Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy for hepatocellular carcinoma patients with portal vein tumor thrombus.

Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. Objectives: The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. Design: This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. Methods: The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. Results: A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3-4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). Conclusion: In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs.

A Tetradentate Ligand Enables Iron-Catalyzed Asymmetric Hydrogenation of Ketones in a CO- or Isocyanide-Free Fashion.

We herein reported the design and synthesis of a ferrocene-based tetradentate ligand that is featured with modular synthesis and rigid skeleton. Its iron(II) complex facilitates asymmetric direct hydrogenation of ketones without the participation of extra strong-field ligand such as CO and isocyanide. Hydride donor lithium aluminum hydride (LAH) converted non-reactive Fe(II) species to reactive Fe(II) hydride species. With this catalyst, various chiral alcohols including the intermediate for montelukast could be prepared with satisfactory yields and enantioinduction.

NIR-Triggered On-Demand Nitric Oxide Release for Enhanced Synergistic Phototherapy of Hypoxic Tumor.

Hypoxia of tumor microenvironments is a major factor restricting tumor treatment, which causes progression and metastasis of tumor. The hypoxic tumor microenvironment not only makes the traditional treatment method, such as chemotherapy, ineffective but also hinders the O2-dependent treatments, such as photodynamic therapy (PDT). Recently, stimuli-responsive nitric oxide (NO) donors have attracted extensive research interest in hypoxic tumor treatment because the NO release process is O2-independent. Besides, NO can distribute more uniformly than drug molecules and more widely than the PDT-generated active species due to its strong diffusion ability (200 µm in cells) and long lifetime (2 s in cells). Encouraged by these advantages, a near infrared light-triggered NO release polymeric nanoplatform (P1-CapNO NPs) was constructed by a thermally sensitive NO release unit, a photothermal unit, and a hydrophilic polyethylene glycol unit. P1-CapNO NPs possess strong absorption in the NIR region (the wavelength of maximal absorption peak was 790 nm with a molar absorption coefficient of 2.4 × 105 M-1 cm-1), great photothermal conversion efficiency (23.8%), and NO release ability (the released NO concentration can reach 1.3 µM) under 808 nm laser irradiation. Owing to these advantages, the great synergistic antitumor effect can be achieved in vitro and in vivo even under the hypoxic environment. The synergistic therapeutic strategy in this work could bypass the obstacles caused by hypoxia in tumor treatment and provide a reference for building a NO-involved therapeutic platform.

N-acetylcysteine combined with insulin alleviates the oxidative damage of cerebrum via regulating redox homeostasis in type 1 diabetic mellitus canine.

Neurodegenerative diseases are one of the major complications of type 1 diabetes mellitus (T1DM). The effect of insulin monotherapy on controlling blood glucose and neurodegeneration associated with diabetes is unsatisfactory. It is revealed that oxidative stress is a key element in T1DM. Therefore, N-acetylcysteine (NAC) was used together with insulin to investigate the therapeutic effect on neuronal damage in T1DM in this study. A total of 40 beagles were randomly divided into 5 groups (control group, DM group, insulin monotherapy group, NAC combined with insulin group, and NAC monotherapy group) to explore the effects of NAC on alleviating the oxidative damage in cerebrum. Our results showed that the contents of H2O2, 8-OHdg and MDA were apparently increased in DM group, while DNA and lipid oxidative damage was alleviated by the treatment of NAC and insulin. Histopathology revealed the sparse of neurofibrils and vacuolar degeneration in DM group. Additionally, compared with the control group, the mRNA expression levels of HO-1, nqo1, GCLC and GSTM1 were significantly decreased in DM group, while the opposite trend could be shown under NAC combined with insulin treatment. Meanwhile, the tight junction proteins of ZO-1, occludin and Claudin-1 were up-regulated with the treatment of NAC combined with insulin. Additionally, NAC further alleviated oxidative damage by enhancing the activity of GSH, Trx and TrxR and reducing the activity of catalase, GSSG and Grx to maintain redox homeostasis. These results demonstrated that NAC combined with insulin exerted protective effects against T1DM-induced cerebral injury via maintaining cerebral redox homeostasis.

