[Prognostic value of left ventricular ejection fraction on admission in patients with septic cardiomyopathy].

OBJECTIVE: To investigate the prognostic value of cardiac ultrasound left ventricular ejection fraction (LVEF) on admission in patients with septic cardiomyopathy. METHODS: A retrospective cohort study was conducted. The patients with septic cardiomyopathy hospitalized in the intensive care unit of Zhoupu Hospital Affiliated to Shanghai Health College from January 2019 to March 2023 were enrolled. The general information including gender and age, LVEF on admission, severity of illness scores within 24 hours after admission [acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score], procalcitonin (PCT), cardiac biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT), and MB isoenzyme of creatine kinase (CK-MB)], mitochondria related indicators [aspartate aminotransferase (AST), AST/alanine aminotransferase (ALT) ratio], blood lactate (Lac), the usage of vasoactive drugs and mechanical ventilation, and the prognosis during hospitalization were collected. The differences in above clinical data between the two groups were compared. The variables with statistically significant differences in univariate analysis were incorporated into multivariate Logistic regression analysis to analyze the independent risk factors for death during hospitalization in patients with septic cardiomyopathy. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the prognostic value of LVEF by echocardiography on admission in patients with septic cardiomyopathy during hospitalization. RESULTS: A total of 62 patients were enrolled, including 36 males and 26 females. Thirty-nine cases died and 23 cases survived during hospitalization, and the mortality was 62.90%. Compared with the survival group, the LVEF of patients on admission was lower in the death group [0.51 (0.40, 0.57) vs. 0.56 (0.51, 0.63), P < 0.01], APACHE II score, SOFA score, Lac, NT-proBNP, CK-MB within 24 hours after admission were higher [APACHE II score: 22.18±8.38 vs. 17.39±8.22, SOFA score: 9.90±3.87 vs. 7.09±3.27, Lac (mmol/L): 5.10 (2.63, 11.50) vs. 2.00 (1.40, 5.00), NT-proBNP (µg/L): 5.24 (2.84, 11.29) vs. 2.53 (0.35, 6.63), CK-MB (U/L): 1.88 (0.21, 5.33) vs. 0.17 (0.02, 1.62), all P < 0.05], and the proportion of vasoactive drug application was higher (82.05% vs. 47.83%, P < 0.01). Multivariate Logistic regression analysis showed that LVEF on admission was an independent risk factor for predicting the prognosis of patients with septic cardiomyopathy during hospitalization [odds ratio (OR) = 0.920, 95% confidence interval (95%CI) was 0.855-0.990, P = 0.025]. ROC curve analysis showed that the area under the ROC curve (AUC) of LVEF on admission for predicting the death of patients with septic cardiomyopathy was 0.715 (95%CI was 0.585-0.845, P = 0.005). When LVEF ≤ 0.52, the sensitivity was 73.9%, and the specificity was 61.5%. CONCLUSIONS: The lower cardiac ultrasound LVEF on admission, the worse the prognosis of patients with septic cardiomyopathy. The cardiac ultrasound LVEF on admission can be used as a clinical index to evaluate the severity of the condition and predict the prognosis of patients with septic cardiomyopathy.

Efficient pH-Responsive Nano-Drug Delivery System Based on Dynamic Boronic Acid/Ester Transformation.

Chemotherapy is currently one of the most widely used treatments for cancer. However, traditional chemotherapy drugs normally have poor tumor selectivity, leading to insufficient accumulation at the tumor site and high systemic cytotoxicity. To address this issue, we designed and prepared a boronic acid/ester-based pH-responsive nano-drug delivery system that targets the acidic microenvironment of tumors. We synthesized hydrophobic polyesters with multiple pendent phenylboronic acid groups (PBA-PAL) and hydrophilic PEGs terminated with dopamine (mPEG-DA). These two types of polymers formed amphiphilic structures through phenylboronic ester linkages, which self-assembled to form stable PTX-loaded nanoparticles (PTX/PBA NPs) using the nanoprecipitation method. The resulting PTX/PBA NPs demonstrated excellent drug encapsulation efficiency and pH-triggered drug-release capacity. In vitro and in vivo evaluations of the anticancer activity of PTX/PBA NPs showed that they improved the pharmacokinetics of drugs and exhibited high anticancer activity while with low systemic toxicity. This novel phenylboronic acid/ester-based pH-responsive nano-drug delivery system can enhance the therapeutic effect of anticancer drugs and may have high potential for clinical transformations.

