Frameless Robot-Assisted Asleep Centromedian Thalamic Nucleus Deep Brain Stimulation Surgery in Patients with Drug-Resistant Epilepsy: Technical Description and Short-Term Clinical Results.

INTRODUCTION: This purpose of this work is to give a detailed description of a surgical technique for frameless robot-assisted asleep deep brain stimulation (DBS) of the centromedian thalamic nucleus (CMT) in drug-resistant epilepsy (DRE). METHODS: Ten consecutively enrolled patients who underwent CMT-DBS were included in the study. The FreeSurfer "Thalamic Kernel Segmentation" module and experience target coordinates were used for locating the CMT, and quantitative susceptibility mapping (QSM) images were used to check the target. The patient's head was secured with a head clip, and electrode implantation was performed with the assistance of the neurosurgical robot Sinovation®. After opening the dura, the burr hole was continuously flushed with physiological saline to stop air from entering the skull. All procedures were performed under general anesthesia without intraoperative microelectrode recording (MER). RESULTS: The mean age of the patients at surgery and onset of seizures was 22 years (range 11-41 years) and 11 years (range 1-21 years), respectively. The median duration of seizures before CMT-DBS surgery was 10 years (2-26 years). CMT was successfully segmented, and its position was verified by experience target coordinates and QSM images in all ten patients. The mean surgical time for bilateral CMT-DBS in this cohort was 165 ± 18 min. The mean pneumocephalus volume was 2 cm3. The median absolute errors in the x-, y-, and z-axes were 0.7 mm, 0.5 mm, and 0.9 mm, respectively. The median Euclidean distance (ED) and radial error (RE) was 1.3 ± 0.5 mm and 1.0 ± 0.3 mm, respectively. No significant difference was found between right- and left-sided electrodes regarding the RE nor the ED. After a mean 12-month follow-up, the average reduction in seizures was 61%, and six patients experienced a ≥ 50% reduction in seizures, including one patient who had no seizures after the operation. All patients tolerated the anesthesia operation, and no permanent or serious complications were reported. CONCLUSIONS: Frameless robot-assisted asleep surgery is a precise and safe approach for placing CMT electrodes in patients with DRE, shortening the surgery time. The segmentation of the thalamic nuclei enables the precise location of the CMT, and the flow of physiological saline to seal the burr holes is a good way to reduce the influx of air. CMT-DBS is an effective method to reduce seizures.

The accuracy of a novel self-tapping bone fiducial marker for frameless robot-assisted stereo-electro-encephalography implantation and registration techniques.

BACKGROUND: We aimed to evaluate the accuracy and safety of a novel self-tapping bone fiducial as a registration technique for stereoelectroencephalography (SEEG) implantation. METHODS: Each patient was installed with five bone fiducial markers. All procedures were performed using the same Sinovation robot system. The accuracy was determined by calculating the target point error (TPE) and the entry point error (EPE) of electrodes. RESULTS: Fourteen patients underwent SEEG implantation surgery; and the average installation time of the markers per patient was 86.1 s. In the operating theatre, the average registration time was 206.6 s, and the average registration error was 0.18 mm. The average TPE of 174 electrodes was 1.98 mm and the average EPE was 0.88 mm. CONCLUSION: Our study provided a bone fiducial marker installation and registration technique that was convenient and fast, highly accurate in registration, and highly tolerated by patients.

Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin-proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

Case Report: Stereoelectroencephalography and Stereoelectroencephalography-Guided Radiofrequency Thermocoagulation in Familial Lateral Temporal Lobe Epilepsy.