Redox chemistry-enabled stepwise surface dual nanoparticle engineering of 2D MXenes for tumor-sensitive T1 and T2 MRI-guided photonic breast-cancer hyperthermia in the NIR-II biowindow.

With the fast advent of two-dimensional (2D) MXenes, several therapeutic paradigms based on 2D MXenes flourish, but a generic strategy for MXene functionalization to achieve theranostic functionalities and desirable performance is still lacking. In this work, we report a facile and efficient stepwise surface-functionalization strategy to achieve distinct tumor microenvironment (TME)-responsive T1 and T2 magnetic resonance (MR) imaging-guided photothermal breast-cancer hyperthermia in the second near-infrared (NIR-II) biowindow. This approach is based on the stepwise growth of superparamagnetic Fe3O4 and paramagnetic MnOx nanocomponents onto the large surface of ultrathin 2D niobium carbide (Nb2C) MXene nanosheets (Fe3O4/MnOx-Nb2C) by making full use of the redox status/chemistry of the 2D MXene surface. Such a surface-nanoparticle engineering strategy endows Fe3O4/MnOx-Nb2C composite nanosheets with a series of properties that include high photothermal-conversion efficiency in the NIR-II biowindow (1064 nm, η 30.9%) for effective photothermal tumor eradication without further reoccurrence. It also allows TME-responsive T1- and T2-weighted MR imaging and high biocompatibility for guaranteeing further potential clinical transformation. This work not only makes the efficient diagnostic T1- and T2-weighted MR imaging-guided photonic hyperthermia of breast cancer possible, but also broadens the biomedical applications of MXene-based nanoplatforms by developing novel surface-engineering strategies to construct 2D Nb2C MXene-based composite multifunctional nanoplatforms.

Overcoming Tumor Hypoxia through Multiple Pathways Using an All-in-One Polymeric Therapeutic Agent to Enhance Synergistic Cancer Photo/Chemotherapy Effects.

Hypoxia is a significant characteristic of tumors, which causes aggressive tumor growth and strong therapy resistance. Inspired by the improved therapeutic efficacy of synergistic treatment, herein, an all-in-one polymeric therapeutic agent was developed, which could overcome tumor hypoxia through multiple pathways. Multiple therapeutic agents were incorporated into the polymer, including the singlet oxygen (1O2) carrier unit to store cytotoxic reactive oxygen species, the photosensitized and photothermal unit to trigger the capture and release of 1O2, and the hypoxia-responsive prodrug unit to maintain a long-term tumor inhibition. In addition, the hydrophilic polyethylene glycol unit was also introduced to improve water-solubility and biocompatibility. Importantly, this study achieved the capture and controllable release of 1O2 just by regulating the power of an 808 nm laser for the first time, which is more convenient and flexible than previous works. As expected, the as-prepared copolymer displayed reduced oxygen dependence, accompanied with promising synergistic anti-tumor and anti-recurrence efficacies under hypoxic in vitro and in vivo environments. Consequently, this synergistic anti-hypoxia strategy may open up new avenues in the design of all-in-one therapeutic platforms for promoting the development of accurate, efficient, and long-acting treatment in clinical studies.

Yolk-shell structured Au nanorods@mesoporous silica for gas bubble driven drug release upon near-infrared light irradiation.

