Engineering

Engineering

Designing Single-Function Therapeutics

Even when beneficial overall, pharmaceuticals often induce harmful side effects – creating a classic trade-off that doctors and their patients routinely confront. NaNots are engineered to do ONE thing – capture a specific type of pathogenic molecule from circulation – and nothing else. Our patented approach enables unparalleled levels of target specificity and off-target rejection, by employing three features:

  1. A core nanoparticle made from biocompatible materials;
  2. A capture agent that binds the core on one end and a specific target on the other; and
  3. Shielding that blocks capture agents from interacting with cell membrane receptors.

We employ various materials, geometries, capture agents and types of shielding, which together enable the creation of single-function NaNots against virtually any molecular target.

Process Summary

  1. NaNots are Injected intravenously like a drug and mix rapidly in circulation (<3 minutes)
  2. Targets collide randomly with NaNots via diffusion (aka Brownian motion) and get captured by agents specific to that target, beneath a shield that blocks cell membrane interactions
  3. NaNots capture a clinically significant quantity of target in 10-20 minutes, at which point scavenging activity ceases
  4. The now-inert NaNots circulate until engulfed by macrophages, which break down the NaNots & their cargo into benign small molecules.

The Role of Diffusion

Diffusion is involved in virtually all biological processes; NaNots rely on diffusion for their mechanism of action to the same fundamental extent that drugs do, but in opposite “directions”.

Diffusion is caused by the tendency of small particles in a gas or liquid medium to “walk” randomly. Objects in a medium are constantly being impacted on all sides by molecules. The smaller the object, the greater the likelihood that random differences in the number of molecules hitting the object from different directions will result in a measurable net force on one side of the object. For objects at the low end of the nano range, such a net force in a given direction, if greater than the inertia of the object, will cause the object to “jump” in that direction. The direction of the net force is constantly changing so the direction of the object’s movement keeps changing too, resulting in the “random walk” that defines Brownian Motion.

The infusion of a drug into the body creates an elevated concentration at the point of infusion, followed by diffusion of the drug – via the random walk of the drug molecules – throughout circulation and into various tissue microenvironments. You can think of drug diffusion as a positive gradient, i.e. the drug migrates from areas of higher concentration to lower concentration throughout the body.

NaNots behave differently than drugs. Upon infusion, they drift “advectively” (i.e. with circulation). Their targets – which are many orders of magnitude smaller than the NaNots themselves – are constantly diffusing throughout circulation. The smaller the target the faster diffusion acts; the cell signals and/or inhibitors that NaNots target are only a few nanometers across and begin colliding with NaNots within seconds of NaNot infusion.

Target Capture

As NaNots capture their selected targets, they reduce concentration of that target wherever the NaNots happen to be in circulation, leading to a systemic drop in target concentration by 80% or more in just 10-20 minutes. Lowering target concentration in circulation creates a negative diffusion gradient that pulls target from whichever microenvironments have elevated concentrations.

One of the advantages of NaNots versus drugs is that they don’t need to contact diseased tissue directly to be therapeutic. NaNots can reduce the concentration of pathogenic targets in virtually any microenvironment without the NaNots themselves ever leaving circulation. For example, NaNots designed to scavenge soluble tumor-generated immune inhibitors from circulation will induce a net migration of these inhibitors from the tumor microenvironment, leading to immune-mediated tumor destruction – without drugs or immune stimulation of any kind. Likewise, NaNots can pull specific soluble targets from the brain without crossing the blood brain barrier.

The vast majority of prior nano-medical therapies have failed because their tissue targeting strategies failed for one reason or another. Eliminating tissue targeting entirely and relying instead on the modulation of circulating target gradients – which we’ve already demonstrated in vitro and in vivo – greatly increases the likelihood that NaNots will prove clinically effective.

Engineering Safety

NaNots do not introduce pharmaceuticals into the body in the conventional sense, but they do incorporate inorganic materials and bioactive capture agents and must therefore be engineered in specific ways to be completely safe. NaNot safety engineering relies on two key principles:

  1. Use of biocompatible structural materials; and
  2. Shielding of capture agents.

There are many biocompatible materials that can be used to construct nano-scavengers. Silicon (the element) and silica (i.e. silicon dioxide, or quartz) are two such materials. Anything grown in soil is loaded with silicon and silica, so not surprisingly extensive data exists on the safety profiles of these materials in humans at far higher plasma concentrations than would result from NaNot infusion.

Capture agents must be shielded because molecules that bind to a bioactive target molecule tend to be bioactive as well. An effective shield is one that allows soluble targets to perfuse through it and get bound by capture agents, yet blocks the capture agents themselves from contacting anything other than the soluble target. Drug side effects generally stem from unintended cell membrane interactions. NaNots prevent this by blocking ALL membrane interactions and only scavenging soluble targets – which still enables a broad array of disease interventions.

Clearance

After scavenging is complete, NaNots are cleared from the body via phagocytosis – primary by Kupffer cells, a type of macrophage concentrated in the liver. This clearance process happens quickly; we control the precise pace of clearance in the NaNot engineering process via application of special coatings on the nanoparticles – either to accelerate or delay recognition of the NaNots by macrophages. Phagocytosis leads to the complete breakdown of NaNots and their cargo into small molecules, which are then excreted.