A tumor-targetable NIR probe with photoaffinity crosslinking characteristics for enhanced imaging-guided cancer phototherapy.

Spatiotemporally manipulating the in situ immobilization of theranostic agents within cancer cells to improve their bioavailability is highly significant yet challenging in tumor diagnosis and treatment. Herein, as a proof-of concept, we for the first time report a tumor-targetable near-infrared (NIR) probe DACF with photoaffinity crosslinking characteristics for enhanced tumor imaging and therapeutic applications. This probe possesses great tumor-targeting capability, intensive NIR/photoacoustic (PA) signals, and a predominant photothermal effect, allowing for sensitive imaging and effective photothermal therapy (PTT) of tumors. Most notably, upon 405 nm laser illumination, DACF could be covalently immobilized within tumor cells through a photocrosslinking reaction between photolabile diazirine groups and surrounding biomolecules resulting in enhanced tumor accumulation and prolonged retention simultaneously, which significantly facilitates the imaging and PTT efficacy of tumor in vivo. We therefore believe that our current approach would provide a new insight for achieving precise cancer theranostics.

Protein sulfenic acid-mediated anchoring of gold nanoparticles for enhanced CT imaging and radiotherapy of tumors in vivo.

Radiotherapy (RT) has become one of the most widely used treatments for malignant tumors in clinics. Developing a novel radiosensitizer for the integration of precise diagnosis and effective radiotherapy against hypoxic tumors is desirable but remains a great challenge. Herein, protein sulfenic acid reactive gold nanoparticles as effective radiosensitizers were for the first time reported for enhanced X-ray computed tomography (CT) imaging and radiotherapy of tumors in vivo. The gold nanoparticles were decorated with biocompatible poly(ethylene glycol), folic acid (FA), and sulfenic acid reactive groups 1,3-cyclohexanedione (CHD). Such a nanostructure enables on-site immobilization within tumors under oxidative stress through the specific reaction between CHD and endogenous protein sulfenic acids resulting in enhanced accumulation and retention of gold nanoparticles within tumors, which remarkably improves the sensitivity of CT imaging and the radiotherapeutic efficacy of tumors in living mice. This study thus is the first to demonstrate that protein sulfenic acid reactive gold nanoparticles with a tumor anchoring function may serve as effective radiosensitizers for clinical X-ray theranostic application in the future.

Sulfenic Acid-Mediated on-Site-Specific Immobilization of Mitochondrial-Targeted NIR Fluorescent Probe for Prolonged Tumor Imaging.

Mitochondria plays pivotal roles in energy production and apoptotic pathways. Mitochondria-targeting strategy has been recognized as a promising way for cancer theranostics. Thus, spatiotemporally manipulating the prolonged retention of theranostic agents within mitochondria is considerably significant in cancer diagnosis and therapy. Herein, as a proof-of concept, we for the first time report a sulfenic acid-responsive platform on controlled immobilization of probes within mitochondria for prolonged tumor imaging. A novel near-infrared (NIR) probe DATC constructed with a NIR dye (Cy5) as signal unit, a cationic triphenylphosphonium (TPP) for mitochondria targeting, and a sulfenic acid-reactive group (1,3-cyclohexanedione) for mitochondrial fixation was rationally designed and synthesized. This probe displayed good target ability to mitochondria and could act as a promising fluorescent probe for specific visualization of endogenous protein sulfenic acids expressed in the mitochondria. Moreover, the probe could be spontaneously fixed on site through the specific reaction and covalent binding to the sulfenic acids of oxidized proteins under oxidative stress, resulting in enhanced intracellular uptake and prolonged retention. We thus believe that this mitochondria-targeted and locational immobilization strategy may offer a new insight for long-term tumor imaging and effective therapy.

A novel αvß3 integrin-targeted NIR-II nanoprobe for multimodal imaging-guided photothermal therapy of tumors in vivo.

