Antibody-Antimicrobial Conjugates for Combating Antibiotic Resistance.

As the development of new antibiotics lags far behind the emergence of drug-resistant bacteria, alternative strategies to resolve this dilemma are urgently required. Antibody-drug conjugate is a promising therapeutic platform to delivering cytotoxic payloads precisely to target cells for efficient disease treatment. Antibody-antimicrobial conjugates (AACs) have recently attracted considerable interest from researchers as they can target bacteria in the target sites and improve the effectiveness of drugs (i.e., reduced drug dosage and adverse effects), abating the upsurge of antimicrobial resistance. In this review, the selection and progress of three essential blocks that compose the AACs: antibodies, antimicrobial payloads, and linkers are discussed. The commonly used conjugation strategies and the latest applications of AACs in recent years are also summarized. The challenges and opportunities of this booming technology are also discussed at the end of this review.

Biofilm microenvironment-responsive polymeric CO releasing micelles for enhanced amikacin efficacy.

Biofilm-associated infections (BAI) have posed serious threats to public health. Novel therapy based on carbon monoxide (CO) is being increasingly appreciated. However, CO therapy like inhaled gas treatment was impeded owing to its low bioavailability. Besides, the direct use of CO releasing molecules (CORM) showed low therapeutic efficacy in BAI. Therefore, it is vital to improve the efficiency of CO therapy. Herein, we proposed polymeric CO releasing micelles (pCORM) from self-assembly of amphiphilic copolymers containing CORM bearing block as hydrophobic part and acryloylmorpholine block as hydrophilic part. The catechol modified CORM were conjugated through pH cleavable boronate ester bonds and releasing CO passively under biofilm microenvironment. When combined with subminimal inhibitory concentration antibiotic amikacin, pCORM could significantly enhance its bactericidal efficiency against biofilm-encapsulated multidrug-resistant bacteria, representing a promising approach to combat BAI.

Enzyme-triggered smart antimicrobial drug release systems against bacterial infections.

The rapid emergence and spread of drug-resistant bacteria, as one of the most pressing public health threats, are declining our arsenal of available antimicrobial drugs. Advanced antimicrobial drug delivery systems that can achieve precise and controlled release of antimicrobial agents in the microenvironment of bacterial infections will retard the development of antimicrobial resistance. A variety of extracellular enzymes are secreted by bacteria to destroy physical integrity of tissue during their invasion of host body, which can be utilized as stimuli to trigger "on-demand" release of antimicrobials. In the past decade, such bacterial enzyme responsive drug release systems have been intensively studied but few review has been released. Herein, we systematically summarize the recent progress of smart antimicrobial drug delivery systems triggered by bacteria secreted enzymes such as lipase, hyaluronidase, protease and antibiotic degrading enzymes. The perspectives and existing key issues of this field will also be discussed to fuel the innovative research and translational application in the future.

Feasibility of Quantitative Flow Ratio Virtual Stenting for Guidance of Serial Coronary Lesions Intervention.

Background Coronary physiology measurement in serial coronary lesions with multiple stenoses is challenging. Therefore, we evaluated the feasibility of Murray fractal law-based quantitative flow ratio (µQFR) virtual stenting for guidance of serial coronary lesions intervention. Methods and Results Patients who underwent elective coronary angiography and had 2 serial de novo coronary lesions of 30% to 90% diameter stenosis by visual estimation were prospectively enrolled. µQFR and fractional flow reserve (FFR) were assessed after coronary angiography. In vessels with an FFR ≤0.80, the lesion with the larger pressure gradient was considered to be the primary lesion and treated firstly, followed by FFR measurement. The second lesion was stented when FFR ≤0.80. All µQFR and predicted µQFR after stenting were calculated from diagnostic coronary angiography before interventions, with the analysts masked to the FFR data. A total of 54 patients with 61 target vessels were interrogated. Percutaneous coronary intervention was performed in 44 vessels with FFR ≤0.80. After stenting the primary lesions, 14 nonprimary lesions had FFR ≤0.80 and a second drug-eluting stent was implanted. There was excellent correlation (r=0.97, P<0.001) and good agreement (mean difference: 0.00±0.03) between baseline µQFR and FFR in identifying flow-limiting lesions. Per-vessel diagnostic accuracy of µQFR on de novo lesions was 96.7% (95% CI, 88.7%-99.6%). µQFR and FFR are highly consistent (93.2%) in identifying the primary lesion requiring revascularization. After stenting the primary lesions, per-vessel diagnostic accuracy of predicted µQFR for identifying the significance of the nonprimary lesion was 90.9%. Predicted residual µQFR with virtual stenting was higher than final FFR (mean difference: 0.05±0.06). Conclusions In vessels with serial coronary lesions, virtual stenting by µQFR can identify the primary flow-limiting lesion for revascularization.

Intratracheal administration of isosorbide dinitrate improves pulmonary artery pressure and ventricular remodeling in a rat model of heart failure following myocardial infarction.

Pulmonary hypertension due to left heart disease is associated with poor outcomes. This study investigated the beneficial effects of isosorbide dinitrate (ISDN) inhalation on pulmonary pressure and ventricular remodeling in a rat model of heart failure (HF) following myocardial infarction (MI). To assess the effect of ISDN on pulmonary pressure, 20 male Sprague-Dawley (SD) rats were randomized to four groups: Normal saline (NS) 1 ml/kg, ISDN 1 mg/kg, NS 3 ml/kg or ISDN 3 mg/kg following coronary ligation. Assessments included pulmonary and systemic artery pressure alterations, lung weight/body weight and plasma nitric oxide (NO) concentration. To assess the effect of ISDN on ventricular remodeling, 30 SD rats were randomized to three groups: Sham surgery, MI-NS (intratracheal NS 3 ml/kg for 13 days following coronary ligation), and MI-ISDN (intratracheal ISDN 3 mg/kg for 13 days following coronary ligation). On day 15, all rats underwent echocardiogram and hemodynamic assessments. The area affected by MI was evaluated using microscopy and vascular endothelial growth factor (VEGF) expression was examined using immunohistochemistry. Plasma epinephrine, norepinephrine and brain natriuretic peptide (BNP) levels were assessed by ELISA. Intratracheal ISDN reduced pulmonary and systematic artery pressure without pulmonary edema when compared with NS. The reduction was associated with increased plasma NO levels. ISDN inhalation for 14 days reduced MI size and alleviated left and right ventricular remodeling following MI. These hemodynamic and morphological improvements were associated with decreased plasma epinephrine, norepinephrine and BNP levels, and an increased VEGF positive area at the border of MI region. In conclusion, intratracheal administration of ISDN was effective in improving ventricular remodeling and cardiac function in a rat model of HF following MI.