Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy.

Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment. However, there are limitations, including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision, associated with gas therapy. In this study, we developed a series of photoactivatable nitric oxide (NO) donors NRh-R-NO (R = Me, Et, Bn, iPr, and Ph) based on an N-nitrosated upconversion luminescent rhodamine scaffold. Under the irradiation of 808 nm light, only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence (FUCL) signal at 740 nm, ascribed to lower N-N bond dissociation energy. We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy, including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation, the superoxide anion O2⋅- produced by the photodynamic therapy (PDT) effect of NRh-Ph, and highly toxic peroxynitrite anion (ONOO‒) generated from the co-existence of NO and O2⋅-. After mild nano-modification, the nanogenerator (NRh-Ph-NO NPs) empowered with superior biocompatibility could target mitochondria. Under an 808 nm laser irradiation, NRh-Ph-NO NPs could induce NO/ROS to generate RNS, causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation, which further induced tumor immunogenic cell death (ICD). In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy, demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging. Collectively, this versatile strategy defines the targeted RNS-mediated cancer therapy.

Rational design of pH-activated upconversion luminescent nanoprobes for bioimaging of tumor acidic microenvironment and the enhancement of photothermal therapy.

The development of effective and safe tumor photothermal therapeutic strategies has attracted considerable attention. Herein, we synthesized tumor microenvironment (TME)-activatable self-assembling organic nanotheranostics (NRhD-PEG-X NPs (X = 1, 2, 3, and 4)) for precise tumor targeting and upconversion image-guided photothermal therapy (PTT). The amphiphilic polymer NRhD-PEG-X consisted of upconversion luminescent probes (NRhD) modified with polyethylene glycol (PEG) of various lengths. The continuous external irradiation-free photothermal NRhD-PEG-4 NPs with pKa 6.70 displayed high sensitivity and selectivity to protons, resulting in the turn-on upconversion luminescence and enhanced photothermal properties in the acidic TME without asynchronous therapy and side effects. This nanotheranostic offers acidic activatability, tumor targetability, and PTT enhancement, thus allowing autofluorescence-free upconversion luminescent imaging-guided precision PTT. Our strategy affords a paradigm to develop activatable theranostic nanoplatforms for precision medicine. STATEMENT OF SIGNIFICANCE: As a hyperthermia-based treatment, activatable photothermal therapy (PTT) is highly significant in tumor treatment. Herein, we develop acidic tumor microenvironment-activatable nanotheranostics for upconversion luminescent imaging-guided diagnosis and precision tumor-targeted PTT. PEGylation of upconversion dyes not only could self-assemble to yield organic nanoparticles in water, but it could also significantly improve biocompatibility, stability, and circulation time and tune significantly the pKa value of nanoparticles. In an acidic tumor microenvironment, NRhD-PEG-4 NPs with pKa 6.70 show high sensitivity to release NRhDH+-PEG-4 NPs, which exhibit good upconversion luminescence and enhanced photothermal effect. Therefore, upconversion luminescence imaging-guided precision PTT has high potential to enhance cancer diagnostic and therapeutic efficiency.

Hot-band absorption assisted single-photon frequency upconversion luminescent nanophotosensitizer for 808 nm light triggered photodynamic immunotherapy of cancer.

Frequency upconversion luminescence (FUCL) based on hot-band absorption has attracted considerable attention in bioimaging and phototherapy fields for deep-seated cancer treatment. Photoimmunotherapy, a promising therapeutic approach induced by photodynamic therapy (PDT), can selectively kill cancer cells, reverse the immunosuppressive system, boost host immune response, and elicit durable antitumor immunity. To date, few near-infrared organic photosensitizers for photodynamic immunotherapy have been reported based on hot-band absorption. Herein, we report an upconversion luminescent phthalocyanine photosensitizer PdPc(OBu)8 with anti-Stokes emission at 748 nm and highly efficient singlet oxygen generation with hot-band absorption at 808 nm. Taking advantage of nanoliposomes, FUCL phthalocyanine nano-photosensitizers (PdPc NPs) were obtained to reduce the aggregation-caused quenching and improve water solubility and biocompatibility. PdPc NPs could be effectively accumulated in tumor tissues through intravenous administration, causing FUCL-induced PDT under 808 nm irradiation. Considering its finite immune responses and tumor ablation after PDT, a combination of PdPc NP-based PDT with checkpoint inhibitors (anti-PD-L1) for near-infrared photoimmunotherapy has been used to potentiate the antitumor efficacy that could simultaneously ablate primary tumors and inhibit the progression of distant tumors. This study can promote the development of upconversion-based PDT combined with immunotherapy for tumor precision therapy.

