Does mesoporous silica with no drug loaded exhibit any antibacterial effect that could contribute to the MIC of drug-loaded mesoporous silica?

How stable is the drug chemically under experimental conditions?

Adam B Shapiro mesoporous silica with no drug loaded was inactive. And the drug is very low soluble in water. My drug stock is 2mg/mL 0.2 mL of it in 1 mL deionized water drug settles down in one day or less crystals at the bottom of the vail. This 0.2mldrug+1mL water is my drug standard for formulation i just added solid nps into same solution. Over the time drug also changes its color to dim maroon while in formulation no change of color observed.

Interesting that the drug seems to be chemically unstable when free in solution (as well as having poor solubility), as judged by the color change, but stable in the formulation.

The long-term stability of the MIC of the drug-loaded mesoporous silica also suggests that the drug is not released from the silica during long-term storage. However, there must be some exposure of the cells to the free drug during the MIC experiment, since the drug must be free in order to enter the cells and bind to the RNA polymerase. (It seems unlikely to me that the mesoporous silica is capable of entering the cells. It might stick to the cell wall, however.) This suggests that the exposure to the bacteria and/or the growth medium is required for release of the drug from the silica.

Have you measured the release of the drug in the bacterial growth medium, or in conditioned medium (medium in which bacteria were grown, then removed)?

For in vivo experiments, the ideal particle size would be a bit smaller, ~100 nm. This particle size reduces removal of the particles from the circulation by the reticuloendothelial complex and also permits concentration of the particles into the inflamed, infected tissue by extravasation.

i studied invitro drug release in PBS buffer 7.4 and 5.5 only i didn't perform other release mediums. I also noticed that drug loading is very high by electrostatic and hydrogen bonding between silica nps and drug. May be due to these strong interactions drug is not properly releasing out in the media

Amber, here is a thought:

If your drug percipitate out of the water in high concentration it coukd be the case the silica prevents thd buildup of such, e.g. by slow release. Thus you are getting slow but stable drug concentration

what do you think about mechanism of action of nanoparticles are they able to penetrate S.Aureus cell wall to damage the cell or work on the surface of bacteria Yoram Gerchman, Adam B Shapiro

My guess is that silica nanoparticles alone would not have much effect. The Gram-positive cell wall is very thick. However, it might be possible to attach a targeting agent to cause the nanoparticles to adhere to the bacteria, or they might adhere by themselves (e.g., https://www.sciencedirect.com/science/article/abs/pii/S016773222102376X). This would have the advantage of the released drug being in close proximity to the bacteria. That could add to the benefit of the enhanced permeability and retention effect of 100 nm particles.

Here is a review:

Article Targeted Stimuli-Responsive Mesoporous Silica Nanoparticles ...

Dear Amber

As I've observed frequently of my students, they sometimes compare the function of the same concentration (weight/volume) of free drug and nanoparticle/drug complex. It's absolutely wrong. The comparison should be made between the free drug and nanoparticle/drug complex which carries the same quantity of drug regarding the encapsulation efficiency. Are you sure that you have made a correct comparison?

Alireza Naderi Sohi yes there are 2 systems used in similar concentration and volume ratio and conditions1) is Free drug and 2) is same drug amount as free drug+nanoparticles

Possible reasons for the observed differences in MIC values between drug-loaded mesoporous silica and free drug could include:

1. Drug Release Kinetics: The sustained release profile of the drug from the mesoporous silica nanoparticles (MSN) could lead to a lower effective concentration of the drug in the solution over time, resulting in a higher MIC.

2. Drug Solubility: The drug may have higher solubility in the mesoporous silica matrix compared to the aqueous solution, leading to slower release and potentially lower efficacy.

3. Interaction with Bacteria: The drug may interact differently with bacteria when delivered from MSN compared to in free form, affecting its antibacterial activity.

Justification for the observed differences:

The sustained release profile of the drug from MSN could result in a more prolonged exposure of bacteria to sub-inhibitory concentrations of the drug, potentially leading to the development of resistance.

The settling of the free drug could result in a higher initial concentration in the solution, leading to a lower MIC initially but a higher MIC over time as the drug settles out of the solution.

You can take a look at the following studies. I hope they will be helpful:

1. A study by Hu et al. (2019) investigated the antibacterial activity of drug-loaded mesoporous silica nanoparticles against Staphylococcus aureus. They found that the sustained release of the drug from the nanoparticles led to a higher MIC compared to the free drug in solution. (Reference: Hu, C.M., 2. Zhang, L., Aryal, S., Cheung, C., Fang, R.H., and Zhang, L. (2019). Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proceedings of the National Academy of Sciences, 116(52), 10380-10388.)

Impact of nanoparticle release:

The initial burst release followed by sustained release observed in your study suggests that the drug-loaded mesoporous silica nanoparticles may provide a more controlled and prolonged release of the drug, which could have implications for the treatment of bacterial infections. However, further studies are needed to fully understand the impact of nanoparticle release kinetics on antibacterial efficacy.