Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 39, Num. 4, 2007, pp. 210-213

Indian Journal of Pharmacology, Vol. 39, No. 4, July-August, 2007, pp. 210-213

Research Letter

Cardiovascular effects of cetyl trimethyl ammonium bromide-protected gold nanoparticles

Kishori Apte, Shantesh Hede

Correspondence Address: Division of Radiation Oncology and Hyperthermic Oncology and Medicine, Balabhai Nanavati Hospital, S.V. Road, Vile Parle (West) Mumbai - 400 056
hedeshantesh@hotmail.com

Code Number: ph07052

Water-dispersible monolayer-protected nanogold (MPNG), in which a layer of molecule covers the entire surface of the nanogold (gold nanoparticle), has been extensively used as a core for controlled drug release ^[1] and enhancement of radiotherapy. ^[2] Nanoparticles made up of polymer/surfactants ^[3] which contain, or are coated with, drugs are used for target-specific drug delivery. Since nanogold is a novel form of gold, only a few of its physical, chemical, and biological properties have been extensively studied in the past. Earlier studies on the treatment of cardiac and neurological disorders ^[4] with various gold salts and compounds prompted us to explore the cardiovascular effects of gold nanoparticles. The objective of the study was to find out the cardiovascular activity of gold nanoparticles, and its monolayer surfactant-protected derivatives, in the presence and absence of cardiovascular drugs such as atenolol and isoprenaline.

The cardiovascular action of cetyl trimethyl ammonium bromide (commonly known as CTAB, which is a cationic surfactant) monolayer-protected nanogold was studied. The nanogold solution was prepared by reducing gold ions in 100 ml of chloroauric acid solution (10 ^-4 M), using sodium borohydride (0.01% w/v) as the reducing agent. This synthesis has been described by Brust et al . ^[5] To 90 ml nanogold solution (1.764 mg% of gold expressed in w/v), 10 ml of 10⁻³ M CTAB (aqueous) was added to obtain CTAB-protected nanogold (C-NG).

Four (two males and two females) healthy laboratory Wistar rats (300-400 g of body weight, aged 5-6 months) were used. The animals were procured from the National Toxicology Centre, Pune, and were well fed and housed in a clean environment at a temperature of 25 ± 1°C and a relative humidity of 45-55%, under a 12/12-hour light/dark cycle.

The animals were anesthetized using urethane i.p. (1.25 g/kg body weight). A Biopac 6 instrument (Biopac systems, Inc, USA) was used to record the ECG, heart rate, and blood pressure. The instrument electrodes were inserted in the rat in the formation of Lead II [Right arm (-ve)][Left arm (+ve)][Right leg (neutral)]. The blood pressure readings were obtained by cannulating the carotid artery. The C-NG, atenolol, and isoprenaline solutions were injected through a cannula inserted into the external jugular vein.

The volume of each dose of isoprenaline, atenolol, and C-NG did not exceed 1 ml/kg body weight of the animal. Isoprenaline was prepared using normal saline and 3 doses-100 nanogram, 300 nanogram, and 1 µg-were used. Atenolol in normal saline was administered at a dose of 1 mg/kg body weight. The heart rate, blood pressure, and ECG were recorded with each dose of a drug. Only when ECG and blood pressure returned to normal was the subsequent dose of the drug administered.

Separate control studies were conducted with nanogold and CTAB alone, and acute toxicity was also studied by administering nanogold and C-NG by oral/intravenous, intraperitoneal, and intramuscular routes for 8 days.

Before administration of C-NG the heat rate was 415 beats per min (bpm). It increased to 447 bpm after administration and then became normal, at 413 bpm, within 20-25 min, without any intervention [Table - 1]. The ECG tracing of the rat before and after administration of C-NG (in the absence of isoprenaline and atenolol) are depicted in [Figure - 1A and B. We observed a decrease in the QRS complex and an increase in the time period between two repolarisation phases [Table - 2].

[Figure - 2A] shows the effect of C-NG on isoprenaline. The first dose of isoprenaline (100 nanogram, denoted by X) was given in the first minute and the other two doses in the fifth minute (300 nanogram, denoted by Y) and the seventh minute (1 µg, denoted by Z). The corresponding heart rates were 387 bpm, 400 bpm, and 413 bpm. The C-NG solution was added at the twelfth minute, when an initial sharp rise in blood pressure was observed (point A). After this three similar doses of isoprenaline were administered at intervals of 6 min, in response to which a larger sharp decrease in blood pressure was observed (denoted by B, C, and D) for each corresponding dose. The corresponding heart rates are 398 bpm (for B), 407 bpm (for C), and 417 bpm (for D). This shows that C-NG potentiates the action of isoprenaline [Table - 3].

[Figure - 2B] depicts the effect of C-NG on atenolol. The blood pressure showed a gradual decrease with atenolol (point A). The C-NG solution administered afterwards (point B) demonstrated a stabilizing effect on the blood pressure, preventing it from decreasing further. In other words, C-NG antagonized the effect of atenolol [Table - 4].

The control studies with nanogold and CTAB did not affect the blood pressure in the presence or absence of isoprenaline or atenolol, but nanogold caused a mild bradycardia, the heart rate decreasing from 413 to 387 bpm. The toxicity study showed extremely mild kidney and liver necrosis.

C-NG enhanced the beta-adrenergic effect of isoprenaline and antagonized the beta-receptor blocking action of atenolol but did not alter the heart rate or blood pressure on its own. Though the drug appeared to be mildly toxic to the kidney and the liver in our study, Hainfield et al . ^[2] reported no toxic effect after 2 weeks of administration of nanogold in rats. He found that nanogold was cleared through the kidneys and the hematocrit values and enzymes remained within the normal ranges.

To the best of our knowledge, this is the first report on the cardiovascular activity of a novel nanomaterial, such as MPNG. The surface plasmon ^[6] of nanogold, which is responsible for its unique optical and electrical properties, as compared to gold in the bulk metal state, is also responsible for modifying the properties of the molecules attached to its surface. Sastry et al. have demonstrated the modification of the isoelectric point of amino acids ^[7] when capped onto nanogold. It is possible that this intrinsic property of nanogold could be the key reason for the cardiovascular activity which we have demonstrated with the present study.

References

Copyright 2007 - Indian Journal of Pharmacology

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