Cochleate Lipid-Crystal Nano-Particle Targeted Drug Delivery
The advancement of medicine has brought us the security and convenience of popping a pill or receiving an injection for many of our ailments and medical conditions. Modern medicine has made great progress and tremendously improved our life-span, health-security and quality of life. However, solutions such as pills and injections typically rely on a diffusion-like process that essentially “soaks” our bodies in medicine with the hope it gets to every anatomical corner where it may be needed. For numerous medications, in particular those with mild side effects, this approach works to reasonable satisfaction.
Unfortunately, many medications come with associated complications. Not all drugs are soluble enough to easily penetrate all desired tissues and many medications have serious side-effects. Medications with high toxicity can cause numerous painful and often damaging side effects in patients such as, nephrotoxicity (kidney toxicity), hepatotoxicity (liver toxicity), headaches, vomiting, and severe chest pains, amongst others. However, doctors continue to use these drugs because they are effective in treating diseases. Many highly effective medications with significant side effects include anti-bacterial, anti-fungal, anti-viral or anti-inflammatory drugs.
Our lipid-crystal nano-particle cochleate formulation technology offers a drug delivery solution with three differentiating and disruptive features:
- Oral availability;
- Multi-organ protection and enhanced safety; and
- Targeted delivery to the site of the infection and inflammation with the ability to effectively penetrate tissues.
Multi-Organ Protection: The key innovation of our cochleate technology is our ability to package medication inside lipid-crystal particles. Because of their crystal nature, these particles are truly solid and hold on tightly to their medication pay-load. This is where the cochleate technology differs markedly from other lipid delivery technology, such as liposomal delivery. Liposomes are liquid delivery systems which typically leak some of their drug content into our circulatory systems, thus still exposing our vulnerable organs and tissues to toxic effects of often potent medications. Keeping organ-toxic medications inside the lipid-crystal particles strongly differentiates our cochleate technology from other drug delivery approaches.
Targeted Delivery: The size of our lipid-crystal cochleate particles is typically in the range of 50-500 nm. This is very small, and by comparison, close to the size of a large virus or a small bacteria. Our body produces several cell-types that are designed to remove viruses and bacteria from our system. These cell types, such as macrophages, are part of our immune system and “swallow” the bacteria and viruses they encounter in order to protect us from infections. Because of the size our lipid-crystal cochleate particles and the phospholipid surface structure (the cell membranes of bacteria are also made up from phospholipids), macrophages tend to absorb these cochleate particles very well. These macrophages may already contain the microbes we would like to eradicate, or may be on their way to a site of infection or inflammation in our body, taking their pay-load along.
Florescent labeled cochleates in the fungus
Cochleate interacting with a macrophage in cell culture
Cochleate Formulations: Cochleate lipid-crystal nano-particles are composed of simple, naturally occurring materials: phosphatidylserine (PS) and calcium. They are stable and have a unique multilayered structure consisting of a large, continuous, solid, lipid bilayer sheet rolled up in a spiral or as stacked sheets, with no internal aqueous space. This unique structure provides protection from degradation for “encochleated” molecules. Components within the interior of the cochleate remain intact, even though the outer layers of the cochleate may be exposed to harsh environmental conditions or enzymes. The structure is formed when a series of solid lipid sheets engulf drug molecules, a process referred to as “encochleation.” “Encochleation” was invented by Dr. Raphael J. Mannino, our Chief Technology Officer when he was Professor of Medicine at Rutgers University, and was further perfected by Dr. Mannino along with some of our key-scientists. Encochleation involves combining calcium and soy-derived PS, two naturally occurring materials classified as GRAS (generally recognized as safe), through a stirring process to envelop the active pharmacological ingredient. The result is a nano-size encochleated drug formulation.
Once the cochleate, with the drug inside, is administered, it is engulfed by target cells in the body, such as macrophages, and taken directly to the site of infection or inflammation. Once the encochleated drug is captured by the macrophage or other cells, the lower calcium levels inside the macrophage compared to the high level of calcium outside the macrophage triggers the cochleate to open, thus releasing the drug inside the cell. Because the drug is locked up in the solid cochleate particle or in the target cells, the rest of the body is protected from the toxicity of the desired medication.
Oral Drug Delivery: Numerous pharmaceutical compounds have been encochleated by us and tested in animals. Our most advanced encochleated medication has also been tested in a phase 1 study in humans. In most of these studies, including the human study, the encochleated medications were orally administered. We believe that the unique cochleate crystal-structure protects the drug from degradation when it passes through the gastrointestinal (GI) tract and that its lipid surface features facilitate the particle to be absorbed into the blood stream.
Many drugs that are currently on the market are only effective in treating diseases when given intravenously (IV). For example, many anti-infective drugs must be administered via IV in order to be effective. IV administration presents several challenges to care, such as risk of infection, patient discomfort from injections, and higher cost of care than oral administration (IV delivery must be performed by a doctor or nurse, often within a very expensive hospital setting). Although several technologies have been used to attempt to convert IV drugs to orally delivered medications, success has been limited due to the difficulty in achieving adequate bioavailability (i.e., the amount of drug that is absorbed into the body) with oral formulation. The potential application of the cochleate technology for the delivery of injectable medications offers significant clinical and commercial value if successfully demonstrated in human clinical trials.
We believe that the anti-fungal medication amphotericin B is a good example to demonstrate the unique features of the cochleate technology (see above). Current commercially available formulations of amphotericin B cannot be absorbed through the GI tract and therefore must be given intravenously. By encochleating amphotericin B, in the above mouse candidiasis (a pathogenic yeast infection) model study which was conducted at the PHRI in Newark NJ, we demonstrated comparable survival with the oral administration at a quarter of the IV dose. The very mild side effect/toxicity profile observed with the encochleated treatment group is consistent with lower dose and drug shielding properties of the cochleate technology. With this technology, we are able to offer a categorically different formulation that delivers amphotericin B, orally, to the target cell, with reduced toxicity.
We have significant experience with a range of pharmaceutical compounds in various animal models. This chart below demonstrates the versatility of the technology and its broad application potential.
We believe our cochleate delivery technology can be used to reformulate a wide variety of molecules and drugs which, (i) require delivery technology to effectively protect molecules and drugs in the body and could benefit from efficient delivery and cellular uptake by target cells, and (ii) are currently only available in IV formulations or, (iii) otherwise experience significant toxicity-related adverse events. Leveraging our cochleate delivery technology, we believe we can develop a robust pipeline of product candidates, either internally or through robust strategic partnerships with pharmaceutical and biotech companies. We have tested a range of pharmaceutical compounds reformulated by our cochleate delivery technology in proof-of-concept animal studies, including oligonucleotides (mRNA, siRNA, DNA plasmids), vaccines, anti-inflammatory agents, NSAIDs and atovaquone. By way of example, in 2016 we received a patent issuance related to cochleate compositions directed against expressions of proteins. The allowed patent claims cover our proprietary methods related to the composition and the formation of encochleated siRNA for potential use as therapy for regulating gene expression. We intend to pursue opportunities to develop products, either alone or in partnership with other pharmaceutical or biotech companies, related to this technology and this remains a key part of our strategy to maximize the value of this unique and disruptive lipid-crystal nanoparticle delivery technology.
Matinas BioPharma is open to exploring partnerships with biotech and pharmaceutical companies to develop new drugs using cochleates. For partnership inquiries, please contact us.