Thread by @raphavisses

@psobolewskiPhD Fig 3 is the most convincing. It shows some photothermal killing dependent on cell type and laser power. No statistics.

@psobolewskiPhD finally, ponder the last line #17's abstract:
"both efficient cancer cell diagnostics and selective photothermal therapy are realized at the same time."

Diagnostics and therapy achieved? These are (very poor) experiments on *cell lines*. The hype is breathtaking.

@psobolewskiPhD That breathtaking hype however is nothing compared to the press release: "Researchers [.] have found tht by using gold nanorods, rather than nanospheres, they can detect malignant tumors hidden deeper under the skin & destroy them with lasers [.] - w/o harming the healthy cells.

PR: sciencedaily.com/releases/2006/…

#18, Panáček et al; Silver Colloid Nanoparticles:  Synthesis, Characterization, and Their Antibacterial Activity
dx.doi.org/10.1021/jp0638…

The paper has three figures and two tables. It is largely about synthesis using different sugars as reducing/capping agents (Fig 1-3, Table 1), and then evaluate their antibacterial activity (Table 2).

From the intro: "Contrary to bactericide effects of ionic silver, the antimicrobial activity of colloid silver particles are influenced by the dimensions of the particlesthe smaller the particles, the greater antimicrobial effect [3,4]"

Ref 3 is Morones et al, #15 - It does not show what Panáček et al says it shows. It does not even test different sizes.

https://twitter.com/raphavisses/status/1110543980289232902

Ref 4, Baker et al, is highly cited (856) but did not quite make it to my hall of fame.
researchgate.net/publication/78…

Ref 4 also does not show that "smaller the particles, the greater the antimicrobial effect".

Back to #18; the synthesis section is pretty cool. Includes nice EM, size distributions and spectra. Silver nanoparticle synthesis is harder than gold. These seem decent particles:

"Antibacterial Study. The smallest size silver nanoparticles having a very narrow size distribution [.] were tested as antimicrobial agents. The average sizes, d, were 44, 50, 25, and 35 nm for Ag particles, prepared by using glucose, galactose, maltose, & lactose, respectively."

Based on the table below, #18 also concludes that smaller leads to better antibacterial killing. That is what their data suggests but dismissing the effect of the capping reagent is not very reasonable. It is clear that it would affect rate of dissolution as well as interactions.

#19, Rosi et al, Oligonucleotide-modified gold nanoparticles for intracellular gene regulation
dx.doi.org/10.1126/scienc…

Those who follow me will already be familiar with this paper. It is the first intracellular application of what would later be coined "Spherical nucleic acids". Joint first author David A. Giljohann is now CEO of Exicure.

#19 is still having an important impact. In a Nov 2018 pitch to investors, Giljohann explains that SNAs "solve the delivery challenge". He refers to #19 (and other papers) to say that "stability [against nuclease] goes 10 to 100 folds higher" [3:30 - 5:30]

There are 3 ongoing clinical trials.
I have been called by @CHADNANO a "scientific terrorist" in front of a packed room #ACSBoston for questionning the conclusions of this and follow up papers. See
raphazlab.wordpress.com/2018/08/29/sci…
and
the-scientist.com/news-opinion/r…

@CHADNANO Enough for recent context. Back to the content of #19.
"We describe the use of gold nanoparticle-oligonucleotide complexes as intracellular gene regulation agents for the control of protein expression in cells."

"Unexpectedly, ASNPs readily enter cells despite their coating with negatively charged DNA."
[...]
"The uptake was studied using confocal fluorescence microscopy. Observation of Cy5.5 fluorescence throughout the cytoplasm provided proof of particle uptake."

The evidence that those particles enter cells is strong. But it should not have been surprising given that gold colloids, including negatively charged, had been used to study endocytosis for decades.

The big question that is nt addressed is how & where do they go inside the cell. Unfortunately the low res microscopy provides no information. The word "endocytosis" is not pronounced. If they enter by endocytosis, they cannot interact with RNA or DNA in the cell. Not discussed.

Fig 1 is a scheme of the particles.
Fig 2 shows entry of particles in the cells. The dark panel in 2A is supposed to show absence of degradation.

2C is in vitro experiments showing that nuclease DNAse I cuts faster the free DNA than the SNA. But degradation still occur and in less than 2h, 25% of the particle is gone. So why should the particle resist for 48h in cells? - not discussed.

Fig 3 is the antisense experiment. Buckle up.
3A and B is just cells expressing GFP; B is a stack in z.
3C and D is same cells exposed antisense nanoparticles supposed to block GFP expression. Red is fluorescence of the oligo attached to NPs; green is still GFP.

The most interesting thing is in 3C. In the bright field images you can see clearly dark spots that are not there in 3A. This means huge amount of particles... and significant absorbance in the visible which would reduce GFP signal even if there was no difference of expression.

Table 1 reveals that effect of the nanoparticles on GFP expression are relatively small (between 11 and 20% reduction).

#20, Xia et al, Comparison of the Abilities of Ambient and Manufactured Nanoparticles To Induce Cellular Toxicity According to an Oxidative Stress Paradigm
dx.doi.org/10.1021/nl0610…

This is a 10 figures paper...

and, well, if I review all figures in detail, I might loose the will to live.

The main message of the article is that "ROS generation and oxidative stress can be used as a paradigm to assess NP toxicity".

What does that mean?

The idea (I think) is that the capability of generating reactive oxygen species (outside of cells) would be a good guide of how toxic particles might be. And that would be because the mechanism would involve ROS causing toxicity.

One pb w/ that "paradigm" is that ROS are often a cellular response to stress. It is quite bizarre tht this is not discussed. ROS are all the way through presented as something NPs do. It was already well known that ROS are signalling molecules ncbi.nlm.nih.gov/pubmed/11356180

The other pb is that their data don't support the idea that looking at ROS production by nanoparticles is predictive of toxicity in any way.

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