Invented by Tarek M. Fahmy, Michael Look, Joseph Craft, Yale University

Inflammatory and autoimmune disorders and conditions are becoming increasingly common, affecting millions of people worldwide. These conditions can be debilitating, and often require long-term treatment with medications that can have significant side effects. However, recent advances in nanotechnology have led to the development of a new class of treatments that show promise in treating these conditions: nanolipogels. Nanolipogels are tiny particles made up of a lipid bilayer that encapsulates a hydrogel core. They are designed to be biocompatible and biodegradable, which makes them ideal for use in medical applications. They can be loaded with drugs, peptides, or other therapeutic agents, and can be targeted to specific tissues or cells in the body. One of the key advantages of nanolipogels is their ability to deliver drugs directly to the site of inflammation or autoimmune activity. This targeted delivery can reduce the amount of drug needed to achieve therapeutic effects, which can minimize side effects and improve patient outcomes. Additionally, nanolipogels can protect drugs from degradation and clearance by the body, which can increase their effectiveness. Several studies have shown that nanolipogels can be effective in treating a range of inflammatory and autoimmune conditions, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. In one study, researchers used nanolipogels to deliver a peptide that inhibits the activity of a protein involved in inflammation. The treatment significantly reduced inflammation in a mouse model of rheumatoid arthritis, and the effects lasted for several weeks. Another study used nanolipogels to deliver a drug that targets immune cells involved in multiple sclerosis. The treatment reduced the severity of symptoms in a mouse model of the disease, and also reduced the number of immune cells in the brain and spinal cord. While these studies are promising, more research is needed to fully understand the potential of nanolipogels in treating inflammatory and autoimmune conditions. Researchers will need to determine the optimal dosing and delivery strategies, as well as investigate any potential long-term side effects. Despite these challenges, the market for methods for treating inflammatory and autoimmune disorders and conditions using nanolipogels is expected to grow in the coming years. The global market for nanolipogels is projected to reach $2.5 billion by 2025, driven by increasing demand for targeted drug delivery systems and the growing prevalence of inflammatory and autoimmune conditions. In conclusion, nanolipogels show great promise as a new class of treatments for inflammatory and autoimmune disorders and conditions. While more research is needed, the potential benefits of targeted drug delivery and reduced side effects make nanolipogels an exciting area of research and development in the field of nanomedicine.

The Yale University invention works as follows

Compositions and methods to treat or ameliorate the symptoms of an autoimmune or inflammatory disease or disorder are described in this document. These compositions include a nanolipogel that allows for sustained delivery of one or more active agent of choice, which is preferably a drug to treat or ameliorate the symptoms of inflammatory disease or disorder. A nanolipogel may include a lipid bilayer around a hydrogel core. This can optionally contain a host molecule such as an absorbent or a cyclodextrin. Preferential embodiments include at least one active agent as an immunosuppressant.

Background for Methods for treating inflammatory and other autoimmune disorders and conditions using nanolipogels.

Autoimmune diseases can be described as an immunological loss of self tolerance. Systemic lupus, which is a classic autoimmune disease, has a hallmark of persistent T and B cells that are abnormally reactive to self antibodies. These T and B lymphocytes can lead to the formation of pathogenic autoantibodies, which accumulate in tissues, and cause inflammation damage (Shlomchik, Rahman, and others, Nat Rev Immunol 1(2):147-53 (2001); Rahman et. al. N Engl J Med 358(9) 929-39 (2008) Recent research has revealed the role of innate antigen-presenting cells. Recent research has shown that macrophages and dendritic cells contribute to lupus pathology through the production of proinflammatory cytokines (Blanco, Science, 294(5546),: 1540-3 (2001); Triantafyllopoulou, Proc Natl Acad Sci USA 107(7), 3012-7 (2010)) as well as promoting the expansion of autoreactive T- and B cells (Teichmann el778 (2010 HTML0).

Current treatments for autoimmune diseases have relied on the long-term administration of hydrophobic drugs (Monneaux et. al. Arthritis Res Ther 11(3):234 (2009) or biological agents (proteins or neutralizing antibodies) (Ronnblom et., Nat Rev Rheumatol 6(6): 339-47 (2009); Navarra et., Lancet 377(97677):721-31 (2011); Sfikakis et, Curr Opin Rheumatol 17(5): 550-7 (2005)), which can inhibiting the activation or proliferation of lymphocytes. The conventional administration of pan-immunosuppressive small molecule therapies, which are often achieved with hydrophobic drugs such as cyclophosphamide, azathioprine, or mycophenolate mofetil (MMF), provides therapeutic immunosuppression by blunt reduction of total immune cell numbers. This can cause organ toxicities, lymphopenias, and anemia and make human patients more vulnerable to opportunistic infection (Lee, Lupus 19(6):703-10 (2010); and Moroni, Clin J Am Soc Nephrol 1(5):925-32 (2006). Although biological agents that deplete T cells costimulatory signals or block B cells may offer a more targeted, cell-specific approach, they might not be effective in reducing autoimmunity due to innate antigen-presenting cells.