Drug release systems co-encapusulated with ammonium bicarbonate (ABC) could facilitate drug release upon acidic or thermal stimulations to improve therapeutic effect. However, it is not easy to control drug release rate, owing to relative stable temperature and acidic condition in living body. Besides, the additional loaded ABC reduces drug loading capacity. Herein, a near-infrared light triggered rapid drug release system with high loading capacity was developed by loading ABC and doxorubicin into yolk-shell structured Au nanorods@mesoporous silica. Gas bubbles were generated from the thermolysis of ABC utilizing photothermal effect of Au nanorods to extrude drug molecules. The mesoporous silica shell was finally destroyed along with growing bubbles, resulting in burst drug release. The photothermal therapeutic effect of Au nanorods also contributed in tumor treatment. The excellent therapeutic effect was demonstrated in cancer cells and tumor-bearing mice, which provides a new reference to achieve controllable rapid drug release in cancer medicine.

Rational Design of Near-Infrared-Absorbing Pt(II)-Chelated Azadipyrromethene Dyes as a New Generation of Photosensitizers for Synergistic Phototherapy.

Pt(II) photosensitizers are emerging as novel Pt anticancer agents for cancer photodynamic therapy (PDT) to avoid uncontrollable toxicity of cisplatin. However, the application of Pt(II) photosensitizers is limited by tumor hypoxia and the poor penetration depth of excitation light. To overcome these drawbacks, exploiting the next generation of Pt anticancer agents is of urgent need. According to theoretical calculations, novel near-infrared (NIR)-absorbing Pt(II)-chelated azadipyrromethene dyes (PtDP-X, where X = N, C, and S) were designed. Importantly, spin-orbit coupling of the Pt atom could promote the intersystem crossing of a singlet-to-triplet transition for converting oxygen to singlet oxygen (1O2), and the azadipyrromethene skeleton could provide a strong photothermal effect. As expected, PtDP-X exhibited intense NIR absorption and synergistic PDT and photothermal effects with low dark cytotoxicity. Furthermore, water-soluble and biocompatible PtDP-N nanoparticles (PtDP-N NPs) were prepared that achieved effective tumor cell elimination with low side effects under 730 nm light irradiation in vitro and in vivo. This pioneering work could push the exploitation of NIR-absorbing metal-chelated azadipyrromethene dyes, so as to promote the positive evolution of phototherapy agents.

A photothermally-induced HClO-releasing nanoplatform for imaging-guided tumor ablation and bacterial prevention.

Photothermal therapy (PTT) is a cure that can inhibit tumor growth effectively and even remove tumor via photo-induced local hyperthermia. However, its shortcoming lies in the fact that excessive heat is most likely to lead to thermal injury at the epidermis of the tumor region and even the area of the surrounding tissue. As a consequence, the exposure of the thermally-induced wound would result in the increased risk of bacterial infection. To date, few PTT platforms have attached importance to the prevention of bacterial infection at the photothermally-induced wound. Herein, we reported a thermally-sensitive liposome nanosystem (Lipo-B-TCCA) containing aza-BODIPY and trichloroisocyanuric acid, which is conductive for the PTT of tumor and the prevention of bacteria. It is observed that the designed nanoplatform could exhibit remarkable stability, high photothermal conversion efficiency (31.4%), and efficient HClO-releasing ability in vitro and in vivo. Moreover, Lipo-B-TCCA is able to eliminate tumor efficiently via near infrared fluorescence and photothermal imaging guidance with low side effects. Most importantly, Lipo-B-TCCA could prevent the growth of S. aureus in the thermal wound during the process of PTT. The imaging-guided photothermally-induced HClO-releasing PTT nanoplatform for tumor ablation and bacterial prevention shows excellent performance and great potential for biomedical applications.

Rational design of near-infrared platinum(II)-acetylide conjugated polymers for photoacoustic imaging-guided synergistic phototherapy under 808 nm irradiation.

