Bio-engineered nano-vesicles for IR820 delivery: a therapy platform for cancer by surgery and photothermal therapy.

Long-term unsolved health problems from pre-/intra-/postoperative complications and thermal ablation complications pose threats to liver-cancer patients. To reduce the threats, we propose a multimodal-imaging guided surgical navigation system and photothermal therapy strategy to improve specific labeling, real-time monitoring and effective treatment of hepatocellular carcinoma. Using a bioengineering approach, G-Nvs@IR820, a kind of human-cell-membrane nano-vesicle, was generated with growth arrest-specific 6 (Gas6) expressed on the membrane and with near-infrared absorbing dye (IR820) loaded into it, which is proven to be an effective nanoparticle-drug-delivery system for Axl-overexpressing hepatocellular carcinoma. G-Nvs@IR820 shows excellent features in vitro and in vivo. As Gas6 binds to Axl specifically, G-Nvs@IR820 has good targeting ability to the tumor site and also has a good ability to guide the further accurate obliteration of carcinoma from adjacent normal tissue in surgery with its highly resolved fluorescence/photoacoustic/surgical-navigation signals. Moreover, the G-Nvs@IR820 represented a new perspective for photothermal therapy. Briefly, Nvs@IR820 was synthesized at a gram scale with high affinity, specificity, and safety. It has promising potential in clinical application for IGS and PTT in Axl-overexpressing hepatoma carcinoma.

Evaluation of the synergistic effects of epigallocatechin-3-gallate-loaded PEGylated-PLGA nanoparticles with nimodipine against neuronal injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and morbidity. Although serious side effects might occur, nimodipine, a second-generation 1,4-dihydropyridine calcium channel blocker, is clinically used to improve neurological outcomes after SAH. Recently, (-)-epigallocatechin-3-gallate (EGCG) has been reported to inhibit Ca2+ overloading-induced mitochondrial dysfunction, oxidative stress, and neuronal cell death after SAH; however, low bioavailability, instability, and cytotoxicity at a high dose limited the clinical application of EGCG. To overcome these limitations, PEGylated-PLGA EGCG nanoparticles (EGCG-NPs) were constructed to enhance the bioavailability by using the double-emulsion method. Antioxidative activity, cytotoxicity, behavioral, and immunohistochemistry studies were carried out to determine the neuroprotective effectiveness after cotreatment with EGCG-NPs (75 mg/kg/d preconditioning for 7 days before SAH) and nimodipine (10 mg/kg/d after 30 min of SAH) by using in vivo SAH models. The optimized EGCG-NPs with a Box-Behnken design showed a small particle size of 167 nm, a zeta potential value of -22.6 mV, an encapsulation efficiency of 86%, and a sustained-release profile up to 8 days in vitro. Furthermore, EGCG-NPs (75 mg/kg/d) had superior antioxidative activity to free EGCG (100 mg/kg/d). EGCG-NPs combined with nimodipine exhibited significant synergistic effects against neuronal cell death by suppressing oxidative stress, Ca2+ overloading, mitochondrial dysfunction, and autophagy after SAH. These results suggest that cotreatment with EGCG-NPs and nimodipine may serve as a promising novel strategy for the treatment of SAH.

Evaluation of (-)-epigallocatechin-3-gallate (EGCG)-induced cytotoxicity on astrocytes: A potential mechanism of calcium overloading-induced mitochondrial dysfunction.

(-)-epigallocatechin-3-gallate (EGCG), the main component of green tea, has long been explored in the treatment and/or prevention of central nervous system (CNS) disorders. However, EGCG has been recently shown to exhibit acute and subacute toxicity. Although a lot of work has been done, the mechanisms of EGCG-induced mitochondrial dysfunction has not been delineated in primary astrocyte. Here, the mitotoxic effect of EGCG on primary astrocytes was investigated by measuring Ca2+ overloading-induced mitochondrial dysfunction. As expected, EGCG dose-dependently inhibited astrocytes growth depending on Ca2+ overloading, especially at 50 µM EGCG group. It is interesting to note that Ca2+ influx from the extracellular space was responsible for an increase in the cytosolic Ca2+ level ([Ca2+]i) by opening voltage-gated calcium channels (VGCCs) and, consequently, mitochondrial Ca2+ ([Ca2+]m) overloaded via the mitochondrial Ca2+ uniporter (MCU). As a result, mitochondrial dysfunction was induced, including the opening of the mitochondrial permeability transition pore (mPTP), mitochondrial membrane depolarization, an increasing in reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Therefore, more apoptotic cells were observed in 50 µM EGCG group than that of in 1 µM EGCG group. These findings suggested that a high dose of EGCG was toxic to astrocytes partly by targeting mitochondria via calcium pathway, which would extend our understanding of the toxicity of EGCG and the underlying mechanisms.

Manganese Oxide-Coated Carbon Nanotubes As Dual-Modality Lymph Mapping Agents for Photothermal Therapy of Tumor Metastasis.

