75 Years of Innovation: FOX Three Molecular Guidance System

SRI 75 Fox 3 Japan blog

How the FOX Three Molecular Guidance System helps large drugs cross barriers

The 75 Years of Innovation series highlights the groundbreaking innovations spanning from SRI’s founding in 1946 to today. Each week, SRI will release an innovation, leading up to its 75th anniversary in November 2021.

SRI 75 Fox 3 Japan blog

Fox Three creates the potential to greatly expand the use of biotherapeutics” Nathan Collins, Ph.D., Chief Strategy Officer, SRI Biosciences, a division of SRI International

The 1960s sci-fi film Fantastic Voyage was about a submarine which was shrunk in size to allow doctors to enter the body of an injured man to repair his brain. The film may have been just a story, but it talks to something very important in the treatment of disease — drug delivery. How to get a medication to ‘hit the right spot’ is as important as the drug itself; this is especially difficult if the drug molecule is large.

SRI International solved the delivery of large molecular drugs with their unique guidance system, known as the FOX Three Molecular Guidance System (MGS). This is how SRI took a big molecule on a ride into new dimensions of drug delivery.

FOX Three MGS Making Sure Big Molecules Hit Where It Helps

Drugs can be differentiated by size, aka, small or large; this classification system is based on the molecular weight (size) and helps inform how a drug can be transported around the body and to specific target sites. Most medicinal drugs are classified as ‘small’, that is under 900 Daltons (Da), which is a unified atomic mass unit. Small molecule drugs can usually be taken orally, in pill form. This means that they are easily distributed to patients who can then take them at home or under supervision. Once ingested, they can then be absorbed into the bloodstream.


However, another class, the large molecule drugs, offer the potential for great medicinal benefits. The trouble is, their sheer size prevents them from being easily delivered to the target site. Examples of large molecules include ‘biologic’ medications such as vaccines, tissues, genes, and blood components, e.g. plasma. Some autoimmune patients, such as those with conditions including dermatomyositis and ulcerative colitis, fail to respond to simpler drugs, such as Methotrexate (454 Da) and so turn to large molecular biologic treatments.

Getting these large molecules into the bodily systems that require medical intervention is complicated. The FOX Three Molecular Guidance System developed by SRI International was designed to overcome the inherent barriers in cellular systems. This is how the MGS works…

Overcoming the Cellular Barriers to Effective Big Module Treatments

The structure of human cells is such that they are built to let certain things in and keep certain things out; to do this, the cell uses a semi-permeable membrane made of three classes of lipids that form a bilayer. In the case of an exogenous molecule, such as a medicine, the drug molecule must cross this membrane to act.


In the case of large molecules, such as biologics, the cell membrane acts like a barrier, the drug molecule being unable to cross, preventing intracellular delivery of biotherapeutics. To overcome this barrier the FOX Three MGS uses a process that provides highly targeted and controlled delivery of a large molecule across the membrane barrier. The FOX Three technology works by using modeling to match the receptor on a target cell to a peptide and then synthesizes the peptide to exact requirements. The peptide becomes a unique delivery agent called an “MGS”, the peptide delivering the cargo (drug) across the membrane and into the target cell. The targeted delivery helps to avoid uptake in other cells and so helps to reduce the potential of drug sensitivity. One of the key differentiators of the FOX Three MGS is that once inside the cell, the peptide directs the drug to the required location, e.g., an organelle. Because the MGS is modular, the cargo can be virtually any bioactive compound.

The MGS can be used for both large and small molecule targeted therapeutics, for many disease states, in vitro and in vivo diagnostics, as well as personalized therapies for cancer, intracellular nanoparticle delivery, and innovative immunotherapies.

Safe and Effective Drug Delivery for Better Patient Outcomes

The 20th century has seen the development of many new types of drugs. These medicines have vastly improved life expectancy and have helped to give sufferers of some of the most complex diseases a better standard of living. New techniques of drug discovery, including molecular modeling and combinatorial chemistry, has brought many drugs onto the market, some of which are large molecules. However, getting these large, complex biologics into a cell to do their job is a challenge. The FOX Three Molecular Guidance System has risen to the challenge and beyond. Unlike its 1960s sci-fi counterpart, this designer peptide acts in a highly-targeted way, taking the guesswork out of molecular medicine.


The FOX Three MGS has been used to deliver drugs directly to targets inside cancer cells, helping scientists to develop new treatments. And, as new diseases like COVID-19 raise their head and look humanity squarely in the cell, the highly targeted mechanisms offered by the FOX Three MGS could potentially be the answer to successful vaccine delivery.


SRI International, SRI International Announces Drug Research Collaboration with Ionis Pharmaceuticals: https://www.prnewswire.com/news-releases/sri-international-announces-drug-research-collaboration-with-ionis-pharmaceuticals-300678330.html

Fantastic Voyage: https://www.imdb.com/title/tt0060397/

Eichman, Chad., Large Molecules vs. Small Molecules: https://phenomenex.blob.core.windows.net/documents/73dc2ce1-822a-4153-babb-19dce099d08b.pdf

Yang NJ, Hinner MJ. Getting across the cell membrane: an overview for small molecules, peptides, and proteins. Methods Mol Biol. 2015;1266:29–53. doi:10.1007/978–1–4939–2272–7_3

Brown, K., et.al., Patent Application PCT/US20 18/04 1403, MOLECULAR GUIDE SYSTEM PEPTIDES AND USES THEREOF, publication date 17 January 2019: https://patentimages.storage.googleapis.com/e4/84/5a/663bf7a492bdab/WO2019014190A1.pdf

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