Dear Hossein,

Surface charge has direct relation with the physical stability of the colloidal systems. Due to the charge on the carrier particles, the particles undergo a repulsion which prevents the particles to aggregate. The surface charge is generally denoted by zeta potential. Ideally zeta potential of a system must be more than +- 30.

Another reason may be the better interaction of the charged particles with the membrane cells.

Surface charge is important for the following: -

1. Stabiliy/ Aggregation of the particles: Particles with near neutral zeta potential or mildly charged surfaces tend to aggregate faster, which can be detrimental in-vivo from the point of recognization byt he RES. Stronger the charge, better is the colloidal stability of the particles and hence a longer shelf life as well.

2. Uptake by the tissues: Strongly cationic particles are known to interact more favorably with the cell membranes thereby enhancing their intracellular uptake. However, cationic particles are also more toxic for the same reason.

3. In many cases a change in the zeta potential is also an indicator of the extent of drug loading in the nanoparticles.

Thank you for your valuable response.

As you menthiond, surface charge resulted in better colloidal stability, but as published in different papers, surface charge causing adsorption of plasma protein to the surface of drug carrier and resulting to recognition by RES and remove from blood circulation.

Yes.... by that i meant formulation stability in-vitro.. i.e. shelf life of the formulation on storage...which is one criticalparameter in development of pharamceuticals.. in-vivo its a diferent ballgame all together, where in my opinion the particle size of the  formulation takes precedence and together with teh surface charge dictates the recognition by RES and opsonization.

Although the aggregation between particles is particularly important in the design of DDS, there are another direct relation between surface charge and the intended application of DDS. That is the interaction of the medium where the drug will be released and the charged or uncharged surface. You need enough affinity between surface and medium to achieve the accurate release because you need higher affinity between drug and medium than drug and the developed material /colloid.

In case of hollow silica, the drug are adsorped by hydrophobicity.  In stomach due to the presence juices which are having high exchange capacity, the drug are desorbed in slow rate.

As Hemat said, particle size and surface charge together dictate the RES recognition. But as I experienced and also see in different publications, surface charge, in some cases, stimulate the adsorption of plasma protein to the surface of drug carrier and resulted in particle size increasing.

By increasing particle size, the RES may be find carrier as a foreign particle and removed it from circulation.

Some excellent answers! Also, it seems like the hydrophilic/phobic nature of the particles must be considered along with their charge. 

Thank you. As I found form answers and my experience, there are different impact on surface charge. Neutral surface charge causes more circulation time and inhibition of plasma protein adsorption to particle surface. positive surface charge could help better interaction with cull membrane and internalization but it could have toxic effect on cells. and, negative charge has less toxic effect but decrease cell adsorption of particles.

By the way, I think introducing positive charge on surface of particles with addition of stealthy materials (such as PEG) or targeting agent could make a suitable carrier for drug delivery systems.

Dear Hossein,

As you said, the zeta-potential largely determines protein adsorption on the particle surface. Our experience with ~200 nm colloidal particles shows that protein adsorption very slightly changes the hydrodynamic diameter of the particles. Indeed, for example, the molecule of albumin (the major plasma protein) is about 5-10 nm in size and if such a protein forms a monolayer over a 200 nm particle, it will increase the effective size to ~210-220 nm, which is ~5-10%.

On the other hand, the type of adsorbed plasma proteins will largely determine the fate of nanoparticles after parenteral (i.v.) administration. Anyway, because all plasma proteins are negatively charged at the physiological pH of blood (7.4), they will surely interact with any positive-charged nanoparticles in the blood. My experience shows that positively charged nanoparticles after interaction with plasma albumin become negatively charged because of adsorption of the negatively charged albumin molecules. So, if you want to know the real zeta-potential, I recommend to measure it at such conditions that resemble the real medium in which the nanoparticles are intended to be used.

One more thing about PEGylated nanoparticles. Adding a non-ionic polymer stabilizer on the surface of otherwise charged particles (no matter positive or negative) will largely decrease the absolute value of the zeta-potential, because the polymer coating will increase the distance between surface charges and the slipping plane (actually, the zeta-potential is the electrical potential difference between the slipping plane and the inner part of the disperse medium). So, I expect the larger PEG molecules you coat on your positive particles, the smaller in absolute value will be the zeta-potential, eventually becoming close to zero for largest PEG molecules. Anyway, the experiment will show what the truth is.

Regards,

GY

I would like to especially thank you for your excellent question...

Thank you for the informative answers,

My question is that which type of PEGylated Nano-particles charges (positive or negative) triggers the immune responses less than the other?

Thank you,

Dear Hossein,

Surface charge on the interactions of the nanoparticles is utmost useful in design of colloidal particles to impart better performance in the physiological system.

Plenty of nanoparticles (NPs) are being tested for use in medical products, particularly in imaging and gene and drug delivery. Cellular uptake is usually a prerequisite and is governed in addition to size by surface characteristics such as hydrophobicity and charge. Surface charge plays an important role in determining the interactions of nanoparticles with biological components. It directly affects the fate of nanoparticles after intravenous administration and absorption of nanoparticles after oral administration. Generally, cationic NPs cause more pronounced disruption of plasma-membrane integrity, stronger mitochondrial and lysosomal damage, and a higher number of autophagosomes than anionic NPs. The NPs were characterized for size, zeta potential, morphology, entrapment and release. The zeta potential of the particles may vary depending on its composition. In general, nonphagocytic cells ingest cationic NPs to a higher extent, but charge density and hydrophobicity are equally important; phagocytic cells preferentially take up anionic NPs. Cells use same uptake routes for cationic and anionic NPs, but high uptake rates are usually linked to greater biological effects.

The in vitro protein adsorption studies revealed that positively charged NPs adsorbed more proteins than other formulations potentially due to highest cell inhibition due to preferential uptake based on electrostatic interactions with cell membranes. Surface charge is undeniably significant in determining the protein adsorption and cellular interactions and must be intently considered during the design of colloidal particles to impart better performance in the physiological system.

Hope content is helpful for you.

Ashish