The preferable photoconversion tunability of conjugated polymers (CPs) is of great interest in cancer phototherapy. However, very few molecular design strategies have been developed for achieving CPs with highly efficient photoconversion performance. Herein, a rational design of near-infrared (NIR) Pt-acetylide conjugated polymer CP3 with highly efficient photoconversion behaviors for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) was demonstrated. CP3 containing boron dipyrromethene (BDP) units displayed intense absorption peaks in the NIR region, which were red-shifted approximately 60 nm compared to the corresponding small-molecule precursor of BDP. Compared with control polymers CP1 and CP2, after the introduction of Pt into CP3, the triplet state, which benefits the generation of reactive oxygen species for photodynamic therapy, was identified clearly in both CP3 and the prepared CP3 nanoparticles (CP3-NPs) by ultrafast femtosecond transient absorption (fs-TA) spectroscopy. Notably, different from the traditional nonradiative decay channel with lifetime of 1.1 ps in CP3, CP3-NPs possess an additional nonradiative decay channel with lifetime of 10 ps, both of which contribute to the superior photothermal conversion effect upon 808 nm irrradiation. All these photoconversion performances lead to excellent tumor ablation. This study elucidates the excited-state dynamics in Pt-acetylide CPs, which provide an insightful understanding and valuable guidelines for the future design of high-performance theranostic agents based on CPs for synergistic cancer phototherapy.

Oxygen self-sufficient NIR-activatable liposomes for tumor hypoxia regulation and photodynamic therapy.

The inherent hypoxic environment in tumors severely resists the efficacy of photodynamic therapy. To address this problem, herein, the strategy of using oxygen self-sufficient liposomes (denoted as CaO2/B1/NH4HCO3 lipo), which contained aza-BODIPY dye (B1) and CaO2 nanoparticles in the hydrophobic layer and NH4HCO3 in the hydrophilic cavity, was presented to overcome hypoxia-associated photodynamic resistance. Under near-infrared (NIR) irradiation, NIR-absorbable B1 was activated to induce hyperthermia and further triggered the decomposition of NH4HCO3. Subsequently, with the aid of NH4HCO3 and CaO2 nanoparticles, oxygen was rapidly and self-sufficiently generated, during which clean by-products were produced. Furthermore, the increased amount of oxygen promoted the singlet oxygen production in the presence of B1, which served as a photosensitizer because of the heavy atom effect. The oxygen self-sufficient system improved the anticancer efficiency and alleviated the hypoxic environment in vivo, which demonstrated a valuable attempt to regulate intratumoral hypoxia and overcome the limitation of current photodynamic therapy systems. To our knowledge, this highlights the first example of using NIR light to activate CaO2 nanoparticle-containing liposomes for the modulation of the hypoxic environment in tumors.

Evaluation of intratumoral heterogeneity by using diffusion kurtosis imaging and stretched exponential diffusion-weighted imaging in an orthotopic hepatocellular carcinoma xenograft model.

BACKGROUND: To investigate the value of diffusion kurtosis imaging (DKI) and diffusion-weighted imaging (DWI) with a stretched exponential model (SEM) in the evaluation of tumor heterogeneity in an orthotopic hepatocellular carcinoma (HCC) xenograft model. METHODS: Thirty orthotopic HCC xenograft nude mice models were established and randomly divided into two groups, the sorafenib induction group (n=15) and control group (n=15). Every mouse in each group underwent MRI with DKI and SEM on a 1.5T MR scanner at 7, 14, and 21 days after sorafenib intervention. DKI and SEM parameters including mean kurtosis (MK), mean diffusivity (MD), α, and distributed diffusion coefficient (DDC) were measured, calculated, and compared between the two groups and among different time points. Sequential correlations between histopathological results including necrotic fraction (NF), micro-vessel density (MVD), Ki-67 index, standard deviation (SD), and kurtosis from hematoxylin-eosin staining, and DKI and SEM parameters were analyzed. RESULTS: MK, MD, and DDC of HCC in the sorafenib induction group were significantly higher than those in the control group at each time point (P<0.05), while α was significantly lower (P<0.05). Significantly positive correlations were found between MK and NF (r=0.693, P=0.010), SD (r =0.785, P=0.003), kurtosis (r=0.779, P=0.003), between MD and NF (r=0.794, P=0.003), SD (r=0.629, P=0.020), kurtosis (r=0.645, P=0.018), and between DDC and NF (r=0.800, P=0.003), SD (r=0.636, P=0.020), kurtosis (r=0.664, P=0.016), and significantly negative correlations were observed between α and NF (r=-0.704, P=0.009), SD (r=-0.754, P=0.003), and kurtosis (r=-0.792, P=0.003) in the sorafenib induction group. CONCLUSIONS: DKI and SEM parameters may be potentially useful for evaluating intratumoral heterogeneity in HCC.