Improved paclitaxel delivery with PEG-b-PLA/zein nanoparticles prepared via flash nanoprecipitation.

Polymeric micelle is a promising vehicle to improve the bioavailability and clinical outcomes of paclitaxel (PTX) which has been proven effective in the treatment of a wide range of cancers. However, conventional PTX formulation with the amphiphilic PEG-b-PLA usually suffers from insufficient PTX loading, low stability of PTX-micelles, and rapid PTX release due to low compatibility between PTX and PLA, limiting its clinical application. In this study, a novel nanoparticle platform was developed to improve the stability of PTX-loaded nanoparticles (NPs) and the delivery efficacy of PTX by integrating the flash nanoprecipitation (FNP) technique and a combination of amphiphilic PEG-PLA and super hydrophobic zein. The incorporation of zein led to the formation of distinct hydrophobic interiors of NPs which enhanced the interaction between PTX and NPs, therefore improving the encapsulation efficiency of PTX and sustained drug release compared with PEG-PLA micelles without zein. In addition, FNP allowed facile fabrication of PTX-NPs with smaller sizes and higher stability. These PTX-NPs showed superior sustained release of PTX and good cancer cell-killing in vitro. Among them, PTX-5k-16k-1Z NPs exhibited excellent biosafety and anti-tumor efficacy in a xenograft tumor model in mice, suggesting great potential in the delivery of hydrophobic drugs for cancer therapy.

Highly Efficient Modular Construction of Functional Drug Delivery Platform Based on Amphiphilic Biodegradable Polymers via Click Chemistry.

Amphiphilic copolymers with pendant functional groups in polyester segments are widely used in nanomedicine. These enriched functionalities are designed to form covalent conjugates with payloads or provide additional stabilization effects for encapsulated drugs. A general method is successfully developed for the efficient preparation of functional biodegradable PEG-polyester copolymers via click chemistry. Firstly, in the presence of mPEG as initiator, Sn(Oct)2-catalyzed ring-opening polymerization of the α-alkynyl functionalized lactone with D,L-lactide or ε-caprolactone afforded linear mPEG-polyesters bearing multiple pendant alkynyl groups. Kinetic studies indicated the formation of random copolymers. Through copper-catalyzed azide-alkyne cycloaddition reaction, various small azido molecules with different functionalities to polyester segments are efficiently grafted. The molecular weights, polydispersities and grafting efficiencies of azido molecules of these copolymers were investigated by NMR and GPC. Secondly, it is demonstrated that the resulting amphiphilic functional copolymers with low CMC values could self-assemble to form nanoparticles in aqueous media. In addition, the in vitro degradation study and cytotoxicity assays indicated the excellent biodegradability and low cytotoxicity of these copolymers. This work provides a general approach toward the preparation of functional PEG-polyester copolymers in a quite efficient way, which may further facilitate the application of functional PEG-polyesters as drug delivery materials.

Kinetic changes in serum procalcitonin predict persistent acute kidney injury in critical patients.

