Neuroprotection of a cocktail therapy involving anti-intercellular adhesion molecule 1 antibody and insulin-like growth factor 1 in treatment of cerebral ischemia/reperfusion injury in cats Nuclear magnetic resonance examination and pathological validatio

BACKGROUND： The pathophysiological mechanisms of ischemia are extremely complicated. It is difficult to confirm and maintain the therapeutic effects if only one neuroprotective agent is used. It is hypothesized that a cocktail therapy involving a combined application of neuroprotective agents is feasible and offers excellent therapeutic potential. OBJECTIVE： To evaluate the neuroprotective effects of a cocktail therapy of insulin-like growth factor 1 （IGF1） combined with anti-intercellular adhesion molecule 1 （ICAM1） antibody in the treatment of cerebral ischemia/reperfusion injury using medical imaging, pathology, and functional neurological deficit scoring techniques. DESIGN, TIME AND SETTING： This randomized, controlled, neuroimaging analysis of function and pathological observation was performed at the Laboratory of Molecular Imaging, Second Hospital, Hebei Medical University between September 2006 and December 2007. MATERIALS： Transient middle cerebral artery occlusion （MCAO） was induced in 24 healthy adult cats. Anti-ICAM1 antibody and IGF1 were sourced from the Shanghai Kangcheng Biological Product Co., Ltd., China. Stereotaxic apparatus was purchased from the Center for Medical Apparatus and Instruments, Shandong Liaocheng People＇s Hospital, China. The in situ apoptosis kit was provided by the Beijing Zhongshan Biotechnique Co., Ltd., China. METHODS： Twenty-four cat models of MCAO were randomly divided into four groups （n = 6）： control, IGF1, anti-ICAM 1 antibody and cocktail therapy. Following a 2-hour ischemia and subsequent lateral cerebral ventricular puncture, 100 μg IGFl（cerebral ventricular）, 100 μg anti-ICAM1 antibody （i.v.）, 50 μg IGFl（lateral cerebral ventricular） ＋ 50 μg anti-ICAM1 antibody （i.v.）, and 100 μg physiological saline （i.v.） were administered to the IGF1, anti-ICAM1 antibody, cocktail therapy and control groups, respectively. On the following day, the same administration was performed again. MAIN OUTCOME MEASURES： Pathological observation of the cerebral dura mater tissue surrounding the MCAO target site was performed by electron microscopy. At days 3 and 7 following MCAO induction, the volume of the cerebral infarction was measured by Philips functional neurological deficit scoring and nuclear magnetic resonance imaging. RESULTS： Pathological observation revealed that the control group exhibited a great number of swollen neurons, glial cells and vascular endothelial cells, and showed severely injured mitochondria with an absence of the double membrane structure. The same phenomena were partially alleviated in the IGF1 and anti-ICAM1 antibody groups, and the most obvious alleviation of injuries was in the cocktail therapy group. At day 6 following MCAO establishment, the cocktail therapy group exhibited the smallest cerebral infarction volumes among the four groups （F = 71.322, P 〈 0.01）. At days 3 and 7 following MCAO induction, the F value of Philips functional neurological deficit scoring was 10.398 and 14.430, respectively （P 〈 0.01）; however, the best neurological functional recovery was in the cocktail therapy group. CONCLUSION： A cocktail therapy of IGF1 combined with anti-ICAMl antibody produces better neuroprotective effects than IGF1 or anti-ICAM1 alone, as judged by injury to mitochondria and swelling in and around neurons and glial cells.

Healing Cocktail Therapy for Non-healing Tissue-ACL

Most clinicians agree that patients with reconstructed ACL or PCL do not possess normal knee functions. With understanding the molecular events involved in the ligament injury, there would be a chance to find a cocktail medicine to help the injured ligament in its healing process, reducing the need of ACL or PCL reconstructions.

Gold mineralized“hybrid nanozyme bomb”for NIR-Ⅱtriggered tumor effective permeation and cocktail therapy

Lung cancer is one of the most common malignant tumors with the fastest increase in the incidence rate and mortality.Even after maximum tumor resection assistance with a radiotherapy and chemotherapy combination,the recurrence of non-small cell lung cancer is still inevitable.In addition,low targeting efficiency and poor permeability of drug delivery systems strongly affect the therapeutic efficiency of anti-cancer drugs on non-small cell lung cancer.Here we designed a gemcitabine(GEM)loaded arginineglycine-aspartic acid-cysteine(RGDc)-modified gold mineralization“hybrid nanozyme bomb”(RGTG)to overcome those obstacles.RGDc modification improved the active targeting of liposomes to the tumor tissues with the second near-infrared(NIR-Ⅱ)-triggered gold-shell disruption and GEM release.The collapsed gold-shell particles with a smaller size could penetrate the tumor solid barrier and act as photothermal therapy(PTT)agents to improve PTT therapy and starvation therapy via generating gluconic acid and reactive oxygen species(ROS).Moreover,the resting reversal effect of gold particles on tumor fibroblasts can achieve accelerating tumor penetration of gold particles and GEM.Compared to monotherapy,RGTG showed significant improvement in tumor inhibition,with a tumor volume reduction of 83%compared to the control group,which provides a promising tumor treatment platform for non-small cell lung cancer(NSCLC).