Emerging Design Principle of Near-Infrared Upconversion Sensitizer Based on Mitochondria-Targeted Organic Dye for Enhanced Photodynamic Therapy.

Upconversion luminescent (UCL) triggered photodynamic therapy (PDT) affords superior outcome for cancer treatment. However, conventional UCL materials which all work by a multiphoton absorption (MPA) process inevitably need extremely high power density far over the maximum permissible exposure (MPE) to laser. Here, a one-photon absorption molecular upconversion sensitizer Cy5.5-Br based on frequency upconversion luminescent (FUCL) is designed for PDT. The unusual super heavy atom effect (SHAE) in Cy5.5-Br strongly enhances its spin-orbit coupling (0.23 cm-1 ), triplet quantum yield (11.1 %) and triplet state lifetime (18.8 µs) while the potential hot-band absorption of Cy5.5-Br is well maintained. Importantly, Cy5.5-Br can efficiently target the tumour site and kill cancer cells by destroying mitochondria under a biosafety MPE to 808 nm laser. The photostability and antitumor results are obviously superior to that of a Stokes process. This work provides a design criterion for FUCL dyes to realize effective PDT upon a biosafety optical density, possibly bringing more clinical benefits than conventional MPA materials.

Superoxide Radical Photogenerator with Amplification Effect: Surmounting the Achilles' Heels of Photodynamic Oncotherapy.

Strong oxygen dependence, poor tumor targeting, and limited treatment depth have been considered as the "Achilles' heels" facing the clinical usage of photodynamic therapy (PDT). Different from common approaches, here, we propose an innovative tactic by using photon-initiated dyad cationic superoxide radical (O2-•) generator (ENBOS) featuring "0 + 1 > 1" amplification effect to simultaneously overcome these drawbacks. In particular, by taking advantage of the Förster resonance energy transfer theory, the energy donor successfully endows ENBOS with significantly enhanced NIR absorbance and photon utility, which in turn lead to ENBOS more easily activated and generating more O2-• in deep tissues, that thus dramatically intensifies the type I PDT against hypoxic deep tumors. Moreover, benefiting from the dyad cationic feature, ENBOS achieves superior "structure-inherent targeting" abilities with the signal-to-background ratio as high as 25.2 at 48 h post intravenous injection, offering opportunities for accurate imaging-guided tumor treatment. Meanwhile, the intratumoral accumulation and retention performance are also markedly improved (>120 h). On the basis of these unique merits, ENBOS selectively inhibits the deep-seated hypoxic tumor proliferation at a low light-dose irradiation. Therefore, this delicate design may open new horizons and cause a paradigm change for PDT in future cancer therapy.

Near-Infrared Light-Initiated Molecular Superoxide Radical Generator: Rejuvenating Photodynamic Therapy against Hypoxic Tumors.

Hypoxia, a quite universal feature in most solid tumors, has been considered as the "Achilles' heel" of traditional photodynamic therapy (PDT) and substantially impairs the overall therapeutic efficacy. Herein, we develop a near-infrared (NIR) light-triggered molecular superoxide radical (O2-•) generator (ENBS-B) to surmount this intractable issue, also reveal its detailed O2-• action mechanism underlying the antihypoxia effects, and confirm its application for in vivo targeted hypoxic solid tumor ablation. Photomediated radical generation mechanism study shows that, even under severe hypoxic environment (2% O2), ENBS-B can generate considerable O2-• through type I photoreactions, and partial O2-• is transformed to high toxic OH· through SOD-mediated cascade reactions. These radicals synergistically damage the intracellular lysosomes, which subsequently trigger cancer cell apoptosis, presenting a robust hypoxic PDT potency. In vitro coculture model shows that, benefiting from biotin ligand, ENBS-B achieves 87-fold higher cellular uptake in cancer cells than normal cells, offering opportunities for personalized medicine. Following intravenous administration, ENBS-B is able to specifically target to neoplastic tissues and completely suppresses the tumor growth at a low light-dose irradiation. As such, we postulated this work will extend the options of excellent agents for clinical cancer therapy.

An intracellularly activatable, fluorogenic probe for cancer imaging.

