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Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA's comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers by leveraging the long-lived endogenous serum protein albumin as an siRNA carrier. We synthesized siRNA conjugated to a diacyl lipid moiety (siRNA-L), which rapidly binds albumin in situ. siRNA-L, in comparison with unmodified siRNA, exhibited a 5.7-fold increase in circulation half-life, an 8.6-fold increase in bioavailability, and reduced renal accumulation. Benchmarked against leading commercial siRNA nanocarrier in vivo jetPEI, siRNA-L achieved 19-fold greater tumor accumulation and 46-fold increase in per-tumor-cell uptake in a mouse orthotopic model of human triple-negative breast cancer. siRNA-L penetrated tumor tissue rapidly and homogeneously; 30 min after i.v. injection, siRNA-L achieved uptake in 99% of tumor cells, compared with 60% for jetPEI. Remarkably, siRNA-L achieved a tumor:liver accumulation ratio >40:1 vs. <3:1 for jetPEI. The improved pharmacokinetic properties of siRNA-L facilitated significant tumor gene silencing for 7 d after two i.v. doses. Proof-of-concept was extended to a patient-derived xenograft model, in which jetPEI tumor accumulation was reduced fourfold relative to the same formulation in the orthotopic model. The siRNA-L tumor accumulation diminished only twofold, suggesting that the superior tumor distribution of the conjugate over nanoparticles will be accentuated in clinical situations. These data reveal the immense promise of in situ albumin targeting for development of translational, carrier-free RNAi-based cancer therapies.
OBJECTIVE - Sustained low efficiency dialysis (SLED) involves the use of standard dialysis machines for prolonged intermittent renal replacement therapy in critically ill patients. In this study we aimed to quantify dialysate amino acid (AA) and albumin losses in 5 patients who underwent successful SLED treatment.
DESIGN - This was a prospective observational study.
SETTING - The study was performed in a general intensive care unit.
SUBJECTS - The study was performed in critically ill patients with acute kidney injury undergoing SLED using low-flux hemodialyzers.
INTERVENTION - We performed total dialysate collection and measured dialysate AA profiles by reverse phase high-pressure liquid chromatography using an automated AA analyser.
MAIN OUTCOME MEASURE - Individual and total amino acid losses.
RESULTS - Albumin was undetectable in dialysate. The median (mean ± SD) total amino acid loss was 15.7 (23.4 ± 19.2) g/treatment, or 122.1 (180.6 ± 148.5) mmol/treatment. Two patients were receiving intravenous nutrition. One patient had severe hepatic failure with encephalopathy, and had high dialysate AA levels with a total loss of 57 g/treatment.
CONCLUSIONS - During SLED with low-flux hemodialyzers, albumin losses are negligible but AA losses to dialysate are comparable to those during continuous renal replacement therapy. Patients' nutritional protein prescriptions should be augmented to account for this.
S-Nitrosated human serum albumin (SNO-HSA) is useful in preventing liver ischemia/reperfusion injury, and SNO-HSA should thus be able to prevent cell injury during liver transplantation. However, the potential protective effect of SNO-HSA on a combination of cold and warm ischemia, which is obligatory when performing liver transplantation, has not been examined. Therefore, we evaluated the protective effect of SNO-HSA added to University of Wisconsin (UW) solution during cold or/and warm ischemia in situ and in vitro. First, we observed that apoptotic and necrotic cell death were increased during cold and warm ischemia, respectively. SNO-HSA, which possesses anti-apoptosis activity at low NO concentrations, can inhibit cold ischemia injury both in situ and in vitro. In contrast, SNO-HSA had no significant effect on warm liver ischemia injury which, however, can be reduced by UW solution. We also demonstrated that the cellular uptake of NO from SNO-HSA can occur during cold ischemia resulting in induction of heme oxygenase-1 within 3h of cold ischemia. Our results indicate that treatment with SNO-HSA or UW solution alone is not sufficient to inhibit liver injury during a period of both cold and warm ischemia. However, a combination of SNO-HSA and UW solution can be used to prevent the two types of ischemia. SNO-HSA-added UW solution could be very useful in transplantation, because the previously imposed constraints on preservation time can be removed. This is a great advantage in a situation as the present one with increased utilization of scarce donor organs for more recipients.
Copyright © 2013 Elsevier Inc. All rights reserved.