Albumin-based near-infrared phototheranostics for frequency upconversion luminescence/photoacoustic dual-modal imaging-guided photothermal therapy.

Engineering versatile phototheranostics for multimodal diagnostic imaging and effective therapy has great potential in cancer treatment. However, developing an inherently versatile molecule is a huge challenge. In this work, a near-infrared organic dye (NRh) was synthesized and further bound with bovine serum albumin (BSA) to construct facile "one-for-all" phototheranostics (NRh-BSA NPs), which exhibited enhanced frequency upconversion luminescence (FUCL, λex/em = 850/825 nm) and excellent photoacoustic (PA) and photothermal properties (λ'ex = 808 nm). Additionally, the BSA-modified phototheranostics NRh-BSA NPs showed specific accumulation in the tumor region through passive targeting. Based on the FUCL/PA dual modal imaging-guidance, the NRh-BSA NPs not only can guarantee the accuracy of imaging of the U87MG tumor sites, but also can improve the therapeutic effect on ablating tumors without recurrence by photothermal therapy (PTT). Collectively, our work proposed a novel strategy to construct versatile phototheranostics with the unique FUCL/PA imaging-guided technique for accurate cancer theranostics.

Mitochondria targeted near-infrared chemodosimeter for upconversion luminescence bioimaging of hypoxia.

We report a mitochondria-targeted near-infrared probe (NRh-O) for frequency upconversion luminescence (FUCL) imaging of hypoxia. Under hypoxic conditions, NRh-O rapidly responds to release the FUCL product NRh (λex/em = 850/825 nm) with high sensitivity and selectivity in mitochondria. This highlights the potential application of a hypoxia-responsive probe in early clinical diagnosis.

Azo-Based Hypoxia-Responsive Self-Assembly Near-Infrared Fluorescent Nanoprobe for In Vivo Real-Time Bioimaging of Tumors.

Hypoxia is an obvious characteristic of cancer, especially solid tumors. which may give rise to the expansion of invasion and metastasis. Exploring near-infrared (NIR) nanoprobes that could accurately evaluate the degree of hypoxia will contribute to the assessment of the degree of malignant neoplasms, so as to adopt more accurate and individualized treatment options Here, we have developed a self-assembled NIR organic nanoprobe to specifically and authoritatively detect the oxygen concentration in vivo and in vitro to evaluate the level of hypoxia. The organic nanoprobe mainly contains two motifs: a fluorophore moiety NRh-NH2 for NIR fluorescence imaging and hypoxia-sensitive moiety Azonaphthalene derivatives for quenching NIR emissions, detecting oxygen in hypoxic regions and improving the hydrophilicity. The nanoprobes were used for detection of oxygen in a variety of living cells under different conditions and real-time bioimaging of neoplasms in live mice. This design strategy provides ideas for the development of nanoprobes for the diagnosis of tumors and other hypoxia-related diseases.

Near-infrared fluorescent chemodosimeter for real-time in vivo evaluation of H2S-release efficiency of prodrug.

Hydrogen sulfide (H2S) is a significant gasotransmitter. A deficiency in H2S might contribute to some serious diseases. The development of H2S drugs has received a great deal of attention. There is a pressing need for an effective method to evaluate H2S release efficiency, especially in in vivo evaluation. In this study, a highly sensitive and selective near-infrared (NIR) fluorescent chemodosimeter (NRh-N3) was synthesized for detecting H2S. Importantly, NRh-N3 was shown to be capable of visually monitoring H2S-release from the prodrug in vitro and in vivo.