Sona vs CTAB

OUR ADVANCEMENTS IN GOLD NANOROD DEVELOPMENT IS MORE EFFICIENT AND EFFECTIVE THEN PREVIOUS METHODS

OUR GOLD NANORODS
MAKE IT POSSIBLE TO HAVE MULTIPLE TEST RESULTS FROM ONE SAMPLE

OUR GOLD NANORODS HAVE THE ABILITY PASS THROUGH THE TEST MEMBRANE WITH MORE SURFACE AREA ASSURING BETTER TESTING RESULTS

Gold Nano Rods – GNR Introduction

Gold nanorods (GNRs) are small particles whose surface plasmon resonance (SPR) frequencies can be altered as a function of the length and width, giving these anisotropic particles optical properties useful in a host of applications.1, 2 GNRs have been used in a number of biomedical applications, including as contrast agents for optical biomedical imaging and for their hyperthermal effects. One of the major barriers in the application of GNR-based materials, especially for in-vivo applications such as hyperthermal cancer treatment, is the efficient exchange and removal of cetyltrimethylammonium bromide (CTAB), the surfactant used exclusively in the large scale synthesis of GNRs. CTAB is a cytotoxic, cationic surfactant with an extremely low critical micelle concentration.3-5 Its function in the synthesis of the gold nanorods is still a matter of debate, but it is generally thought that the CTAB forms a strongly adsorbed bilayer around the surface of the growing gold particle.6-8 The concentration of CTAB that is most often used in the synthesis of gold nanorods is 0.10 M or 100 times its critical micelle concentration, meaning a significant amount of CTAB remains in the bulk of the solution after the GNRs are made, which serves to stabilize the GNRs (prevents them from self-aggregating in solution).6 The CTAB surfactant, so critical for GNR synthesis, is a significant impediment to in-vivo applications. A number of methods have been used to “remove” or partially exchange the CTAB including frequent solvent washing, treatments with surface active materials such as PEGylated thiols or other polymers.9-11 However, during surface exchange CTAB-coated GNR dispersions are destabilized, which results in particle aggregation and low recovery yields of GNRs. In addition, these surface modified GNRs are often contaminated with residual CTAB.9

CTAB Cytotoxicity

The most common synthesis method to produce a high yield of GNRs is the seed-mediated synthesis that involves the use of CTAB and silver nitrate to control the nanorod length and aspect ratio. 12 In this synthetic modification, the tightly bound CTAB bilayer remains adsorbed on the gold surface in addition to silver ions that are reduced and deposited on the gold surface in the form of atomic silver monolayers or sub-monolayers. Any CTAB remaining in the colloidal GNR solutions poses a threat to many biological systems, as it is known to be cytotoxic. It has been reported in the literature that the cytotoxic mechanism of CTAB proceeds by two pathways:13, 14

• The destruction of the lipid bilayer of the cell membrane forming nanoscale holes within the membrane due to the electrostatic interaction of the cationic surfactant head group with the negatively charged cell membrane;

• The catalytic action of one of CTAB’s dissociation products, the CTA+ cation, which causes quenching of the enzyme ATP synthase and thus leads to energy deprivation and death of the cell.

It has been suggested in the literature that of the two reported mechanisms, the second mechanism, which depends on the concentration of free CTA+ in solution, is the most lethal and can be effective at micromolar amounts of free CTA+. Therefore, many reviews articles concerning the biological applications of gold nanorods have one common, defining conclusion – the ability to completely remove CTAB and maintain GNR colloidal stability are key requirements toward their in vivo diagnostic and therapeutic applications. 4, 12, 15, 16