Familial lateral temporal lobe epilepsy (FLTLE) is genetic focal epilepsy usually characterised by auditory symptoms. Most FLTLE cases can be controlled by anti-seizure medications, and to our best knowledge, there are no previous reports about stereoelectroencephalography (SEEG) used for patients with FLTLE. In this report, we present two patients with FLTLE in one family and their SEEG performances, together with 18F-fluorodeoxyglucose (18F-FDG) PET and MRI results. In case 1, fast activities originated from the right superior temporal gyrus and spread rapidly to the right anterior insular lobe and hippocampus. In case 2, there were two seizure patterns: (1) The fast activities or sharp slow waves were identified at the left superior temporal gyrus, then, sharp waves and spike waves spread in the left superior temporal gyrus; (2) There were fast activities and slow-wave oscillation originated in the left superior temporal gyrus, then, the fast activities spread in the left superior temporal gyrus and finally spread to the other sites. An SEEG-guided radiofrequency thermocoagulation was performed for both patients and one of them underwent resection surgery. Seizures are well-controlled and the patients are very satisfied with the therapeutic effects.

Robot-Assisted Percutaneous Balloon Compression for Trigeminal Neuralgia: Technique Description and Short-Term Clinical Results.

Objective: Percutaneous balloon compression (PBC) is a minimally invasive treatment for trigeminal neuralgia (TG) with a favorable cost-effectiveness ratio, but this technique has a steep learning curve. This study presents our initial clinical experience of robot-assisted PBC using a neurosurgical robot on six consecutive patients with TG. Methods: We fixed the patient's head with a skull clamp and connected it with the linkage arms of a Sinovation® neurosurgical robot, which was then registered using four bone fiducials by the robotic pointer. The puncture needle was positioned at the entry point on the skin using a robotic arm and advanced to the target point after the skin had been incised with a pointed surgical blade. This procedure was repeated for a second trajectory. A balloon was then advanced and inflated using 0.3 ml of a contrast agent. Upon injection of 0.6 ml contrast agent, the ganglion was kept compressed for 120 s. After removal of the balloon and puncture needle, compression of the face was performed to achieve hemostasis. Results: All patients achieved immediate pain relief following PBC. No permanent or severe complications were registered, and there was no pain recurrence in any of the patients during the follow-up period. Conclusions: Despite requiring a longer time for preoperative preparation, robot-assisted PBC provided a high degree of accuracy and safety, and it can also shorten the learning curve for surgeons unfamiliar with PBC. Robot-assisted surgical approaches should be further developed and adopted for PBC.

Ultra-Fast Computation of Excited-States Spectra for Large Systems: Ultraviolet and Fluorescence Spectra of Proteins.

A workable approach named xTB-sTDDFT was selected to investigate the excited-state spectra of oxytocin (135 atoms), GHRP-6 (120 atoms) and insulin (793 atoms). Three different Hartree-Fock components functionals (wB97XD3: 51%, LC-BLYP: 53%, wB97X: 57%) were used to calculate the excitation spectra, and the results calculated by wB97XD3 functional well agree with the experiments. It's a deep impression that computed time cost reduced by more than 80%. For polypeptide (oxytocin and GHRP-6), both UV and fluorescence spectra were obtained, and the errors between the calculated and experimental values approximately were 20 nm. For Insulin, the errors are within 15 nm. UV spectrum peak is λcal = 262 nm (λexp = 277 nm, Δλ = 15 nm), and fluorescence spectrum peak is λcal = 294 nm (λexp = 304 nm, Δλ = 10 nm). In summary, a suitable theoretical model is established to ultra-fast calculate the electronic excitation spectra of large systems, such as proteins and biomacromolecules, with good calculation accuracy, fast calculation speed and low cost.

LHRH-Targeted Redox-Responsive Crosslinked Micelles Impart Selective Drug Delivery and Effective Chemotherapy in Triple-Negative Breast Cancer.