De Novo Design of Polymeric Carrier to Photothermally Release Singlet Oxygen for Hypoxic Tumor Treatment.

Intratumoral hypoxia extremely limits the clinic applications of photodynamic therapy (PDT). Endoperoxides allow thermally releasing singlet oxygen (1O2) in a defined quantity and offer promising opportunities for oxygen-independent PDT treatment of hypoxic tumors. However, previous composite systems by combining endoperoxides with photothermal reagents may result in unpredicted side effects and potential harmful impacts during therapy in vivo. Herein, we de novo design an all-in-one polymer carrier, which can photothermally release 1O2. The strategy has been demonstrated to effectively enhance the production of 1O2 and realize the photodamage in vitro, especially in hypoxic environment. Additionally, the polymer carrier accumulates into tumor after intravenous injection via the enhanced permeation and retention effects and accelerates the oxygen-independent generation of 1O2 in tumors. The oxidative damage results in good inhibitory effect on tumor growth. Realization of the strategy in vivo paves a new way to construct photothermal-triggered oxygen-independent therapeutic platform for clinical applications.

Controllable Tuning of Cobalt Nickel-Layered Double Hydroxide Arrays as Multifunctional Electrodes for Flexible Supercapattery Device and Oxygen Evolution Reaction.

The rational design and fabrication of promising electrodes with prominent energy storage property and conversion performance is crucial for supercapacitors and electrocatalysis. Herein, potato chip-like cobalt nickel-layered double hydroxide@polypyrrole-cotton pad (CoNi-LDH@PCPs) composite was synthesized by in situ polymerization, which was coupled with facile solution reaction and ion-exchange etching process. An interesting potato chip-like structure can effectively expedite the kinetics of the electrode reactions, while the three-dimensional PCPs texture affords efficient pathways for charge transport, and the voids between adjacent fibers are thoroughly accessible for electrolytes and bubble evolution. When evaluated as a positive electrode for wearable supercapattery, the hierarchical CoNi-LDH@PCPs electrode displayed high specific capacity and excellent flexibility. As an oxygen evolution reaction catalyst, this PCP-based electrode also reveals the lowest overpotential of 350 mV at 10 mA cm-2 and a Tafel slope of ∼58 mV dec-1. In addition, density functional theory calculations suggest that the synthesis strategy for controllable tuning of hollow CoNi-LDH arrays reported here represents a critical step toward high-performance electrodes for energy storage and electrochemical catalysis.

Facile Phototherapeutic Nanoplatform by Integrating a Multifunctional Polymer and MnO2 for Enhancing Tumor Synergistic Therapy.

