Efficient Photoacoustic Imaging With Biomimetic Mesoporous Silica-Based Nanoparticles

Indocyanine green (ICG), a near-infrared (NIR) fluorescent dye approved by the Food and Drug Administration (FDA), has been extensively used as a photoacoustic (PA) probe for PA imaging. However, its practical application is limited by poor photostability in water, rapid body clearance, and non-specificity. Herein, we fabricated a novel biomimetic nanoprobe by coating ICG-loaded mesoporous silica nanoparticles with the cancer cell membrane (namely, CMI) for PA imaging. This probe exhibited good dispersion, large loading efficiency, good biocompatibility, and homologous targeting ability to Hela cells in vitro. Furthermore, the in vivo and ex vivo PA imaging on Hela tumor-bearing nude mice demonstrated that CMI could accumulate in tumor tissue and display a superior PA imaging efficacy compared with free ICG. All these results demonstrated that CMI might be a promising contrast agent for PA imaging of cervical carcinoma.

Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.

Aminopolycarboxylate Chelators Are Effective for Whole-body Clearance of Free 225ac: A Method to Reduce Unexpected Radiation Exposure During Targeted Alpha Therapy

Purpose: Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labelling of bifunctional chelating ligands is effective, previous in vivo studies have reported that free 225Ac can be released from the drugs. Notably, such free 225Ac predominantly accumulates in the liver and can cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT, methods for addressing unexpected toxicity are therefore needed. In this study, we evaluated various chelators in vitro and in vivo with regard to reducing and excreting free 225Ac and compared their chemical structures. Methods: Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were tested. In vitro interaction of 225Ac and chelators was investigated. Biodistribution and dosimetry of free 225Ac were examined in mice prior to the in vivo chelating study. For in vivo chelation, nine candidate chelators were administered 1 h after free 225Ac injection, and biodistribution was compared 4 h after 225Ac injection in mice. Two favourable chelators were then investigated intensively for biodistribution 24 h after the 225Ac injection.Results: The liver exhibited pronounced 225Ac uptake corresponding to an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and the remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen for Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA.Conclusions. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac, with a significant reduction in the liver. This method could reduce undesirable radiation exposure from free 225Ac during 225Ac TAT.

Pharmacokinetics of anti-infective agents during CytoSorb hemoadsorption

Cytokine hemoadsorption might be beneficial in patients with sepsis. However, its effect on anti-infective agents' disposition remains largely unknown. We sought to determine the influence of hemoadsorption on the pharmacokinetics of common anti-infective agents. This is an interventional experimental study, conducted in 24 healthy pigs. Animals were randomly allocated to either hemoadsorption (cases) or sham extracorporeal circuit (controls) and to drug combinations (3 cases and 3 controls for each combination). Hemoadsorption was performed with CytoSorb (CytoSorbents Corporation, USA). We evaluated 17 drugs (clindamycin, fluconazole, linezolid, meropenem, piperacillin, anidulafungin, ganciclovir, clarithromycin, posaconazole, teicoplanin, tobramycin, ceftriaxone, ciprofloxacin, metronidazole, liposomal amphotericin B, flucloxacillin and cefepime). Repeated blood sampling from the extracorporeal circulation (adsorber inlet/outlet, sham circuit) was performed over six hours following administration. Total clearance and adsorber-specific clearance were computed. Hemoadsorption was associated with increased clearance of all study drugs, except ganciclovir. Its impact on total body clearance was considered as moderate for fluconazole (282%) and linezolid (115%), mild for liposomal amphotericin B (75%), posaconazole (32%) and teicoplanine (31%) and negligible for all other drugs. Hemoadsorber clearance declined over time, with even delayed desorption for beta-lactams. It was moderately correlated with drug's lipophilicity (p = 0.01; r2 = 0.43). Hemoadsorption with CytoSorb appears to increase to a clinically significant extent the clearance of five among 17 tested anti-infectives. Studies in human patients are required to confirm the need for dosage adjustment of these agents.