Systemic chemotherapy is efficacious against triple-negative breast cancer (TNBC), but it is often associated with serious side effects. Here, a luteinizing hormone-releasing hormone (LHRH) receptor-targeted and tumor microenvironment-responsive nanoparticle system to selectively deliver chemotherapeutic drugs to TNBC cells, is reported. This delivery system (termed "LHRH-DCMs") contains poly(ethylene glycol) and dendritic cholic acid as a micellar carrier, reversible intra-micellar disulfide bond as a redox-responsive crosslink, and synthetic high-affinity (D-Lys)-LHRH peptide as a targeting moiety. LHRH-DCMs exhibit high drug loading efficiency, optimal particle size, good colloidal stability, and glutathione-responsive drug release. As expected, LHRH-DCMs are more efficiently internalized into human TNBC cells through receptor-mediated endocytosis, resulting in stronger cytotoxicity against these cancer cells than the non-targeted counterpart when encapsulated with paclitaxel (PTX). Furthermore, near-infrared fluorescence and magnetic resonance imaging demonstrate that LHRH-DCMs facilitate the tumor distribution and penetration of payloads in three different animal models of breast cancer, including cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and transgenic mammary carcinoma. Finally, in vivo therapeutic studies show that PTX-LHRH-DCMs outperform both the corresponding nontargeted PTX-DCMs and the current clinical formulation (Taxol) in an orthotopic TNBC model. These results provide new insights into approaches for precise drug delivery of TNBC.

Localization of the epileptogenic zone based on ictal stereo-electroencephalogram: Brain network and single-channel signal feature analysis.

Accurate localization of the epileptogenic zone (EZ) is crucial for refractory focal epilepsy patients to achieve freedom from seizures following epilepsy surgery. In this study, ictal stereo-electroencephalography data from 35 patients with refractory focal epilepsy were analyzed. Effective networks based on partial directed coherence were analyzed, and a gray level co-occurrence matrix was applied to extract the time-varying features of the in-degree. These features, combined with the single-channel signal time-frequency features, including approximate entropy and line length, were used to localize the EZ based on a cluster algorithm. For all seizure-free patients (n = 23), the proposed method was effective in identifying the clinical-EZ-contacts and clinical-EZ-blocks, with an F1-score of 62.47 % and 72.18 %, respectively. The sensitivity was 96.00 % for the clinical-EZ-block identification, which provided the information for the decision-making of clinicians, prompting clinicians to focus on the identified EZ-blocks and their nearby contacts. The agreement between the EZ identified by the proposed method and the clinical-EZ was worse for non-seizure-free patients (n = 12) than for seizure-free patients. Furthermore, our method provided better results than using only brain network or single-channel signal features. This suggests that combining these complementary features can facilitate more accurate localization of the EZ.

Multi-Modal Visualization of Uptake and Distribution of Iron Oxide Nanoparticles in Macrophages, Cancer Cells, and Xenograft Models.

Iron oxide nanoparticles (IONPs) have shown great potential in various biomedical applications. However, information on the interaction between IONPs and biological systems, especially the uptake and distribution of IONPs in cells and tissues, as well as the mechanism of biological action, is relatively limited. In the present study, multi-modal visualization methods, including confocal fluorescence microscopy, transmission electron microscopy, magnetic resonance imaging, and fluorescence optical imaging, were utilized to unveil the uptake and distribution of IONPs in macrophages, cancer cells, and xenograft models. Our results demonstrated that uptake of IONPs in RAW264.7 macrophages and SKOV-3 cancer cells were dose- and cell type-dependent. Cellular uptake of IONPs was an energy-dependent process, and caveolae-mediated endocytosis was the main uptake pathway. All the IONPs were primarily present in endocytic compartments (e.g., endosomes, lysosomes) inside the cells. At 48 hours after intravenous injection of IONPs in SKOV-3 tumor bearing mice, most of the IONPs was distributed in the liver and spleen, with obvious uptake in the tumor, less but significant amount in the kidney and brain. Taken together, multi-modal visualization approaches in our study provide detailed information on the cellular uptake and tissue distribution of IONPs from multiple levels and perspectives.

The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression.

The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.

Lead Failure After Vagus Nerve Stimulation Implantation: Radiographic Examination and Revision Surgery.

