Brain-tumor-seeking and serpin-inhibiting outer membrane vesicles restore plasmin-mediated attacks against brain metastases.

Many chemotherapeutic and molecular targeted drugs have been used to treat brain metastases, e.g., anti-angiogenic vandetanib. However, the blood-brain barrier and brain-specific resistance mechanisms make these systemic therapeutic approaches inefficacious. Brain metastatic cancer cells could mimic neurons to upregulate multiple serpins and secrete them into the extracellular environment to reduce local plasmin production to promote L1CAM-mediated vessel co-option and resist anti-angiogenesis therapy. Here, we developed brain-tumor-seeking and serpin-inhibiting outer membrane vesicles (DE@OMVs) to traverse across the blood-brain barrier, bypass neurons, and specially enter metastatic cancer cells via targeting GRP94 and vimentin. Through specific delivery of dexamethasone and embelin, reduced serpin secretion, restored plasmin production, significant L1CAM inactivation and tumor cell apoptosis were specially found in intracranial metastatic regions, leading to delayed tumor growth and prolonged survival in mice with brain metastases. By combining the brain-tumor-seeking properties with the regulation of the serpin/plasminogen activator/plasmin/L1CAM axis, this study provides a potent and highly-selective systemic therapeutic option for brain metastases.

Suppressing Wnt signaling of the blood‒tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases.

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, e.g., Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

Nanomodulators targeting endothelial WNT and pericytes to reversibly open the blood-tumor barrier for boosted brain tumor therapy.

The blood-brain barrier (BBB)/blood-tumor barrier (BTB) impedes brain entry of most brain-targeted drugs, whether they are water-soluble or hydrophobic. Endothelial WNT signaling and neoplastic pericytes maintain BTB low permeability by regulating tight junctions. Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases. At the optimal NTZ/IBR mass ratio (1:2), BTB opening reached the optimum effect at 48-72 h without any sign of intracranial edema and cognitive impairment. The combination of NI@I-NPs and chemotherapeutic drugs (doxorubicin and etoposide) extended the median survival of mice with breast cancer brain metastases. Targeting BTB endothelial WNT signaling and tumor pericytes via NI@I-NPs could open the BTB to improve chemotherapeutic efficiency against brain metastases.

Serum Derived Exosomes From Pancreatic Cancer Patients Promoted Metastasis: An iTRAQ-Based Proteomic Analysis.

BACKGROUND: Pancreatic cancer (PC) is one of the most aggressive malignancies and has a poor prognosis despite being extensively researched. The role of serum-derived exosomes in tumorigenesis and the development of PC is still unclear. METHOD: The present study employed iTRAQ-based proteomic analysis to search for differences between the serum exosomes of PC patients and those from control patients. Then, bioinformatics methods were used to analyze the functions of the identified proteins, and the possible functions were verified through cell culture experiments. RESULTS: A total of 611 proteins were identified from exosomes, and 141 proteins were differentially expressed, with 91 up- and 50 down regulated proteins in PC cancer compared to healthy controls. Further analysis indicated that APOE serves as an important hub in the network. In addition, CRP, VWF, APOA2, NIN, and GSK3B potentially interact with many other proteins. We then tested the effect of patient serum-derived exosomes on pancreatic cancer cells and found that patient serum-derived exosomes, but not those from healthy controls, induced cell proliferation, migration, and EMT, supporting the role of exosomes in metastasis. CONCLUSION: Our data suggest that exosomes derived from PC patients may promote PC metastasis.

[Influence of the venous catheter site on data of pulse indicator continuous cardiac output monitoring].

OBJECTIVE: To compare the use of subclavian vein catheter and femoral vein catheter, in monitoring pulse indicator continuous cardiac output (PiCCO) monitoring data cardiac index (CI), extravascular lung water index (EVLWI), and global end-diastolic volume index (GEDVI) with central venous injection of the bolus cold saline injection, in order to determine whether the femoral vein access, which is not typically used, could be used to obtain reliable data. METHODS: Thirteen patients in Beijing Hospital intensive care unit (ICU) were involved, from January 2007 to March 2009. Each patient was monitored with PiCCOplus device, after an injection of cold saline bolus via both femoral and subclavian venous catheter. Paired t-test and Bland-Altman analysis were used to compare CI, EVLWI and GEDVI values. RESULTS: Data of 39 measurements were collected. The bias between femoral injection and subclavian injection were CI (0.28+/-0.46) L x min(-1) x m(-2), EVLWI (1.05+/-1.89) ml/kg, GEDVI (195.2+/-105.7) ml/m(2), and they were statistically significant (P values was 0.000 5, 0.001 3, <0.0001, respectively). The Bland-Altman analysis showed an clinically overestimation of GEDVI after femoral injection (limit of concordance was -11.9, 402.3), compared with that after subclavian injection. CONCLUSION: Measurements with a cold saline bolus via a femoral catheter, compared to those via a subclavian catheter, lead to overestimation of CI, EVLWI and GEDVI values, and a great bias of GEDVI should be taken into account in clinical work.

[Study on safety and efficacy of concentrated potassium chloride infusions in critically ill patients with hypokalemia].

OBJECTIVE: To explore the safety and clinical efficacy of intravenous infusion of concentrated potassium chloride using micro-pumps in critically ill patients with hypokalemia. METHODS: One hundred and twenty-eight critically ill patients with hypokalemia, the endogenous creatinine clearance rate over 0.5 ml/second and the urine output over 50 ml/hour were randomly divided into the therapy group (n=64) and the control group (n=64). Patients in therapy group received 1,208 mmol/L (9%) KCl, while those in the control group received 201 mmol/L (1.5%) potassium chloride, intravenously with the aid of a micro-pump, with hourly equal quantity of KCl in both groups. Patients in both groups were monitored strictly, and the potassium infusion was stopped whenever the serum potassium exceeded or equal to 3.5 mmol/L. RESULTS: It took (15.55+/-3.22) hours and (14.18+/-4.93) hours for the therapy group and the control group to correct the hypokalemia respectively, and there was no significant difference (P>0.05). Potassium infusion brought larger amount of fluid in the control group than the therapy group [(124.36+/-25.79) ml vs. (680.83+/-236.70) ml, P<0.01]. All patients tolerated the infusion without evidence of hemodynamic change, hyperkalemia or acute heart dysfunction. For all the patients, renal function did not throw significant influence on the potassium infusion time. An inverse correlation was observed between preinfusion potassium concentration and the quantity of potassium infused (r= -0.259, P<0.01). CONCLUSION: Under meticulous monitoring, it is safe and effective to infuse concentrated potassium for the critically ill patients with hypokalemia. This strategy can also be followed in patients with mild renal dysfunction but without oliguria or anuria under careful monitoring.