PURPOSE: Persistent acute kidney injury (AKI) has been shown to be closely associated with poor prognosis in critical patients. Recent studies have shown that procalcitonin (PCT) is valuable for the early prediction of AKI in critically patients. Our aim was to determine whether PCT and its kinetic changes could predict the occurrence of persistent AKI in critical patients. METHODS: This is a prospective observational study. The definition of AKI was based on the Kidney Disease: Improving Global Outcomes criteria. Persistent AKI was defined as renal function that does not return to baseline serum creatinine levels within 48 h. Blood samples were obtained at the onset of AKI and two subsequent days of hospital stay. 24-h PCT change (ΔPCT-24 h) was defined as 24 h PCT minus baseline PCT (day 0). RESULTS: A total of 91 critical patients with AKI were included in this study. The persistent AKI group had a stepwise increase in PCT concentration. ΔPCT-24 h was higher in the persistent AKI group (p < .01). Logistic regression analysis showed that ΔPCT-24 h (p = .04) was independent predictors of persistent AKI. The receiver operating characteristic curves showed that area under the curve of ΔPCT-24 h was 0.84 (p < .01), and the cut-off value for PCT to predict persistent AKI was 0.56 ng/ml. CONCLUSION: Our study showed that the observation of kinetic changes in PCT is more significant for the early prediction of persistent AKI than the index of PCT at a single time point. ΔPCT-24 h is a good predictor of persistent AKI in critical patients.

Enzyme-Responsive Nanoparticles for Anti-tumor Drug Delivery.

The past few decades have seen great progress in the exploration of nanoparticles (NPs) as novel tools for cancer treatments and diagnosis. Practical and reliable application of nanoparticle-based technology in clinical transformation remains nevertheless an ongoing challenge. The design, preparation, and evaluation of various smart NPs with specific physicochemical responses in tumor-related physiological conditions have been of great interests in both academic and clinical research. Of particular, smart enzyme-responsive nanoparticles can predictively and selectively react with specific enzymes expressed in tumor tissues, leading to targeted delivery of anti-tumor drugs, reduced systemic toxicity, and improved therapeutic effect. In addition, NPs interact with internal enzymes usually under mild conditions (low temperature, aqueous media, neutral or close to neutral pH) with high efficiency. In this review, recent advances in the past 5 years in enzyme-responsive nanoparticles for anti-tumor drug delivery are summarized and discussed. The following contents are divided based on the different action sites of enzymes toward NPs, notably hydrophobic core, cleavable/uncleavable linker, hydrophilic crown, and targeting ligand. Enzyme-engaged destruction of any component of these delicate nanoparticle structures could result in either targeting drug delivery or controlled drug release.

Cell-Penetrating Peptide Modified PEG-PLA Micelles for Efficient PTX Delivery.

On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7) in vitro. But when further used in vivo, TAT-NP-PTX showed an acceleration of the drug's plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide's positive charges may be a hot topic to overcome the present dilemma.

Self-assembling poly(ethylene glycol)-block-polylactide-cabazitaxel conjugate nanoparticles for anticancer therapy with high efficacy and low in vivo toxicity.

Traditional approaches used for transforming hydrophobic anticancer drugs into therapeutically available nanoparticles heavily rely on the noncovalent formulation of drugs within amphiphilic copolymers. However, these nanotherapies have not yet shown the expected favorable clinical outcomes in cancer patients, presumably due to their insufficient stability. To solve this dilemma, we conceive a new class of nanotherapies assembled with polymeric prodrugs that maintain pharmacological activity while substantially alleviate the drug toxicity in animals. By exploiting methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (mPEG-PLA) as a promoiety, cabazitaxel is tethered to the terminus of the PLA fragment via a hydrolysable ester linkage. These conjugates recapitulate the self-assembly to produce colloidal stable nanotherapies. In a xenograft model of prostate cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable nanotherapy.

Selection of fluorescent dye for tracking biodistribution of paclitaxel in live imaging.