A newly designed, dual-functional probe based on intracellular activation has been successfully developed for the detection of cancer cells. The probe is nearly non-fluorescent in buffer due to its highly efficient FRET quenching, but it can be specifically activated with dramatic fluorescence enhancement upon intracellular cathepsin B cleavage in target cancer cells after selective internalization via folate receptor-dependent endocytosis. Therefore, this probe enables "turn-on" visualization of cancer cells with desirable specificity and contrast enhancement. This targeted, intracellularly activatable probe exhibits low fluorescence-quenched background when compared with "always-on" probes and avoids non-specific activation by non-specifically expressed enzymes in normal tissue, which normally occurs when using common "turn on" probe design strategies. Therefore, this probe can be potentially applied in intraoperative inspection during clinical cancer surgery with higher contrast and sensitivity.

Smart J-aggregate of cyanine photosensitizer with the ability to target tumor and enhance photodynamic therapy efficacy.

Photodynamic therapy (PDT) has been demonstrated to be effective for cancer treatment. Design of photosensitizers (PS) featuring tumor targeting, long excitation wavelengths, and high singlet oxygen quantum yields (Φ(1O2)) is the crucial point of highly efficient PDT. However, it is especially difficult to integrate above features into one photosensitizer. Herein, we put forwards a PS J-aggregation method, simultaneously endowing PS with the ability of tumor targeting, the red-shift of spectra, and the increase of Φ(1O2). Cyanine PS 4-((E)-3-((E)-5-iodo-1,3,3-trimethylindolin-2-ylidene)prop-1-en-1-yl)-1-methylquinolin-1-ium iodide (IDMQ) is firstly designed and synthesized by us. IDMQ can form smart response-type J-aggregates under the control of negatively charge in microenvironments. In blood, IDMQ J-aggregates target tumor via "enhanced permeability and retention (EPR)" effect. Then the intracellular IDMQ J-aggregates assembled by RNA facilitate the red shift of absorption peak with deeper penetration, and compared to free state IDMQ, improve the Φ(1O2), resulting in the bathochromic shift of optimal PDT wavelength from 630 (free state IDMQ) to 700 nm (IDMQ J-aggregates). This intelligent J-aggregation method establishes a promising way for endowing photosensitizer with the ability of tumor-targeting and the synchronous improvement of PDT efficacy and further boosts the development of PDT.

TXNDC5 protects synovial fibroblasts of rheumatoid arthritis from the detrimental effects of endoplasmic reticulum stress.

TXNDC5 is an endoplasmic reticulum (ER)-resident chaperone that protects the endothelium from secondary effects of ER stress. Previous studies by the current authors identified TXNDC5 as a key pathological factor in promoting the inflammatory phenotype of fibroblast-like synoviocytes (FLSs) from rheumatoid arthritis (RA). However, its activity in RA FLSs under ER stress remains unclear. The current study found that TXNDC5 is responsive to ER stress in RA FLSs since its expression was induced by ER stress at both the endogenous and secretory level. A functional study indicated that silencing TXNDC5 reduced the viability of RA FLSs more markedly in the presence of ER stressors. In contrast, rhTXNDC5 attenuated a decrease in cell viability as a result of ER stress. Moreover, silencing TXNDC5 attenuated the induction of IL-6 and IL-8 from RA FLSs in response to ER stress. In addition, rhTXNDC5 induced a greater increase in VEGF production during ER stress. These findings confirm the pro-survival and pro-inflammation roles of TXNDC5 under ER stress in RA FLSs. TXNDC5 appears to act as a mediator linking ER stress and inflammation of RA.

Development of a novel anti-tumor theranostic platform: a near-infrared molecular upconversion sensitizer for deep-seated cancer photodynamic therapy.

