Towards potent but less toxic nanopharmaceuticals – lipoic acid bioconjugates of ultrasmall gold nanoparticles with an anticancer drug and addressing unit

Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units. The application of lipoic acid enabled the control of the gold nanoparticle functionalities leading to enhanced solubility and allowing for attachment of both the folic acid and the cytotoxic drug, doxorubicin. More robust attachment of doxorubicin to the nanoparticle through the amide bond resulted in toxicity comparable with that of the drug alone, opening a new perspective for designing more potent, but less toxic nanopharmaceuticals. The increased uptake was accompanied by pronounced nuclear accumulation and observable cytotoxicity. Doxorubicin binding via covalent amide bonds enhanced stability of the whole drug vehicle and provided much better control over doxorubicin release in the cell environment, as compared to physical adsorption or pH sensitive bonding commonly used for anthracycline carriers. Confocal microscopy revealed that the bond was stable in the cytoplasm for 22 h. The ability to slow down the rate of drug release may be crucial for the application in sustained anticancer drug delivery. Biological analyses performed using MTT assay and confocal microscopy confirmed that the ultrasmall AuNPs with the lipoic acid derivative of folic acid exhibit relatively low cytotoxicity, however when loaded with a chemotherapeutic, they cause a significant reduction in the cell viability.

Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units.     

Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication

The study aimed at determining the effect of melatonin on the activity of protective antioxidative enzymes in the heart and of lipid peroxidation products in the course of intoxication with doxorubicin (DOX). The rats were categorized into four groups, receiving: 0.9% NaCl i.p. (NaCl control); melatonin [20 mg/kg body weight (b.w.)] s.c. (control Mel); DOX (2.5 mg/kg b.w.) i.p.; melatonin plus DOX in doses as above. All the substances were administered once in a week for four consecutive weeks. Homogenates of heart tissue were examined for activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), levels of reduced glutathione (GSH) and of lipid peroxidation indices (MDA + 4-HDA). Administration of melatonin alone did not induce alterations in levels of MDA + 4-HDA, GSH, or in activity of GPx, SOD or CAT, as compared to the group receiving 0.9% NaCl. GSH levels decreased following DOX but remained at normal levels following DOX and melatonin. The level of MDA + 4-HDA increased following DOX, as compared with the control, a change prevented by the combination of DOX + melatonin. Activities of GPx, SOD and CAT were higher in groups receiving DOX and/or DOX plus melatonin than in control groups. Activity of CAT and the level of GSH in the group receiving DOX plus melatonin were significantly higher than in the group intoxicated with DOX alone. The obtained results demonstrate that, when given in parallel with DOX, melatonin protects cardiomyocytes from damaging effects of the cytostatic drug (reflected by the levels of MDA + 4-HDA). The protective effect resulted, in part from the augmented levels of GSH and from stimulation of CAT activity by melatonin in cardiomyocytes subjected to the action of DOX.     

Prognostic value of angiographic markers of myocardial reperfusion in patients treated with primary coronary angioplasty for anterior wall acute myocardial infarction

BACKGROUND: Modern therapy of acute myocardial infarction (AMI) is aimed at rapid and persisting restoration of blood flow in an infarct-related artery (IRA). However, in some patients myocardial reperfusion is not achieved in spite of effective IRA recanalisation. Myocardial Blush Grade (MBG) is one of the angiographic markers useful for the detection of this phenomenon. AIM: To assess the prognostic value of MBG in patients with anterior AMI treated with primary angioplasty. METHODS: The study group consisted of 104 patients (74 males, 30 females, mean age 62+/-13 years) treated with primary angioplasty due to anterior ST-segment elevation AMI. MBG was assessed after the procedure. The mortality and major cardiovascular event (MACE) rates were analysed one and six months after AMI. RESULTS: Patients with preserved myocardial reperfusion following angioplasty (MBG 2-3, n=64 (61.5%)) had a trend towards lower one-month mortality and significantly reduced six-month mortality compared with 40 (38.5%) patients with an impaired (MBG 0-1) myocardial reperfusion (3% vs 12.5%, NS; and 6.25% vs 20%, p<0.05, respectively). The rate of MACE was significantly lower in patients with rather than without reperfusion both after one and six months of follow-up (9.4% vs 27.5%, p=0.027 and 12.5% vs 42.5%, p<0.001, respectively). Compared with patients with a high MBG score, patients with altered reperfusion more frequently had diabetes (30% vs 12.5%, p=0.04), hypertension (67.5% vs 45%, p=0.043), longer time from the onset of symptoms to balloon inflation (355.9+/-199 min vs 215.5+/-113 min, p<0.001) and lower left ventricular ejection fraction, measured 3 days after AMI (43.3%+/-8 vs 47.4%+/-9, p=0.02). CONCLUSIONS: MBG has a significant prognostic value in patients with anterior AMI treated with primary angioplasty. Diabetes, hypertension and long delay of treatment are associated with the impairment of myocardial reperfusion.     

Subacute stent thrombosis following coronary angioplasty: incidence and risk factors

BACKGROUND: Subacute stent thrombosis was a significant complication in the early years of coronary stenting, often leading to myocardial infarction, need for urgent surgery or even death. The introduction of intracoronary ultrasound enabled the identification and proper treatment of the main causes of stent thrombosis, reducing the rate of this complication to 1%. AIM: To identify risk factors of subacute stent thrombosis. METHODS: Data concerning 845 procedures with a single stent implantation in patients with stable or unstable angina, undergoing this procedure between 1998 and 2000, were analysed. RESULTS: Subacute stent thrombosis occurred in 13 (1.54%) patients. Risk factors for this complication included urgent procedures (so-called bailout stenting), improper pre-treatment with drugs ("ad hoc" procedures), dissection uncovered by stent, and poor final result of procedure (higher degree of residual stenosis). The majority of these patients developed myocardial infarction in spite of the fact that the patency of stented vessel was quickly achieved in all but one patient. CONCLUSIONS: Urgent stenting, improper drug pre-treatment and suboptimal result of the procedure are the risk factors of subacute stent thrombosis.