OBJECTIVE: The present study assessed the most common types of lead failures, identified the causes, and discussed the potential procedures for revision surgery after vagus nerve stimulator implantation in patients with epilepsy. METHODS: In a retrospective study during an 8-year period, 13 patients had undergone revision surgery because of lead failure. Lead failure was classified as either lead intrinsic damage or lead pin disengagement from the generator header. On the radiographic image, we defined a rear lead connector (RC) ratio that represented the portion of the rear lead connector in the header receptacle. It was used to quantitatively evaluate the mechanical failure of the lead-header interface. The optimal procedures to identify and manage lead failure were established. RESULTS: All 13 patients presented with high lead impedance of ≥9 kOhms at the time of revision. Of 10 patients with lead damage, 7 had presented with an increased seizure frequency after a period of seizure remission. In contrast to lead damage occurring relatively late (>15 months), lead pin disengagement was usually found within the early months after device implantation. A significant association was found between an elevated RC ratio (≥35%) and lead pin disengagement. The microsurgical technique permitted removal or replacement of the lead without adverse effects. CONCLUSIONS: The method of measuring the RC ratio developed in the present study is feasible for identifying lead disengagement at the generator level. Lead revision was an effective and safe procedure for patients experiencing lead failure.

The mono(catecholamine) derivatives as iron chelators: synthesis, solution thermodynamic stability and antioxidant properties research.

There is a growing interest in the development of new iron chelators as novel promising therapeutic strategies for neurodegenerative disorders. In this article, a series of mono(catecholamine) derivatives, 2,3-bis(hydroxy)-N-(hydroxyacyl)benzamide, containing a pendant hydroxy, have been synthesized and fully characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy and mass spectrum. The thermodynamic stability of the chelators with FeIII, MgII and ZnII ions was then investigated. The chelators enable formation of (3 : 1) FeIII complexes with high thermodynamic stability and exhibited improved selectivity to FeIII ion. Meanwhile, the results of 1,1-diphenyl-2-picryl-hydrazyl assays of mono(catecholamine) derivatives indicated that they all possess excellent antioxidant properties. These results support the hypothesis that the mono(catecholamine) derivatives be used as high-affinity chelator for iron overload situations without depleting essential metal ions, such as MgII and ZnII ions.

Reversibly disulfide cross-linked micelles improve the pharmacokinetics and facilitate the targeted, on-demand delivery of doxorubicin in the treatment of B-cell lymphoma.

Doxorubicin (DOX) is commonly used to treat human malignancies, and its efficacy can be maximized by limiting the cardiac toxicity when combined with nanoparticles. Here, we reported a unique type of reversibly disulfide cross-linked micellar formulation of DOX (DOX-DCMs) for the targeted therapy of B-cell lymphoma. DOX-DCMs exhibited high drug loading capacity, optimal particle sizes (15-20 nm), outstanding stability in human plasma, and stimuli-responsive drug release profile under reductive conditions. DOX-DCMs significantly improved the pharmacokinetics of DOX, and its elimination half-life (t1/2) and area under curve (AUC) were 5.5 and 12.4 times of that of free DOX, respectively. Biodistribution studies showed that DOX-DCMs were able to preferentially accumulate in the tumor site and significantly reduce the cardiac uptake of DOX. In a xenograft model of human B-cell lymphoma, compared with the equivalent dose of free DOX and non-crosslinked counterpart, DOX-DCMs not only significantly inhibited the tumor growth and prolonged the survival rate, but also remarkably reduced DOX-associated cardiotoxicity. Furthermore, the exogenous administration of N-acetylcysteine (NAC) at 24 h further improved the therapeutic efficacy of DOX-DCMs, which provides a "proof-of-concept" for precise drug delivery on-demand, and may have great translational potential as future cancer nano-therapeutics.

"One-Pot" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics.

