TOXICOLOGICAL AND PHARMACOLOGICAL ASSESSMENT OF GOLD NANORODS IN NORMAL RATS

Objective: assessment of acute, subchronic and chronic toxicity of pegylated gold nanorods (PEG-gold NRs) in Wistar rats of both sex in three routes of administration {intravenous (IV), intramuscular (IM) and subcutaneous (SC)}.Methods: in the acute toxicity study; PEG-gold NRs were injected once by three different routes, blood and tissue samples were collected after 14 d. In the subchronic and chronic studies; PEG-gold NRs were injected via three different routes, at 0.225, 0.45 and 0.9 mg/kg, once daily for 5 consecutive days, followed by a 23-day recovery period, for three and six months in the subchronic and chronic toxicity studies, respectively. Hematology, urinalysis, biochemical and histopathological examinations were conducted at the end of each study.Results: acute toxicity showed a significant decrease in serum triglycerides and cholesterol levels after single IV, IM and SC injection of PEG-gold NRs, while serum creatinine was significantly increased after IV and IM injection. Subchronic results revealed a significant decrease in serum triglycerides and cholesterol levels. The chronic study showed a significant decrease in serum triglycerides, sodium levels, total leukocytes count and significant increase in serum creatinine after IV injection. IM injection resulted in significant decrease in serum alkaline phosphatase, triglycerides, cholesterol, sodium levels and total leukocytes count. SC injection resulted in significant decrease in serum triglycerides, glucose, red blood cell count with increased creatinine and hematocrit.Conclusion: PEG-gold NRs at the three examined doses is apparently safe since no serious signs of toxicity were detected. IM and SC routes of injection were irritating, so we recommend the IV route.Â

Tissue Distribution and Efficacy of Gold Nanorods Coupled with Laser Induced Photoplasmonic Therapy in Ehrlich Carcinoma Solid Tumor Model

<div><p>Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.</p> </div

Tissue accumulation of GNRs after repeated I.V. administration to male and female normal animals.

<p>GNRs were administered by I.V. injection (0.1 mg/kg for five consecutive days of each month and repeated for 6 months). Three week after the last injection major target organs (liver, spleen, kidney and brain) were assayed for tissue concentration of GNRs (A) and the percent residual amount of the total administered dose (B). Data are presented as mean ± SEM (n=6).</p

Histological examination for EACC solid tumor treated with gold NRs coupled with laser induced photo plasmonic thermal therapy.

<p>EACC tumors of control group (A); gold NRs IT treated group (B); and IV treated group (C) were stained by H&E regular stain. GNR coupled with PTT showed massive tissue destruction appeared as non-cellular debris eosinophilic areas (arrows) Scale bar = 20 µm.</p

Physical properties of GNRs.

<p>TEM image of GNRs with Plasmon band energies at 800 nm (A) and UV- Visible NIR absorption spectra of the GNRs (B) prepared using single surfactant mixtures. Scale bar = 100 nm.</p

Tissue pharmacokinetics of GNRs after I.V. and I.T. administration to EACC tumor bearing mice.

<p>GNRs were administered by I.V. (◌) or I.T. (●) injection (1.5 mg/kg) to tumor bearing mice. Tissue concentration of gold in tumor (A), liver (B), spleen (C), and kidney (D) tissues were assayed for Gold conetnt at different time intervals until two weeks. Data are presented as mean ± SEM (n=3).</p

Tissue distribution of GNRs after single I.V. administration to male and female normal animals.

<p>GNRs were administered by I.V. injection (0.1 mg/kg) and assayed after two weeks in major excretory organs (liver, spleen and kidney). Concentration of GNRs (A) and the percent residual amount of the total administered dose (B) are presented. Data are presented as mean ± SEM (n=6).</p

Antitumor activity of GNRs coupled with laser induced photo plasmonic thermal therapy in EACC solid tumor bearing mice.

<p>EACC tumor bearing mice were given gold NRs (1.5 mg/kg every three weeks) by I.V. (▲) and I.T. (■) administration compared to PBS treated animals (●). Animals were exposed to laser plasmonic beam (50 W/cm² for 2 min) every week. Tumor size was measured every three days and plotted (A). Representative tumors are shown in panel (B). Data are presented as mean ± SEM (n=10).</p