A novel dosing strategy of ceftolozane/tazobactam in a patient receiving intermittent hemodialysis

We describe a case of a 54 years old male receiving intermittent hemodialysis (iHD) who was found to have P. aeruginosa bacteremia secondary to osteomyelitis of the calcaneus bone. The patient was clinically cured without recurrence using a ceftolozane/tazobactam (CTZ) dosing strategy of 100/50mg every 8 hours (standard dosing) and 1000/500mg thrice weekly following iHD. Utilizing a susceptibility breakpoint of ≤ 4 µg/ml for P. aeruginosa, the T>MIC for standard dosing and the 1000/500mg thrice weekly following iHD regimen were calculated to be 92.7% and 94.1%, respectively. Ceftolozane total body clearance for the standard q 8 h dosing and the 1000/500mg thrice weekly following iHD regimen were calculated to be 0.196 L/h and 0.199 L/h, respectively. To our knowledge, this is the first report to illustrate the administration of CTZ at a dose of 1000/500mg thrice weekly following iHD.

Controllably mixed-charged co-assembly of dendritic lipopeptides into invisible capsid-like nanoparticles as potential drug carriers

Invisible feature is vital to drug nanocarriers for prolonging blood transportation, owing to excellent resistance to protein adsorption and body clearance. In this work, we reported a well-designed molecular and...

Pharmacokinetics of Anti-Infective Agents During CytoSorb Hemoadsorption: An Experimental Study

Background: Cytokine hemoadsorption might be effective in patients with sepsis. However, its effect on anti-infective agents' pharmacokinetics remains largely unknown. We sought to determine the influence of hemoadsorption on the pharmacokinetics of common anti-infective agents. Methods: This is an interventional experimental study, conducted in 24 healthy pigs. Animals were randomly allocated to either hemoadsorption (cases) or sham procedure (controls) and to a drug combination (3 cases and 3 controls for each combination). Hemoadsorption was performed with CytoSorb® (CytoSorbents Corporation, USA). We evaluated 17 drugs (clindamycin, fluconazole, linezolid, meropenem, piperacillin, anidulafungin, ganciclovir, clarithromycin, posaconazole, teicoplanin, tobramycin, ceftriaxone, ciprofloxacin, metronidazole, liposomal amphotericin B, flucloxacillin and cefepime). Repeated blood sampling from the extracorporeal circulation (adsorber inlet/outlet, sham circulation) were performed within six hours of administration. Total clearance and adsorber-specific clearances were computed at each time point.Results: Hemoadsorption was associated with increased clearance of all study drugs, except for ganciclovir. Its impact on total body clearance was major for fluconazole (+282%), linezolid (+115%) and amphotericin B (+75%). It was minor for posaconazole (+32%), teicoplanin (+31%), anidulafungin (+23%), piperacillin (+19%), flucloxacillin (+16%), metronidazole (+16%) and ciprofloxacin (+15%) and insignificant (<10%) for all other drugs. Hemoadsorber clearance declined over time with even delayed desorption for beta-lactams. It was moderately correlated with drug's lipophilicity (p=0.01; r2=0.43). Conclusions: Hemoadsorption with CytoSorb® has limited effect on the pharmacokinetics of most tested anti-infective drugs but appears to increase fluconazole, linezolid and liposomal amphotericin B clearance. Studies in humans with sepsis are required to confirm these findings.

Slower Elimination of Tofacitinib in Acute Renal Failure Rat Models: Contribution of Hepatic Metabolism and Renal Excretion

Tofacitinib is a Jak inhibitor developed as a treatment for rheumatoid arthritis. Tofacitinib is metabolized mainly through hepatic CYP3A1/2, followed by CYP2C11. Rheumatoid arthritis tends to increase renal toxicity due to drugs used for long-term treatment. In this study, pharmacokinetic changes of tofacitinib were evaluated in rats with gentamicin (G-ARF) and cisplatin-induced acute renal failure (C-ARF). The time-averaged total body clearance (CL) of tofacitinib in G-ARF and C-ARF rats after 1-min intravenous infusion of 10 mg/kg was significantly decreased by 37.7 and 62.3%, respectively, compared to in control rats. This seems to be because the time-averaged renal clearance (CLR) was significantly lower by 69.5 and 98.6%, respectively, due to decreased creatinine clearance (CLCR). In addition, the time-averaged nonrenal clearance (CLNR) was also significantly lower by 33.2 and 57.4%, respectively, due to reduction in the hepatic CYP3A1/2 and CYP2C11 subfamily in G-ARF and C-ARF rats. After oral administration of tofacitinib (20 mg/kg) to G-ARF and C-ARF rats, both CLR and CLNR were also significantly decreased. In conclusion, an increase in area under plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib in G-ARF and C-ARF rats was due to the significantly slower elimination of tofacitinib contributed by slower hepatic metabolism and urinary excretion of the drug.