Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near‐infrared window (NIR‐II) has been regarded as a ...promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR‐II organic renal‐clearable probes are hampered by their low brightness (ϵmaxΦf>1000 nm<10 M−1 cm−1) and limited blood circulation time (t1/2<2 h), which impede the targeted imaging performance. Herein, we develop the aza‐boron‐dipyrromethene (aza‐BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmaxΦf>1000 nm≈60 M−1 cm−1), which is about 10‐fold higher than that of previously reported NIR‐II renal‐clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non‐invasively diagnosis of renal ischemia‐reperfusion injury (RIR) earlier than clinical serum‐based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2≈6.1 h) and higher brightness than traditional PEGylated renal‐clearable control fluorophores (t1/2<2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.
A series of bright NIR‐II brush macromolecular fluorophores (FBP) with high renal‐clearance efficiency and long‐blood circulation time has been developed. These achieve real‐time in vivo NIR‐II imaging of renal ischemia‐reperfusion injury, tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.
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Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, ...zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems.
Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.
Adrenaline and vasopressin for cardiac arrest Finn, Judith; Jacobs, Ian; Williams, Teresa A ...
Cochrane database of systematic reviews,
01/2019, Letnik:
2019, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background
Adrenaline and vasopressin are widely used to treat people with cardiac arrest, but there is uncertainty about the safety, effectiveness and the optimal dose.
Objectives
To determine ...whether adrenaline or vasopressin, or both, administered during cardiac arrest, afford any survival benefit.
Search methods
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and DARE from their inception to 8 May 2018, and the International Liaison Committee on Resuscitation 2015 Advanced Life Support Consensus on Science and Treatment Recommendations. We also searched four trial registers on 5 September 2018 and checked the reference lists of the included studies and review papers to identify potential papers for review.
Selection criteria
Any randomised controlled trial comparing: standard‐dose adrenaline versus placebo; standard‐dose adrenaline versus high‐dose adrenaline; and adrenaline versus vasopressin, in any setting, due to any cause of cardiac arrest, in adults and children. There were no language restrictions.
Data collection and analysis
Two review authors independently identified trials for review, assessed risks of bias and extracted data, resolving disagreements through re‐examination of the trial reports and by discussion. We used risk ratios (RRs) with 95% confidence intervals (CIs) to compare dichotomous outcomes for clinical events. There were no continuous outcomes reported. We examined groups of trials for heterogeneity. We report the quality of evidence for each outcome, using the GRADE approach.
Main results
We included 26 studies (21,704 participants).
Moderate‐quality evidence found that adrenaline increased survival to hospital discharge compared to placebo (RR 1.44, 95% CI 1.11 to 1.86; 2 studies, 8538 participants; an increase from 23 to 32 per 1000, 95% CI 25 to 42). We are uncertain about survival to hospital discharge for high‐dose compared to standard‐dose adrenaline (RR 1.10, 95% CI 0.75 to 1.62; participants = 6274; studies = 10); an increase from 33 to 36 per 1000, 95% CI 24 to 53); standard‐dose adrenaline versus vasopressin (RR 1.25, 95% CI 0.84 to 1.85; 6 studies; 2511 participants; an increase from 72 to 90 per 1000, 95% CI 60 to 133); and standard‐dose adrenaline versus vasopressin plus adrenaline (RR 0.76, 95% CI 0.47 to 1.22; 3 studies; 3242 participants; a possible decrease from 24 to 18 per 1000, 95% CI 11 to 29), due to very low‐quality evidence.
Moderate‐quality evidence found that adrenaline compared with placebo increased survival to hospital admission (RR 2.51, 95% CI 1.67 to 3.76; 2 studies, 8489 participants; an increase from 83 to 209 per 1000, 95% CI 139 to 313). We are uncertain about survival to hospital admission when comparing standard‐dose with high‐dose adrenaline, due to very low‐quality evidence. Vasopressin may improve survival to hospital admission when compared with standard‐dose adrenaline (RR 1.27, 95% CI 1.04 to 1.54; 3 studies, 1953 participants; low‐quality evidence; an increase from 260 to 330 per 1000, 95% CI 270 to 400), and may make little or no difference when compared to standard‐dose adrenaline plus vasopressin (RR 0.95, 95% CI 0.83 to 1.08; 3 studies; 3249 participants; low‐quality evidence; a decrease from 218 to 207 per 1000 (95% CI 181 to 236).
There was no evidence that adrenaline (any dose) or vasopressin improved neurological outcomes.
The rate of return of spontaneous circulation (ROSC) was higher for standard‐dose adrenaline versus placebo (RR 2.86, 95% CI 2.21 to 3.71; participants = 8663; studies = 3); moderate‐quality evidence; an increase from 115 to 329 per 1000, 95% CI 254 to 427). We are uncertain about the effect on ROSC for the comparison of standard‐dose versus high‐dose adrenaline and standard‐does adrenaline compared to vasopressin, due to very low‐quality evidence. Standard‐dose adrenaline may make little or no difference to ROSC when compared to standard‐dose adrenaline plus vasopressin (RR 0.97, 95% CI 0.87 to 1.08; 3 studies, 3249 participants; low‐quality evidence; a possible decrease from 299 to 290 per 1000, 95% CI 260 to 323).
The source of funding was not stated in 11 of the 26 studies. The study drugs were provided by the manufacturer in four of the 26 studies, but neither drug represents a profitable commercial option. The other 11 studies were funded by organisations such as research foundations and government funding bodies.
Authors' conclusions
This review provides moderate‐quality evidence that standard‐dose adrenaline compared to placebo improves return of spontaneous circulation, survival to hospital admission and survival to hospital discharge, but low‐quality evidence that it did not affect survival with a favourable neurological outcome. Very low ‐quality evidence found that high‐dose adrenaline compared to standard‐dose adrenaline improved return of spontaneous circulation and survival to admission. Vasopressin compared to standard dose adrenaline improved survival to admission but not return of spontaneous circulation, whilst the combination of adrenaline and vasopressin compared with adrenaline alone had no effect on these outcomes. Neither standard dose adrenaline, high‐dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome. Many of these studies were conducted more than 20 years ago. Treatment has changed in recent years, so the findings from older studies may not reflect current practice.
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Polyethylene glycol (PEG) is a popular biocompatible polymer and PEGylated nanoparticles passively accumulate in tumor tissues because of their enhanced permeability and retention ...effects. Recently, the anti-PEG immunity of PEGylated nanoparticles has become an issue that needs to be solved for their clinical applications. Dendrimers are highly branched and well-defined polymers with many terminal groups, which act as potent drug carriers. In this study, we examined the pharmacokinetics, biodistribution, anti-PEG immunity, and tumor accumulation of a fully PEGylated polyamidoamine (PAMAM) dendrimer after the first and second injections and compared them to those of a PEGylated liposome with the same lipid component as Doxil®. The PEGylated dendrimer showed greater blood circulation than that of the PEGylated liposome after the first and second injections in rats. In mice injected with the PEGylated dendrimer, much less anti-PEG immunoglobulin M (IgM) was generated than that in mice injected with the PEGylated liposome. The PEGylated dendrimer accumulated in the tumor after both the first and second injections. Our results indicated that the PEGylated dendrimer with a small size and high PEG density showed attenuated anti-PEG immunity and overcame the accelerated blood clearance phenomenon, which is useful for drug delivery systems for cancer treatment.
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