Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer.

BACKGROUND: Excessive extracellular matrix (ECM) deposition in pancreatic ductal adenocarcinoma (PDAC) severely limits therapeutic drug penetration into tumors and is associated with poor prognosis. Collagen is the most abundant matrix protein in the tumor ECM, which is the main obstacle that severely hinders the diffusion of chemotherapeutic drugs or nanomedicines. METHODS: We designed a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that combined ECM degradation, active targeting, immune evasion, near-infrared (NIR) light-triggered drug release, and synergistic antitumor therapy and diagnosis into one nanoplatform. PDAC tumor cell membranes were extracted and coated onto doxorubicin (Dox)-loaded Au nanocages, and then collagenase was added to functionalize the cell membrane through lipid insertion. We evaluated the physicochemical properties, in vitro and in vivo targeting, penetration and therapeutic efficacy of the nanoplatform. RESULTS: Upon intravenous injection, this nanoplatform efficiently targeted the tumor through the homologous targeting properties of the coated cell membrane. During penetration into the tumor tissue, the dense ECM in the PDAC tissues was gradually degraded by collagenase, leading to a looser ECM structure and deep penetration within the tumor parenchyma. Under NIR irradiation, both photothermal and photodynamic effects were produced and the encapsulated chemotherapeutic drugs were released effectively, exerting a strong synergistic antitumor effect. Moreover, this nanoplatform has X-ray attenuation properties that could serve to guide and monitor treatment by CT imaging. CONCLUSION: This work presented a unique and facile yet effective strategy to modulate ECM components in PDAC, enhance tumor penetration and tumor-killing effects and provide therapeutic guidance and monitoring.

[Thresholds of CT perfusion in predicting ischemic penumbra and infarct core in patients with acute ischemic stroke].

OBJECTIVE: To determine the optimal parameters and their thresholds on CT perfusion (CTP) to predict the penumbra and core in patients with acute ischemic stroke. METHODS: The data of 39 thrombolytic candidates with acute cerebral anterior-circulation ischemic stroke admitted in the Second Affiliated Hospital, Zhejiang University School of Medicine from June 2009 to October 2013 were retrospectively reviewed. Patients all underwent CTP at admission and CTP or magnetic resonance perfusion (MRP) 24 h after thrombolysis. Patients were classified as non-reperfusion group (to define the threshold of penumbra, n=10) and reperfusion group (to define the threshold of infarct core, n=21) by reperfusion status. According to the baseline CTP and 24 h imaging, the volumes of threshold-based hypoperfusion lesions and final infarction were calculated. Paired t test, correlation analysis and Bland-Altman plot were performed to assess the optimal thresholds for predicting the penumbra and infarct core. RESULTS: In non-reperfusion group, the best agreement was found between final infarct volume and delay time>3 s (bias 3.3 ml, 95% limits of agreement:-41.7 to 48.3 ml, r=0.933, P<0.001), while in reperfusion group, the best agreement was noted between final infarct volume and rCBF<30% (bias -2.2 ml, 95% limits of agreement:-25.6 to 21.2 ml; r=0.923, P<0.001). CONCLUSION: Delay time>3 s and rCBF<30% are the optimal thresholds for predicting the penumbra and infarct core on CTP, respectively. These thresholds may be of help to estimate the mismatch status and select eligible patients for thrombolysis.

[Dynamic CT angiography in evaluation of collateral flow and outcome of acute ischemic stroke patients after intravenous thrombolysis].

OBJECTIVE: To evaluate the collateral flow of patients with acute ischemic stroke by dynamic CT angiography (CTA) and to analyze the relationship between collateral flow and outcome after intravenous thrombolysis. METHODS: We retrospectively analyzed CT perfusion (CTP) imaging of 22 acute ischemic stroke patients with middle cerebral artery (MCA) or internal carotid artery (ICA) occlusion undergoing intravenous thrombolysis, and reconstructed the images for dynamic CTA in the Second Affiliated Hospital, Zhejiang University School of Medicine from June 2009 to October 2013. The total extent and flow speed of collateral flow based on dynamic CTA images of these patients were evaluated. The scores of National Institute of Health stroke scale (NIHSS) in different collateral flows were compared with repeated measuring. The nonparametric Spearman's rank correlation was used to assess the relationship between collateral flow and modified Rankin scale (mRS) at 3 months after thrombolytic therapy. RESULTS: Compared with the poor collateral flow group, patients with good collateral flow had lower NIHSS at 1 month after thrombolysis (4.7±5.0 vs 25.1±15.1, P=0.001) and higher reperfusion percentage (69%±32% vs 23%±54%, P=0.044). The total condition score of collateral flow was positively correlated with mRS at 3 months after treatment (r=0.450, P=0.001). CONCLUSION: Acute ischemic stroke patients with good collateral flow after intravenous thrombolysis have a better outcome. The dynamic CTA can be used to evaluate the collateral flow and to predict clinical outcomes in patients with acute ischemic stroke after thrombolysis therapy.

[Histopathological changes in rat transplanted hepatoma after lipiodol transarterial embolization].

OBJECTIVE: To study the histopathological effect of hepatic arterial infusion of lipiodol on transplanted hepatoma in rats. METHODS: Fourty-one rats bearing Walker-256 transplanted hepatoma were randomly divided into embolization group (n = 35, divided in 5 subgroups, with 7 rats in each) and control group (n = 6). Lipiodol (0.5 ml/kg)emulsified with 0.2 - 0.3 ml of 76% urografin (v:v = 1:1) was infused via gastroduodenal artery into hepatic artery in embolization group. Rats in the control group were given via the same route urografin only. Histopathological changes of the treated tumors were examined by light and transmission electron microscopy. RESULTS: In the control rats treated with urografin alone, the average tumor size increased 2.8 fold on day 3, while that in the lipiodol treated rats increased 1.7 fold (P < 0.01). Compared with the control group, on day 3, 5, 10 after embolization treatment, tumor necrosis was more extensive (P < 0.01). In one of the treated rats, the tumor was completely necrotic on day 10. Inflammatory reaction was marked in the early post-embolic period, but it was replaced by fibrous tissue encapsulation. From day 1 on, in 17 of the 18 treated rats, apoptotic cells, identified by typical morphology under light and electronic microscopes, were observed, mainly in the tumor periphery. CONCLUSION: In addition to cellular necrosis, apoptosis may be another important mechanism leading to cell death in hepatoma treated with transarterial embolization.