Nanoparticle-based theranostic agents have emerged as a new paradigm in nanomedicine field for integration of multimodal imaging and therapeutic functions within a single platform. However, the clinical translation of these agents is severely limited by the complexity of fabrication, long-term toxicity of the materials, and unfavorable biodistributions. Here we report an extremely simple and robust approach to develop highly versatile and biocompatible theranostic poly(vinyl alcohol)-porphyrin nanoparticles (PPNs). Through a "one-pot" fabrication process, including the chelation of metal ions and encapsulation of hydrophobic drugs, monodispersenanoparticle could be formed by self-assembly of a very simple and biocompatible building block (poly(vinyl alcohol)-porphyrin conjugate). Using this approach, we could conveniently produce multifunctional PPNs that integrate optical imaging, positron emission tomography (PET), photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery functions in one formulation. PPNs exhibited unique architecture-dependent fluorescence self-quenching, as well as photodynamic- and photothermal- properties. Near-infrared fluorescence could be amplified upon PPN dissociation, providing feasibility of low-background fluorescence imaging. Doxorubicin (DOX)-loaded PPNs achieved 53 times longer half-life in blood circulation than free DOX. Upon irradiation by near infrared light at a single excitation wavelength, PPNs could be activated to release reactive oxygen species, heat and drugs simultaneously at the tumor sites in mice bearing tumor xenograft, resulting in complete eradication of tumors. Due to their organic compositions, PPNs showed no obvious cytotoxicity in mice via intravenous administration during therapeutic studies. This highly versatile and multifunctional PPN theranostic nanoplatform showed great potential for the integration of multimodal imaging and therapeutic functions towards personalized nanomedicine against cancers.

New tris(dopamine) derivative as an iron chelator. Synthesis, solution thermodynamic stability, and antioxidant research.

A new tris(dopamine) derivative, containing three dopamine chelate moieties which were attached to a trimesic acid molecular scaffold, has been prepared and fully characterized by NMR, FTIR and HRMS. The solution thermodynamic stability of the chelator with Fe(III), Mg(II), Zn(II) and Fe(II) ions was investigated. Results demonstrated that the chelator exhibited effective binding ability and improved selectivity to Fe(III) ion. The chelator possessed affinity similar to that of diethylenetriaminepentaacetic acid chelator for Fe(III) ion. The high affinity could be attributed to the favorable geometric arrangement between the chelator and Fe(III) ion coordination preference. The chelator also exhibited high antioxidant activity and nontoxicity to neuron-like rat pheochromocytoma cells. Hence, the chelator could be used as chelating agent for iron overload situations without depleting essential metal ions, such as Mg(II) and Zn(II) ions.

Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer.

The overall prognosis of bladder cancer has not been improved over the last 30 years and therefore, there is a great medical need to develop novel diagnosis and therapy approaches for bladder cancer. We developed a multifunctional nanoporphyrin platform that was coated with a bladder cancer-specific ligand named PLZ4. PLZ4-nanoporphyrin (PNP) integrates photodynamic diagnosis, image-guided photodynamic therapy, photothermal therapy and targeted chemotherapy in a single procedure. PNPs are spherical, relatively small (around 23 nm), and have the ability to preferably emit fluorescence/heat/reactive oxygen species upon illumination with near infrared light. Doxorubicin (DOX) loaded PNPs possess slower drug release and dramatically longer systemic circulation time compared to free DOX. The fluorescence signal of PNPs efficiently and selectively increased in bladder cancer cells but not normal urothelial cells in vitro and in an orthotopic patient derived bladder cancer xenograft (PDX) models, indicating their great potential for photodynamic diagnosis. Photodynamic therapy with PNPs was significantly more potent than 5-aminolevulinic acid, and eliminated orthotopic PDX bladder cancers after intravesical treatment. Image-guided photodynamic and photothermal therapies synergized with targeted chemotherapy of DOX and significantly prolonged overall survival of mice carrying PDXs. In conclusion, this uniquely engineered targeting PNP selectively targeted tumor cells for photodynamic diagnosis, and served as effective triple-modality (photodynamic/photothermal/chemo) therapeutic agents against bladder cancers. This platform can be easily adapted to individualized medicine in a clinical setting and has tremendous potential to improve the management of bladder cancer in the clinic.

HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy.

Photodynamic therapy (PDT) is a promising non-invasive therapeutic modality that has been proposed for treating prostate cancer, but the procedure is associated with limited efficacy, tumor recurrence and photo-toxicity. In the present study, we proposed to develop a novel multifunctional nano-platform for targeted delivery of heat, reactive oxygen species (ROS) and heat shock protein 90 (Hsp90) inhibitor simultaneously for combination therapy against prostate cancer. This new nano-platform combines two newly developed entities: 1) a unique organic and biocompatible nanoporphyrin-based drug delivery system that can generate efficient heat and ROS simultaneously with light activation at the tumor sites for dual-modal photothermal- and photodynamic- therapy (PTT/PDT), and 2) new nano-formulations of Hsp90 inhibitors that can decrease the levels of pro-survival and angiogenic signaling molecules induced by phototherapy, therefore, further sensitizing cancer cells to phototherapy. Furthermore, the nanoparticles have activatable near infrared (NIR) fluorescence for optical imaging to conveniently monitor the real-time drug delivery in both subcutaneous and orthotopic mouse models bearing prostate cancer xenograft. This novel multifunctional nano-platform has great potential to improve the care of prostate cancer patients through targeted combination therapy.

Role of surface charge in determining the biological effects of CdSe/ZnS quantum dots.

The growing potential of quantum dots (QDs) in biomedical applications has provoked the urgent need to thoroughly address their interaction with biological systems. However, only limited studies have been performed to explore the effects of surface charge on the biological behaviors of QDs. In the present study, three commercially available QDs with different surface coatings were used to systematically evaluate the effects of surface charge on the cellular uptake, cytotoxicity, and in vivo biodistribution of QDs. Our results demonstrated that charged QDs entered both cancer cells and macrophages more efficiently than neutral ones, while negative QDs internalized mostly. Upon entry into cells, QDs were localized in different subcellular compartments (eg, cytoplasm and lysosomes) depending on the surface charge. Interestingly, inconsistent with the result of internalization, positive QDs but not negative QDs exhibited severe cytotoxicity, which was likely due to their disruption of cell membrane integrity, and production of reactive oxygen species. Biodistribution studies demonstrated that negative and neutral QDs preferentially distributed in the liver and the spleen, whereas positive QDs mainly deposited in the kidney with obvious uptake in the brain. In general, surface charge plays crucial roles in determining the biological interactions of QDs.

A smart and versatile theranostic nanomedicine platform based on nanoporphyrin.

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart 'all-in-one' nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.

MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death.

It has become evident that AKT inhibitors have great potential in cancer treatment. In this study, we investigate the anticancer activity of MK-2206, a novel AKT inhibitor, on HepG2 hepatocellular carcinoma cell, and to show whether MK-2206 enhances the apoptosis-inducing potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The cell growth inhibition was evaluated by MTT assay and colony formation assay. Cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by AnnexinV-FITC/PI double staining assay and caspase-9, casapse-7, caspase-3, and PARP cleavage. The results of present study showed that MK-2206-induced G1-phase arrest was associated with a marked decrease in the protein expression of cyclin D1 with concomitant induction of p21 and p27. MK-2206-induced apoptosis was characterized by cleavage of a pro-caspase in a concentration-dependent manner. Moreover, the MAP family kinases p38 kinase and JNK were activated by exposure to MK-2206. SB203580, an p38-specific inhibitor, partially blocked MK-2206-induced death of HepG2 cells and caspase activation. A combination of MK-2206 with TRAIL significantly inhibited growth of TRAIL resistant HepG2 cells. Taken together, our findings provide a new insight to better understand anticancer mechanisms of MK-2206, at least in HepG2 cell. Using of MK-2206 as a potent sensitizer to TRAIL-induced apoptotic cell death offers a promising means of enhancing the efficacy of TRAIL-based HCC treatments.