Recent studies indicate that the synergistic phototherapy (SPT) process can simultaneously generate heat for photothermal therapy (PTT) and singlet oxygen (1 O2 ) for photodynamic therapy (PDT) to overcome the recurrence of tumors. However, the hypoxic environment in tumors seriously limits the therapeutic effect of the oxygen-dependent PDT, leading to the domination of PTT in the SPT process. Therefore, it is urgent to develop a novel SPT platform for overcoming hypoxia in tumors and improving the therapeutic effect of both PTT and PDT. In this work, a novel phototherapeutic platform based on a nanocomposite of aza-BODIPY/manganese dioxide (MnO2 ) is developed via simple electrostatic self-assembly. In this design, MnO2 nanosheets, which could produce heat and catalyze endogenous hydrogen peroxide (H2 O2 ) to generate oxygen, are prepared as a nanocarrier. After being coated with the as-prepared water-soluble aza-BODIPY-based polymer (PPAIB), the obtained MnO2 @PPAIB performs as a smart phototherapeutic agent for enhancing the efficiency of both PTT and PDT. More importantly, compared to PPAIB, MnO2 @PPAIB generates more heat and reactive oxygen species to realize the enhanced therapy effects of PTT and PDT. Hence, this work provides a new method to enhance the therapeutic efficacy of SPT by using a polymer/MnO2 nanoplatform to improve the oxygen concentration and produce more heat.

Rational Design of Efficient Organic Phototherapeutic Agents via Perturbation Theory for Enhancing Anticancer Therapeutics.

The development of efficient phototherapeutic agents (PTA) through rational and specific principles exhibits great potential to the biomedical field. In this study, a facile and rational strategy was used to design PTA through perturbation theory. According to the theory, both the intersystem crossing rate for singlet oxygen generation and nonradiative transition for photothermal conversion efficiency can be simultaneously enhanced by the rational optimization of donor-acceptor groups, heavy atom number, and their functional positions, which can effectively decrease the energy gap between the singlet and triplet states and increase the spin-orbit coupling constant. Finally, efficient PTA were obtained that showed excellent performance in multimode-imaging-guided synergetic photodynamic/photothermal therapy. This study therefore expands the intrinsic mechanism of organic PTA and should help guide the rational design of future organic PTA via perturbation theory.

Smart NIR-Light-Mediated Nanotherapeutic Agents for Enhancing Tumor Accumulation and Overcoming Hypoxia in Synergistic Cancer Therapy.

The efficacy of photodynamic therapy (PDT) still shows limited success in clinical application due to hypoxia in the solid tumor, low tumor accumulation and limited light penetration depth of photosensitizers (PS). The previously reported MnO2-based nanotherapeutic agents always required intratumoral injection or complex targeting modification process to improve the therapeutic efficacy. Herein, new MnO2-based nanotherapeutic agents (honeycomb MnO2/IR780/BSA nanoparticles, HMIB NPs) are designed and prepared to achieve excellent phototherapeutic performance characterized by NIR-light-mediation, deep diffusion via TME response and O2 self-supply. The ex vivo and in vivo NIR fluorescence imaging results demonstrate that the honeycomb nanostructure of HMIB NPs facilitates the high tumor accumulation of hydrophobic IR780 via enhanced permeability and retention (EPR) effect after intravenous injection. The immunofluorescence results demonstrate that the TME response of HMIB NPs not only provides O2 for relieving hypoxia but also reduces size for improving deep intratumoral diffusion. As a result, under the synergy of NIR fluorescence imaging, photothermal effect and PDT of IR780 with TME responsive size-change, and O2 self-supply of honeycomb MnO2, the HMIB NPs have achieved all-in-one NIR fluorescence and photothermal dual-model imaging guided synergistic PDT/PTT under a single-wavelength NIR light irradiation.

Highly Stable and Multifunctional Aza-BODIPY-Based Phototherapeutic Agent for Anticancer Treatment.

