Westwood Bioscience have developed a multifunctional mesoporous silica nanoparticle (MSNP) platform that has been adapted to provide high-dose chemotherapy that is encapsulated in the particle by a lipid bilayer.
The “Silicasome” is a comprised of a mesoporous silica core (resembling a hollow glass bubble), which is surrounded by a lipid bilayer that encapsulates drugs inside the pores as well as inside the bilayer itself.
Although Silicasomes morphologically resemble liposomes, there are important differences in the amount of chemotherapeutic agent that can be loaded, the carrier stability, amount of drug that is delivered to the cancer site, efficacy and toxicity reduction.
These differences are due to the increased packaging space for chemotherapeutic agents like irinotecan in the silicasome as well as the stability of the lipid bilayer during the phase of systemic biodistribution and storage. The supported lipid bilayer in the silicasome is more stable than the non-supported bilayer in a liposome.
The increased leakage of highly toxic drug like irinotecan from liposome can lead to systemic toxicity, allowing us to demonstrate major toxicity reduction by an irinotecan silicasome carrier in organs such as the gastrointestinal tract, liver, and bone marrow compared to a liposome.
These features also allow for the improved pharmacokinetics and treatment efficacy of Silicasomes versus liposomes in an animal pancreas cancer model.
The composition of the Silicasome allows for different drug loading methods that can use both the interior packaging space of the particle as well as its lipid bilayer to incorporate the drugs.
For instance, the irinotecan carrier encapsulates the drugs into the porous interior of the particle, while the combined delivery of gemcitabine and paclitaxel by the silicasome is achieved by loading gemcitabine into the particle pores while incorporating paclitaxel into the lipid bilayer.
It is also possible to put a proton-releasing trapping agent into the porous interior, which could allow multiple weak basic drugs to be remotely imported across the lipid bilayer for drug delivery.
In the case of the dual delivery gemcitabine/paclitaxel nanocarrier, Westwood scientists have demonstrate that these drugs can be loaded in a ratiometric fashion to allow synergistic drug action at the pancreas cancer site. This allowed the Silicasome to significantly outperform (an order of magnitude) a combination of free gemcitabine plus Abraxane™ (commercial albumin nanoparticle that packages paclitaxel) in a orthotopic pancreas cancer model.
Importantly, the improved efficacy outcomes with Silicasome carriers have been achieved by “passive” delivery without the need to add targeting ligands. While the addition of targeting ligands are frequently speculated to improve drug delivery, this adds higher cost and potential therapeutic problems.
However, it is quite feasible to add ligands to the Silicasome, or enhanced particle uptake at the tumor site by a cyclical peptide that increases transcytosis or the release of small molecule inhibitors that open the pancreas cancer stromal-vascular gate.
Silicasomes have proven to be safe and biodegradable in preclinical animal studies.
Mesoporous silica is biodegradable in water and biological media, and breaks down into silicic acid. In an animal study that used a metabolic chamber, 94% of the injected silica dose in the mesoporous nanoparticles could be recovered in the urine and feces within 7 to 10 days in mice. Moreover, intact mesoporous silica nanoparticles have not been shown to exhibit the reactive surface chemistry that can render nanoparticles hazardous. The lipid bilayer, which is the homologous to the lipid composition of the cell surface membrane, is also biodegradable and contributes to the toxicity reduction by encapsulating hazardous chemo agents.