Upconversion-based photon-initiated therapeutic modalities, photodynamic therapy (PDT) in particular, have shown significant clinical potential in deep-seated tumor treatment. However, traditional multiphoton upconversion materials involving lanthanide (ion)-doped upconversion nanoparticles (UCNPs) and two-photon absorption (TPA) dyes often suffer from lots of inherent problems such as unknown systematic toxicity, low reproducibility, and extremely high irradiation intensity for realization of multiphoton upconversion excitation. Herein, for the first time, we report a one-photon excitation molecular photosensitizer (FUCP-1) based on a frequency upconversion luminescence (FUCL) mechanism. Under anti-Stokes (808 nm) excitation, FUCP-1 showed excellent photostability and outstanding upconversion luminescence quantum yield (up to 12.6%) for imaging-guided PDT. In vitro cellular toxicity evaluation presented outstanding inhibition of 4T1 cells by FUCP-1 with 808 nm laser irradiation (the half maximal inhibitory concentration was as low as 2.06 µM). After intravenous injection, FUCP-1 could specifically accumulate at tumor sites and obviously suppress the growth of deep-seated tumors during PDT. More importantly, FUCP-1 could be fully metabolized from the body within 24 h, thus dramatically minimizing systemic toxicity. This study might pave a new way for upconversion-based deep-seated cancer PDT.

Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis.

INTRODUCTION: Abnormal glycolytic metabolism contributes to joint inflammation and destruction in rheumatoid arthritis (RA). We examine the expression and function of hexokinases in RA and evaluate the potential of their specific inhibitor for clinical treatment. METHODS: Detection of HKs was assessed in synovial tissue by immunohistology and Western blot. SiRNA and a specific hexokinases inhibitor, lonidamine (LND), were used to evaluate the role of hexokinase-I/II (HK-I/II). Pro-inflammatory and glycolysis factors, cell viability, and apoptosis were assessed by ELISA, RT-qPCR, MTS, and flow cytometry. The clinical effects of LND on type II collagen-induced arthritis (CIA) in DBA-/1 mouse model was evaluated by scoring their clinical responses, synovitis, and cartilage destructions, and ELISA was employed to analyze the concentrations of antibody in the serum of CIA model. RESULTS: HK-I/II expression and their activities increased in the synovium of RA compared with osteoarthritis (OA). Silencing HK-I/II (siHK-I/II) or LND treatment decreased the production of pro-inflammatory factors, such as IL-6, IL-8, CXCL9, CXCL10, and CXCL11, and cell viability, but induced cell apoptosis of RASFs. The expression of TNF-α and IL-1ß of macrophage in response to LPS stimulation were depressed as well after treatment with siHK-I/II or LND. Furthermore, leucocyte infiltration co-cultured with RASFs was also suppressed after inhibiting the expression or activity of HK-I/II. These anti-inflammatory effects overlapped with their anti-glycolytic activities. Treatment with LND in mice with CIA decreased the production of antibodies against IgG1, IgG2a, and IgG2b and consequently attenuated joint inflammation and destruction. CONCLUSIONS: HK-I/II contribute to shape the inflammatory phenotype of RASFs and macrophages. LND may be a potential drug in treating patients with RA.

A novel multifunctional poly(amidoamine) dendrimeric delivery system with superior encapsulation capacity for targeted delivery of the chemotherapy drug 10-hydroxycamptothecin.

With the aim of developing an efficient targeted delivery system for cancer therapy that overcomes drug leakage during circulation, we prepared a novel multifunctional dendrimeric carrier by integrating long hydrophobic C12 alkyl chains, poly(ethylene glycol) chains and c(RGDfK) ligands presented on the surface. This dendrimer was able to tightly encapsulate the hydrophobic anticancer drug 10-hydroxycamptothecin (10-HCPT) through simple complexation and selectively target the drug to cancer cells overexpressing integrin αvß3 through high affinity interactions. The complex has a high loading efficiency, with each molecule encapsulating approximately 20 drug molecules; high stability, without any detectable drug release during dialysis for three days; and high water solubility, achieving an approximately 600-fold increase over the water solubility of free 10-HCPT. This complex exhibited notably high cytotoxicity against 22RV1 cells overexpressing integrin αvß3 and a far lower cytotoxicity against MCF-7 cells, which express low levels of integrin αvß3. We expected encapsulated 10-HCPT to regain its anti-cancer activity following selective internalization of the complex into carcinoma cells via integrin receptor mediated endocytosis. As the drug remains inactive before internalization, this carrier has the ability to overcome problems associated with drug leakage in the circulation and off-target effects on normal tissues.