Phototherapy, as an important class of noninvasive tumor treatment methods, has attracted extensive research interest. Although a large amount of the near-infrared (NIR) phototherapeutic agents have been reported, the low efficiency, complicated structures, tedious synthetic procedures, and poor photostability limit their practical applications. To solve these problems, herein, a donor-acceptor-donor (D-A-D) type organic phototherapeutic agent (B-3) based on NIR aza-boron-dipyrromethene (aza-BODIPY) dye has been constructed, which shows the enhanced photothermal conversion efficiency and high singlet oxygen generation ability by simultaneously utilizing intramolecular photoinduced electron transfer (IPET) mechanism and heavy atom effects. After facile encapsulation of B-3 by amphiphilic DSPE-mPEG5000 and F108, the formed nanoparticles (B-3 NPs) exhibit the excellent photothermal stabilities and reactive oxygen and nitrogen species (RONS) resistance compared with indocyanine green (ICG) proved for theranostic application. Noteworthily, the B-3 NPs can remain outstanding photothermal conversion efficiency (η = 43.0%) as well as continuous singlet oxygen generation ability upon irradiation under a single-wavelength light. Importantly, B-3 NPs can effectively eliminate the tumors with no recurrence via synergistic photothermal/photodynamic therapy under mild condition. The exploration elaborates the photothermal conversion mechanism of small organic compounds and provides a guidance to develop excellent multifunctional NIR phototherapeutic agents for the promising clinical applications.

Phosphorothioate-Modified AP613-1 Specifically Targets GPC3 when Used for Hepatocellular Carcinoma Cell Imaging.

Glypican-3 (GPC3), the cellular membrane proteoglycan, has been established as a tumor biomarker for early diagnosis of hepatocellular carcinoma (HCC). GPC3 is highly expressed in more than 70% HCC tissues detected by antibody-based histopathological systems. Recently, aptamers, a short single-strand DNA or RNA generated from systematic evolution of ligands by exponential enrichment (SELEX), were reported as potential alternatives in tumor-targeted imaging and diagnosis. In this study, a total of 19 GPC3-bound aptamers were successfully screened by capillary electrophoresis (CE)-SELEX technology. After truncated, AP613-1 was confirmed to specifically target GPC3 with a dissociation constant (KD) of 59.85 nM. When modified with a phosphorothioate linkage, APS613-1 targeted GPC3 with a KD of 15.48 nM and could be used as a specific probe in living Huh7 and PLC/PRF/5 imaging, GPC3-positive cell lines, but not in L02 or A549, two GPC3-negative cell lines. More importantly, Alexa Fluor 750-conjugated APS613-1 could be used as a fluorescent probe to subcutaneous HCC imaging in xenograft nude mice. Our results indicated that modified AP613-1, especially APS613-1, was a potential agent in GPC3-positive tumor imaging for HCC early diagnosis.

Extending Hypochlorite Sensing from Cells to Elesclomol-Treated Tumors in Vivo by Using a Near-Infrared Dual-Phosphorescent Nanoprobe.

Reactive oxygen species (ROS), when beyond the threshold, can exhaust the capacity of cellular antioxidants and ultimately trigger cell apoptosis in tumor biology. However, the roles of hypochlorite (ClO-) in this process are much less clear compared with those of ROS, and its detection is easily obstructed by tissue penetration and endogenous fluorophores. Herein, we first synthesized a near-infrared (NIR) ratiometric ClO- probe (Ir NP) composed of two kinds of phosphorescent iridium(III) complexes (Ir1 and Ir2) encapsulated with amphiphilic DSPE-mPEG5000. Ir NPs are dual-emissive and show obvious changes in phosphorescence intensity ratios and lifetimes of two emission bands upon exposure to ClO-. During the ClO- detection, ratiometric photoluminescence imaging is much more reliable over the intensity-based one for its self-calibration, while time-resolved photoluminescence imaging (TRPI) could distinguish the phosphorescence with long lifetime of Ir NPs from short-lived autofluorescence of tissues, resulting in the high accuracy of ClO- determination. With NIR emission, a long phosphorescence lifetime, fast response, and excellent biocompatibility, Ir NPs were applied to the detection of ClO- in vitro and in vivo by means of ratiometric phosphorescence imaging and TRPI with high signal-to noise-ratios (SNR). Importantly, we demonstrated the elevated ClO- in elesclomol-stimulated tumors in living mice for the first time, which holds great potential for the visualization of the boost of ClO- in anti-carcinogen-treated tumors and the further investigation of ROS-related oncotherapeutics.