethenes (aza-BODIPY,NA1020) with the thermal-sensitive nitric oxide (NO) donor (S-nitroso-N-acetylpenicillamine, SNAP). An enhanced intramolecular charge transfer mechanism is proposed to achieve the NIR-II-peak absorbance (λmax = 1020 nm) on NA1020, thereby obtaining its deep tissue penetration depth. The NA1020 exhibits a remarkable photothermal conversion, making it feasible for the deep-tissue orthotopic osteosarcoma therapy and providing favorable NIR-II emission to precisely pinpoint the tumor for a visible PTT process. The simultaneously investigated atraumatic therapeutic process with an enhanced cell apoptosis mechanism indicates the feasibility of the synergistic NO/low-temperature PTT for osteosarcoma. Herein, this gas/phototheranostic strategy optimizes the existing PTT to present a repeatable and atraumatic photothermal therapeutic process for deep-tissue tumors, validating its potential clinical applications.

Bioapplications of small molecule Aza-BODIPY: from rational structural design to in vivo investigations.

Boron-dipyrromethene (BODIPY) belongs to a family of organoboron compounds, commercialized as fluorescent dyes by Invitrogen™. As BODIPY derivatives, Aza-boron-dipyrromethene (Aza-BODIPY) dyes display superior spectral performances, such as red-shifted spectra and high molar extinction coefficients, and are considered to be extremely attractive organic materials for various bioapplications. Therefore, scientists from different disciplinary backgrounds would benefit from a review that provides a timely summary and outlook regarding Aza-BODIPY dyes. In this review, we report on the latest advances of Aza-BODIPY dyes, along with the empirical design guidelines and photophysical property manipulation of these dyes. In addition, we will discuss the biological applications of Aza-BODIPY dyes in probing various biological activities, as well as in fluorescence bioimaging/detection, newly-emerging photoacoustic bioimaging/detection, and phototherapy together with future challenges and implications in this field. We aim at providing an insightful design guideline and a clear overview of Aza-BODIPY dyes, which might entice new ideas and directions.

Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity.

Protein disulfide isomerase (PDI), a chaperone protein mostly in endoplasmic reticulum, catalyzes disulfide bond breakage, formation, and rearrangement to promote protein folding. PDI is regarded as a new target for treatment of several disorders. Here, based on the combination principle, we report a new PDI reversible modulator 16F16A-NO by replacing the reactive group in a known PDI inhibitor 16F16 with nitric oxide (NO) donor. Using molecular docking experiment, 16F16A-NO could embed into the active cavity of PDI. From newly developed fluorescent assay, 16F16A-NO showed rapid NO release. Furthermore, it is capable to moderately inhibit activity of PDI and S-nitrosylate the protein, indicating by insulin aggregation assay and biotin-switch technique. Finally, it displayed a dose-dependent antiproliferative activity against SH-SY5Y and HeLa tumor cells. Our designed hybrid compound 16F16A-NO showed a reasonable activity and might offer a promising avenue to develop novel PDI inhibitors for disease treatments.

Structure-Based Specific Detection and Inhibition of Monoamine Oxidases and Their Applications in Central Nervous System Diseases.

Monoamine oxidases (MAOs) are the enzymes that catalyze the oxidation of monoamines, such as dopamine, norepinephrine, and serotonin, which serve as key neurotransmitters in the central nervous system (CNS). MAOs play important roles in maintaining the homeostasis of monoamines, and the aberrant expression or activation of MAOs underlies the pathogenesis of monoamine neurotransmitter disorders, including neuropsychiatric and neurodegenerative diseases. Clearly, detecting and inhibiting the activities of MAOs is of great value for the diagnosis and therapeutics of these diseases. Accordingly, many specific detection probes and inhibitors have been developed and substantially contributed to basic and clinical studies of these diseases. In this review, progress in the detecting and inhibiting of MAOs and their applications in mechanism exploration and treatment of neurotransmitter-related disorders is summarized. Notably, how the detection probes and inhibitors of MAOs were developed has been specifically addressed. It is hoped that this review will benefit the design of more effective and sensitive probes and inhibitors for MAOs, and eventually the treatment of monoamine neurotransmitter disorders.