ABSTRACT
Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.
ABSTRACT
Objective To analyze the effect of Shuxuetong injection on microcirculation in patients with septic shock and its therapeutic effect. Methods A prospective study was conducted. Eighty patients with septic shock treated in Department of Critical Care Medicine of Hebei Provincial Traditional Chinese Medical Hospital were randomly divided into a Shuxuetong group and a conventional therapy group according to random number table, 40 cases in each group. The conventional treatment in the two groups was energetically carried out in accord to the sepsis shock guidelines, such as positive fluid resuscitation, anti-infection, etc. In the Shuxuetong group, additionally Shuxuetong injection 6 mL in 5% glucose injection 250 mL intravenous drip was given once a day for 7 days. The levels of urine output, lactic acid (Lac), blood urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), left ventricular ejection fraction (LVEF), and cardiac index (CI) in the two groups were observed before and after treatment; the total dosages of dopamine, dobutamine, noradrenaline, etc. vascoactive agent used for the patients and 28-day mortality in the two groups were also recorded. Results The comparisons of levels of urine output, Lac, BUN, Cr, AST, ALT, LVEF, and CI before treatment between the two groups were of no statistical significant differences (all P>0.05). After treatment in the two groups, the urine output, LVEF, and CI were increased compared with those before treatment, whereas the Lac, BUN, Cr, AST, and ALT were significantly decreased, and the changes were more obvious in Shuxuetong group [urine output (mL/h):112.1±39.8 vs. 73.3±28.5, LVEF:0.49±0.15 vs. 0.44±0.14, CI (mL·s-1·m-2):66.2±5.7 vs. 54.2±6.2, Lac (mmol/L):3.83±1.65 vs. 4.72±2.25, BUN (mmol/L):7.1±2.7 vs. 9.3±3.5, Cr (μmol/L): 73.9±16.2 vs. 95.7±15.8, AST (U/L): 39.8±9.5 vs. 45.8±12.7, ALT (U/L):34.3±9.7 vs. 41.7±11.3, all P<0.05]. The total dosages of all kinds of vascoactive agent of Shuxuetong group were remarkably less than those in the conventional therapy group [dopamine (mg): 993.1±261.7 vs. 1 340.9±356.4, dobutamine (mg):776.2±281.0 vs. 1 049.2±364.3, noradrenaline (mg):56.4±34.6 vs. 107.6±51.3, all P<0.05]. The 28-day mortality of Shuxuetong group was obviously lower than that of conventional therapy group [40.0%(16/40) vs. 60.0%(24/40), P<0.05]. Conclusion Shuxuetong injection can improve the microcirculation perfusion in patients with septic shock and reduce their mortality.