Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology.

INTRODUCTION: Nanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery. AIMS AND OBJECTIVES: The aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells. MATERIAL AND METHODS: We performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180-200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested. RESULTS: We designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both). CONCLUSIONS: Gold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.

Gold nanoparticles - the theranostic challenge for PPPM: nanocardiology application.

The article overviews the potential biomedical applications of nanoscale gold particles for predictive, preventive and personalised nanomedicine in cardiology. The review demonstrates the wide opportunities for gold nanoparticles due to their unique biological properties. The use of gold nanoparticles in cardiology is promising to develop fundamentally new methods of diagnosis and treatment. The nanotheranostics in cardiovascular diseases allows the non-invasive imaging associated with simultaneous therapeutic intervention and predicting treatment outcomes. Imaging may reflect the effectiveness of treatment and has become a fundamental optimisation setting for therapeutic protocol. Combining the application of biomolecular and cellular therapies with nanotechnologies foresees the development of complex integrated nanodevices. Nanocardiology may challenge existing healthcare system and economic benefits as cardiovascular diseases are the leading cause of morbidity and mortality at present.

Doxorubicin dose for congestive heart failure modeling and the use of general ultrasound equipment for evaluation in rats. Longitudinal in vivo study.

INTRODUCTION: For the evaluation of the congestive heart failure (CHF) in rat models, the use of special equipment for echocardiography for dynamic evaluation is suggested. The optimal doxorubicin dose for CHF induction has still not been established. AIMS: The aims of our study was to find a reliable doxorubicin CHF rat model using a general ultrasound (US) equipment for in vivo ultrasound examination of the systemic circulation, to establish the optimal doxorubicin dose, and to assess the feasibility of US guided administration of the drug. MATERIAL AND METHODS: Sixty Wistar rats, weighing 180-200 g were assigned to 3 groups (n=20 in each): group A - 4 time intraperitoneal doxorubicin "Sigma"administration, cumulative dose 2.49 mg/animal or 12.45 mg/kg; group B and 5 time doxorubicin administration, cumulative dose 3.03 mg/animal or 15.15 mg/kg; and group C- controls (injected same volume of saline). Dynamic US using linear 12 MHz transducer was used to establish the CHF modifications. Two rats with CHF were injected under US guidance in the pleural cavity with 0.06 ml cardiotropic drug levosimendan and two rats in the pericardial cavity. RESULTS: We established the optimal cumulative doxorubicin dose for CHF induction at 12.45 mg/kg. At a higher dose, more than 40% of animals died. A lower dose did not induce significant clinical and US CHF criteria. Congestion (followed by weight gain) led to lower animal mortality. Preliminary results indicate a similar positive cardioprotective effect of drug injection into pericardial and pleural cavities under US guidance, demonstrating that this technique is useful for drug administration. CONCLUSIONS: US is an effective modality for in vivo monitoring of the rat organs for the study of cardiovascular function or for drug administration under US guidance. Suggested model (optimal dose of doxorubicin for simulation of CHF of 2.5 mg/animal, a cumulative dose of 12.45 mg/kg in 4 injections every 3 days) can be used for research purposes.

Mitral valvar anomalies and discrete subaortic stenosis.

On the basis of our clinical experience, we hypothesized that the role of mitral valvar anomalies in the development and recurrence of discrete subaortic stenosis might be underestimated. From January 1994 to October 2000, the anatomy of the mitral valve and its relationship to the other components of the left ventricular outflow tract were studied by echocardiography in a series of 73 consecutive patients referred to our institution for surgical correction of discrete subaortic stenosis. In all patients for whom it was considered advisable, surgical correction of the mitral anomaly was performed, together with resection of the fibro-muscular subaortic stenosis. One or more mitral valvar anomalies were found in 35 patients (48%). They could be grouped into five categories: insertion of a papillary muscle into the aortic leaflet, insertion of a papillary muscle into the ventricular wall, "muscularization" of the subaortic portion of the aortic leaflet, anomalous insertion of the valvar tissue into the ventricular wall, and accessory valvar tissue. In all cases with anomalous mitral valvar anatomy, surgical correction was feasible. It consisted of transection of the anomalous papillary muscle or its attachment, resection of accessory valvar tissue, and/or patch enlargement of the aortic leaflet. The incidence of mitral valvar anomalies associated with subaortic stenosis is probably underestimated. Our data suggest that they should be systematically searched for during the evaluation of all cases of subaortic stenosis. Their surgical correction is generally feasible, and might improve the mid and long term results.