Lymph node (LN) status is a major indicator of stage and survival of lung cancer patients. LN dissection is a primary option for lung cancer LN metastasis; however, this strategy elicits adverse effects and great trauma. Therefore, developing a minimally invasive technique to cure LN metastasis of lung cancer is desired. In this study, multiwalled carbon nanotubes (MWNTs) coated with manganese oxide (MnO) and polyethylene glycol (PEG) (namely MWNTs-MnO-PEG) was employed as a lymphatic theranostic agent to diagnose and treat metastatic LNs. After single local injection and lymph drainage were performed, regional LNs were clearly mapped by T1-weighted magnetic resonance (MR) of MnO and dark dye imaging of MWNTs. Meanwhile, metastatic LNs could be simultaneously ablated by near-infrared (NIR) irradiation under the guidance of dual-modality mapping. The excellent result was obtained in mice bearing LNs metastasis models, showing that MWNTs-MnO-PEG as a multifunctional theranostic agent was competent for dual-modality mapping guided photothermal therapy of metastatic LNs.

Neuroprotective Effect of Radix Trichosanthis Saponins on Subarachnoid Hemorrhage.

Redox homeostasis has been implicated in subarachnoid hemorrhage (SAH). As a result, antioxidants and/or free radical scavengers have become an important therapeutic modality. Considering that radix trichosanthis (RT) saponins exhibited strong antioxidant ability both in vivo and in vitro, the present study aimed to reveal whether the neuroprotective activities of RT saponins were mediated by p38/p53 signal pathway after SAH. An established SAH model was used and superoxide dismutase (SOD), malondialdehyde (MDA), induced nitric oxide synthase (iNOS), nitric oxide (NO), lactate dehydrogenase (LDH), p-p38, and p53 activation were detected after 48 h of SAH. The results showed that RT saponins inhibited iNOS expression to restore NO to basal level. Moreover, compared with Cu/Zn-SOD, RT saponins (2 mg/kg/d dosage) significantly increased Mn-SOD activity after SAH. Accompanied with lowered NO and elevated SOD, decreased p38 phosphorylation and p53 activities were observed, especially for RT saponins at 2 mg/kg/d dosage. In this setting, the neurological outcome was also improved with less neuronal cells damage after RT saponins pretreatment. Our findings demonstrated the beneficial effects of RT saponins in enhancing neuroprotective effects by deducing iNOS activity, normalizing SOD level, and inhibiting p-p38 and p53 expression, hence offering significant therapeutic implications for SAH.

Antioxidant activities of saponins extracted from Radix Trichosanthis: an in vivo and in vitro evaluation.

BACKGROUND: Radix Trichosanthis (RT), the dry root tuber of Trichosanthis kirilowii Maxim (Cucurbitaceae), is a traditional Chinese medicine. Although a wide range of saponin pharmacological properties has been identified, to our knowledge, this may be the first report to investigate the crude saponins from RT. The purpose of this study was to delineate the antioxidant activity both in vitro and in vivo by using ethyl acetate (EtOAc), n-butanol, and the mixture of n-butanol and EtOAc fractions. METHODS: In vitro antioxidant activity was detected by using DPPH free radical, hydrogen peroxide scavenging, and reducing power assays. After pretreatment with different fractions saponins at 2 mg/kg/d and 3 mg/kg/d of crude drug, respectively, an established CCl4 induced acute cytotoxicity model was used to evaluate the in vivo antioxidant potential by detection of superoxide dismutase (SOD), malonaldehyde (MDA), lactate dehydrogenase (LDH), and total antioxidant capacity (T-AOC) levels. RESULTS: The in vitro assay showed that the antioxidant activity of all the three fractions was promising. The reducing power of the EtOAc and the mixture of n-butanol and EtOAc extracts increased in a dose dependent manner. However, both the n-butanol and the mixture of n-butanol and EtOAc fractions in low dose exhibited in a time dependent manner with prolonged reaction time. As for hydrogen peroxide scavenging capability, the n-butanol fraction mainly demonstrated a time dependent manner, whereas EtOAc fraction showed a dose dependent manner. However, in case of in vivo assay, an increase of SOD and T-AOC and decrease of MDA and LDH levels were only observed in n-butanol (2 mg/kg/d of crude drug) extracts pretreatment group. CONCLUSIONS: RT saponins in n-butanol fraction might be a potential antioxidant candidate, as CCl4-induced oxidative stress has been found to be alleviated, which may be associated with the time dependent manner of n-butanol saponins in a low dose. Further studies will be needed to investigate the active individual components in n-butanol extract, in vivo antioxidant activities and antioxidant mechanisms.

Neuroprotective effect of tea polyphenols on oxyhemoglobin induced subarachnoid hemorrhage in mice.

Tea polyphenols are of great benefit to the treatment of several neurodegenerative diseases. In order to explore the neuroprotective effects of tea polyphenols and their potential mechanisms, an established in vivo subarachnoid hemorrhage (SAH) model was used and alterations of mitochondrial function, ATP content, and cytochrome c (cyt c) in cerebral cortex were detected. This study showed that the alteration of mitochondrial membrane potential was an early event in SAH progression. The trend of ATP production was similar to that of mitochondrial membrane potential, indicating that the lower the mitochondrial membrane potential, lesser the ATP produced. Due to mitochondrial dysfunction, more cyt c was released in the SAH group. Interestingly, the preadministration of tea polyphenols significantly rescued the mitochondrial membrane potential to basal level, as well as the ATP content and the cyt c level in the brain cortex 12 h after SAH. After pretreatment with tea polyphenols, the neurological outcome was also improved. The results provide strong evidence that tea polyphenols enhance neuroprotective effects by inhibiting polarization of mitochondrial membrane potential, increasing ATP content, and blocking cyt c release.