Developing novel small-molecule-based probes with both deep tissue imaging and therapeutic functions is highly significant in cancer diagnosis and treatment. Herein, we report a novel second near-infrared (NIR-II) fluorescent probe QT-RGD constructed with a NIR-II emissive organic fluorophore and two cyclic-(arginine-glycine-aspartic acid) (cRGD) peptides that can specifically bind to the tumor-associated αvß3 integrin for accurate tumor diagnosis and targeting therapy. The isotopic 125I-labeled probe exhibited great tumor targeting ability and emitted intensive NIR-II/photoacoustic (PA)/single-photon emission computed tomography (SPECT) signals, which allows specific and sensitive multimodal visualization of tumors in vivo. More notably, this probe could also be applied for effective imaging-guided photothermal therapy (PTT) of tumors in mouse models owing to its prominent photothermal conversion efficiency and excellent photothermal stability. We thus envision that our work which unveils a combination of NIR-II/PA/SPECT imaging and PTT would offer a valuable means of improving tumor diagnostic accuracy as well as therapeutic efficacy.

A light-up near-infrared probe with aggregation-induced emission characteristics for highly sensitive detection of alkaline phosphatase.

Developing activatable near-infrared (NIR) probes to specifically monitor and visualize the activities of cancer-related enzymes is highly significant yet challenging in early cancer diagnosis. Taking advantage of the unique photophysical characteristics of aggregation-induced emission (AIE) fluorophores, here we design and synthesize a novel activatable probe QMTP by conjugating an AIE fluorophore quinolone-malononitrile to a hydrophilic phosphate-modified phenol group. The probe was initially non-fluorescent in aqueous solution due to its good water solubility, but was readily activated to generate a strong NIR fluorescence upon treatment with alkaline phosphatase (ALP), which enables specific detection of ALP activity. Furthermore, we have employed QMTP to monitor and spatially map the activity of endogenous ALP both in cancer cells and in drug-treated zebrafish larvae. The experimental results reveal that the QMTP probe has great specificity and sensitivity for ALP detection. We thus believe that our work offers a promising tool for accurate detection of ALP-associated diseases in preclinical applications.

Rational Design and Synthesis of a Metalloproteinase-Activatable Probe for Dual-Modality Imaging of Metastatic Lymph Nodes in Vivo.

Lymphatic metastasis is an important prognostic indicator for cancer progression. It is therefore considerably meaningful to develop molecularly targeted imaging probes for noninvasive and accurate identification of metastatic lymph nodes (MLNs) at early stages of tumor metastasis. Herein, we report a novel matrix metalloproteinase-2 (MMP-2)-activatable probe constructed with a near-infrared dye (Cy5), a quencher (QSY21), and a tumor-targeting peptide cRGD covalently linked through a radionuclide (125I)-labeled peptide substrate for accurate detection of MLNs. Upon cleavage with activated MMP-2, the above probe emitted MMP-2 concentration-dependent near-infrared fluorescence, which allows sensitive and specific visualization of MLNs via both optical and single-photon emission computed tomography imaging techniques. We thus envision that this probe would serve as a useful tool for studying tumor-induced lymphangiogenesis.

Light-Triggered Covalent Coupling of Gold Nanoparticles for Photothermal Cancer Therapy.

Manipulating the cross-coupling of gold nanoparticles (AuNPs) to maximize the photothermal effect is a promising strategy for cancer therapy. Here, by taking advantage of the well-known tetrazole/alkene photoclick chemistry, we have demonstrated for the first time that small AuNPs (23 nm) decorated with both 2,5-diphenyltetrazole and methacrylic acid on their surfaces can form covalently crosslinked aggregates upon laser irradiation (λ=405 nm). In vitro studies indicated that the light-triggered assembling shifted the surface plasmon resonance of AuNPs significantly to near-infrared (NIR) regions, which as a consequence effectively enhanced the efficacy of photothermal therapy for 4T1 breast cancer cells. We thus believe that this new light-triggered cross-coupling approach might offer a valuable tool for cancer treatment.