Mitigation Attempts

Scientists first realized CTAB was going to be an impediment to in-vivo applications, a tremendous amount of research has been done on the development of surface functionalization methods aimed at the replacement of CTAB with bio-compatible surface ligands, such as thiol-terminated polyethylene glycol (HS-PEG), alkanethiols, glycols, and thiolated CTAB analogues.10, 11, 17, 18 Among these ligands, thiolated PEGs are the most commonly used molecules as they, theoretically, provide GNRs with a high degree of bio-compatibility.19 However, the main drawback of these PEGylation methods is that only the more weakly bound CTAB molecules at the tips of the rods are replaced with thiolated PEG, producing only partially functionalized GNRs.10, 18 Other methods have been developed to achieve higher PEGylation efficiencies, but these techniques leave a small quantity of CTAB on the GNRs.20, 21 Given the information on the toxic pathways for CTAB above, it has been stated that the amount of CTAB still present is enough to cause cytotoxicity at the elevated GNR concentrations required for their high cellular uptake, as in hyperthermal treatments. In fact, despite the above-mentioned advances, significant challenges for the surface modification of GNRs with bio-compatible molecules abound. First, many existing methods suffer from low PEGylation efficiencies that can limit the effectiveness of the PEG layer as surface coverage has been shown to be important for the effectiveness of PEG layers. Secondly, some encapsulation methods lead to significant decreases in cellular uptake!12 Thirdly, all encapsulation/exchange procedures are subject to experience serious loss of GNRs due to irreversible nanorod aggregation during the purification/separation process. Finally, a fourth, and almost never discussed issue is that these procedures only really deal with the free CTAB in solution, and not the CTAB that is strongly adsorbed to the GNR. A number of reports in the literature have dealt with the problems of stability and bio-compatibility of GNRs via the modification of the CTAB containing GNR surface. In fact, only partial replacement of CTAB on the rods was qualitatively confirmed in many of these cases, but the exact surface composition of nanorods and the amount of residual CTAB was either unknown or not possible to determine.2, 12 For that reason, it is never safe to assume that these rods are CTAB free as there will always be some CTAB wrapped up as part of the bilayer coating and it has been shown that both surface-adsorbed CTAB and monomers in solution are responsible for cytotoxicity observed with CTAB-prepped GNRs!10

Cellular Uptake

Finally, it has been shown in a couple of review articles that understanding the mechanism of cellular uptake of GNRs is critical in their application for hyperthermal treatments. 6, 7 As an example, Hwu et al.22 found that by replacing CTAB with a nonionic polyethylene glycol, the cytotoxicity was substantially reduced. However, these authors also noted that the cellular uptake dropped by approximately 94% resulting in almost no nanorods entering the cell. Hence, to improve the cellular uptake, many researchers use bio-compatible polyelectrolytes to randomly wrap around the CTAB bilayer. This has been shown to increase the uptake, and in one publication, the average number of rods entering the cell was found to have increased from a few hundred to one hundred thousand.9, 23 However, even with these polyelectrolyte-coated GNRs, only a very tiny amount of the material, amounting to a tiny fraction of a typical cell mass, enters into the cell. This small weight fraction may explain the somewhat limited success of hyperthermal therapy for the destruction of tumor cells, which is strongly dependent on the actual number of nanorods present inside the cells. Therefore, an obvious goal is to make gold nanorods without the toxic CTAB that can easily enter cancer cells in large quantities. Moreover, as the CTAB on the surface of gold nanorods cannot be easily replaced with bio-molecules, again removing CTAB from the surface may cause the uncontrollable aggregation of gold nanorods. Finally, concerning the question of cell viability, it is clear that cell viability decreases with the increase in the amount of CTAB-synthesized GNRs and that cell viability is obviously related to the amount of residual CTAB and Ag on the GNRs as stated above! In order for truly bio-compatible rods to be prepared, it is believed that only the complete removal of CTAB on the surface layer of the GNRs will ultimately lead to the best cell viability of the GNRs.24

The SONA Difference

This is the crux of the SONA strategy. Instead of fussing around with ways to coating, removing, exchanging CTAB and hoping for the best, why not make GNRs without CTAB altogether? Our company’s major goal is to introduce to the world a simple, reliable, robust CTAB-free method of making GNRs, one that guarantees colloidally stable and bio-compatible (i.e., CTAB-free) GNRs. These stable and non-toxic (CTAB-free) nanorods could enter cells in much larger quantities, and indeed lead to much improved hyperthermal treatment methodologies, as well as a host of other in-vivo applications.

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Liu, K.; Zheng, Y.; Lu, X.; Thai, T.; Lee, N. A.; Bach, U.; Gooding, J. J. Langmuir 2015, 31, 4973-4980.

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