Sneaking drugs into cells using new nanoparticle materials

 

 

Short interference RNA, or siRNA, are a class of naturally occurring molecules that help regulate protein levels in our cells by “silencing” genes that encode specific proteins. They have great potential as therapeutic agents due to their ability to regulate protein levels, which could otherwise reach toxic levels and cause degeneration of cells, such as in prion disease or amyloidosis. However, scientists have difficulty getting siRNA to where they need to be in the body because as drugs, they are unstable and generate an immune response, prompting the body to quickly dispel them.

Researchers led by Pieter Vader — a professor of experimental cardiology and regenerative medicine at the University of Utrecht, the Netherlands — have been developing an advanced delivery system to overcome this limitation.

“siRNA has potential as a drug treatment for diseases in which specific genes or disease-causing proteins need to be silenced” Vader explained. “siRNA needs to be active in the cytoplasm of target cells. However, as a large, negatively charged and polar molecule, it cannot readily cross cellular membranes.”

The team created hybrid nanoparticles to package and protect siRNA from enzymes that would degrade them. The new platform takes advantage of the amphiphilic nature of liposomes (fatty droplets which come together to naturally form a protective ‘bubble’ or sphere) and the natural delivery system of extracellular vesicles (EVs) (particles secreted by cells to communicate with other sites in the body).

siRNA can be easily packaged into the hybrid nanoparticles and shielded from the body’s defense mechanisms due to the ability of liposomes to self-assemble around the drug and forming a protective hydrophobic coating.  The encapsulated siRNA can also easily reach the target location in the body due to EVs’ natural ability to pass through a cell’s outer membrane and deliver cargo.

The team used a technique whereby a mixture of lipids and solvent are dehydrated to leave a thin lipid film, that is then rehydrated in water containing EVs and/or drug molecules (in this case siRNA). Subsequently, siRNA is encapsulated by lipid droplets to form liposome-EV-siRNA hybrids.

“We show that with increasing relative EV content in our hybrids, uptake into cells becomes no longer dictated by the liposome content,” explained Vader. “Thus, the EV surface molecules now seem to dictate which cells can internalize and process these hybrids.”

By altering the ratio of EV to liposome in the hybrid formulation, it is possible to selectively choose which cells will take up the drug. Moreover, multiple cell types including kidney, nerve and ovarian cells were capable of taking up the hybrid particles without any toxic effect or adverse effect. These are important factors when designing new drugs because, in the body, hybrids have to potential to target only diseased cells types and limit unwanted side-effects.

Next, the team investigated what would happen if the hybrid formulation contained EVs from a specific population of stem cells and , interestingly, they promoted healing and survival of breast cancer cells. The ability of these nanoparticles to retain stem cell function, when exposed to a variety of different diseased cell types, would hold great promise for the development of new drugs targeted at cancer and degenerative disease.

 “It’s too soon to tell where the most potential lies for our delivery system, but we know that EVs derived from progenitor cells have intrinsic regenerative properties” said Vader. “Thus, regenerative medicine applications seem most logical.”

As with any new drug formulation, however, the team still have some hurdles to overcome before this treatment platform can become commercially available. Nonetheless, these results are insightful and show potential for the future of drug delivery for difficult-to-treat diseases.

 

Ref:https://www.advancedsciencenews.com/sneaking-drugs-into-cells-using-new-nanoparticle-materials/

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