Fluorescence imaging is widely used to determine biodistribution of drugs in mice. However, the dye distribution may not be able to exactly reflect the true distribution of drug molecules. We synthesized PTX-Cy5.5 and mPEG-PLA-Cy5.5, and then prepared dye-loaded nanoparticles (NPs) (Cy5.5, DiR, PTX-Cy5.5, and mPEG-PLA-Cy5.5), dye and PTX co-loaded NPs, and PTX-loaded NPs, respectively. The particle sizes of resulting NPs were between 42.7 nm and 68.8 nm, and Zeta potential was between -0.86 mV and -8.49 mV. The biodistribution of fluorescent NPs (dye-loaded NPs and dye and PTX co-loaded NPs) on Bel-7402 tumor-bearing mice was studied via in vivo fluorescence imaging assays, results of which suggested that Cy5.5 loaded NPs and Cy5.5 conjugates (PTX-Cy5.5 and mPEG-PLA-Cy5.5) formulated NPs can reflect the tissue distribution of PTX whether it was incorporated or not. However, DiR failed to reflect true tissue distribution of PTX unless it was co-loaded with PTX. Based on these results, a guidance for the selection of dyes in drug distribution investigations and disease-targeted treatment was presented.

[Effects of penehyclidine hydrochloride on the splanchnic perfusion of patients with septic shock].

OBJECTIVE: To observe the effect of penehyclidine hydrochloride on the treatment of septic shock. METHODS: Forty-five patients with a confirmed diagnosis of septic shock were enrolled, and they were randomly and equally divided into 3 groups, namely penehyclidine hydrochloride group, anisodamine group and control group (each n=15). Gastric intramucosal carbon dioxide partial pressure (PgCO2) was determined by gastric mucosa tonometry, partial pressure of carbon dioxide in arterial blood (PaCO2) was determined by blood gas analysis and then gastric-arterial carbon dioxide partial pressure gap [P(g-a) CO2] was calculated prior to medication (0 hour) and 1, 6, 12 and 24 hours after medication respectively. The heart rate, mean arterial pressure (MAP), central venous pressure (CVP), urine volume, central venous oxygen saturation (ScvO2) and prognosis were observed. RESULTS: Compared with control group, P(g-a) CO2 decreased significantly (P<0.05, respectively) at each time point after medication, whereas no significant difference in MAP or CVP was seen between penehyclidine hydrochloride group and anisodamine group. No marked change in heart rate was found in penehyclidine hydrochloride group, but it increased significantly in anisodamine group (P<0.05). The number of patients that attained the traditional goal of shock resuscitation was 13 in penehyclidine hydrochloride group, 12 in anisodamine group, and 10 in control group. The incidence of compensated covert shock [gastric mucosa remained ischemic with normalized hemodynamic parameters, namely P(g-a) CO2>or=1.2 kPa] was lower in penehyclidine hydrochloride group and anisodamine group [7.7% (1/13), 16.7% (2/12)] than in control group [60.0% (6/10), P<0.05, respectively], P(g-a) CO2 in patients that attained normal hemodynamic parameters were lower in penehyclidine hydrochloride group and anisodamine group [(0.82+/-0.13) kPa and (0.91+/-0.18) kPa] than in control group [(1.22+/-0.21) kPa, P<0.01 and P<0.05]. The time for attaining the satisfactory goal of shock resuscitation was shorter in penehyclidine hydrochloride group and anisodamine group [(4.21+/-0.82) hours and (5.12+/-1.02) hours] than in control group [(6.51+/-1.22) hours, P<0.05, respectively]. However, the time to attain the satisfactory goal of shock resuscitation was shorter in penehyclidine hydrochloride group than in anisodamine group (P<0.05), but no statistically significant difference was found among other findings. CONCLUSION: Penehyclidine hydrochloride could significantly improve the microcirculation and compensated covert shock without adverse influence on heart rate, shortening of the time of shock resuscitation, and it might have the possibility of decreasing death rate in patients with septic shock. At present penehyclidine hydrochloride is one of the most promising vasoactive drugs in releasing vasoconstriction of microcirculation in patients with septic shock.