An ideal therapeutic strategy would combine the pan-suppressive effect of small molecule therapies with specificity targeting immune cells involved in Lupus pathogenesis. For therapeutic purposes in other diseases, such as cancer, nanoparticles are being actively investigated (Blanco, and al. Cancer Sci,102(7):1247-52 (2012)) and infectious pathogens. (Look, al.,Adv Drug Deliv Rev. 62(4-5),:378-93 (2010)). These nanoparticle drug delivery devices can be loaded with therapeutic substances using a variety of methods. Their use in vivo may improve their bioavailability and target specific tissues or cells of therapeutic importance (Fahmy, Materials Today, 8(8), 18-26 (2005). The effectiveness of nanoparticles in drug delivery vehicles for therapeutic immunosuppression has been largely overlooked. The only published research on nanoparticles in lupus is limited to studies of nanoparticles designed to travel to the relevant site of lupus pathology (Scindia, Serkova, and al., Radiology 58(12),:3884-91 (2008), Serkova, Serkova, and al., Radiology 255(2):517-256). However, no studies have shown that these nanoparticles can be used to deliver therapeutic drugs. It is not known how nanoparticles interact with the different immune cells in Lupus and if these interactions can be exploited for improved lupus immunotherapies.

Numerous types of nanoparticle systems are used, including liposomes, synthetic polymeric matrix formulations, and nanoparticles. This purpose is possible with several nanoparticle platforms. These platforms can be either vesicular (such as liposomes), or comprise solid biodegradable matrixes (such a polyester-based nanoparticles). Although liposomes can be easily modified to encapsulate small hydrophilic molecules and proteins, the stability and release profiles of encapsulated substances can be problematic (Maurer et al. Expert Opinion on Biological Therapy 1(6):923-947 (2001). Biodegradable solid particles such as those fabricated from poly(lactic-co-glycolic acid) (PLGA), are highly stable and have controllable release characteristics, but pose complications via induction of maturation of dendritic cells (Yoshida, et al., J Biomed Mater Res A, 80(1):7-12 (2007)) and degradation into acidic byproducts that may promote inflammation (Shive, et al., Adv Drug Deliv Rev, 28(1):5-24 (1997)).

There is no other effective treatment for Lupus than generalized immunosuppression.

It is, therefore, the object of this invention to provide compositions that treat lupus more selectively and with greater efficacy.

It is also the object of this invention to provide a method of treating lupus with greater selectivity, efficacy, and efficacy.

This document describes compositions and methods to treat or ameliorate the symptoms of an autoimmune or inflammatory disease or disorder. These compositions include a nanolipogel that allows for sustained delivery of one or more active agent of choice, preferably a drug to treat or ameliorate one or more of the symptoms of an autoimmune or inflammatory disease. A nanolipogel may include a lipid bilayer around a hydrogel core. This can optionally contain a host molecule such as an absorbent like a cyclodextrin, or ion exchange resin. Preferential embodiments include at least one active agent as an immunosuppressant. Some nanolipogels include a targeting moiety which increases the specificity of the particle for activated cells T cells or antigen-presenting cells.

There are also methods for incorporating agents into nanolipogels. The nanolipogel may be loaded with one or more drugs to allow for controlled release. The nanolipogel may be loaded with one or several first agents during its formation, and one or two second agent(s), following the formation of the nanolipogel by the process for rehydration in the presence or absence of the second agents. Agent(s) may be dispersed in the hydrogel matrix and associated with one or several host molecules. They can also be covalently attached to the nanoliposomal membrane, as well as combinations thereof. You can selectively incorporate drugs at these locations within the nanolipogel.

The compositions described herein can also be used to treat or alleviate symptoms of autoimmune or inflammatory diseases or disorders. The preferred embodiment of the treatment includes suppression of both T- and B-cell effector types. These methods may include activation, proliferation, response, and function of T cells or increasing tolerance to antigen-presenting cell, or combinations thereof. The formulations can be used to target and inhibit these immune cells using immunosuppressive drugs with lower doses and less toxicity than conventional methods. This technology can be used to treat a variety of inflammatory and allergic disease states. It can also be used to suppress allograft rejection, treatment of allergic disorders, and for the treatment of autoimmune diseases.

I. Definitions

?Nanolipogel,? “?Nanolipogel” is a core-shell nanoparticle with a polymer matrix core that can contain a host mole, and a liposomal shell which may be unilamellar (bilamellar) or optionally crosslinked.

?Host molecule,? As used in this document, the host molecule is a molecule that reversibly associates itself with an active agent to create a complex. In particular, the host refers to a molecule which forms an inclusion complex with an agent. Inclusion complexes form when the guest (i.e. the active agent) inserts into the cavity of another molecule or group of molecules or material (i.e. the host). A small molecule, oligomer or polymer can be used as the host. Examples of hosts are polysaccharides like amyloses and cyclodextrins and other cyclic and helical compounds that contain a plurality aldose rings. For example, compounds formed by 1,4 and 1,6 bonds of monosaccharides (such a glucose, fructose and galactose), and disaccharides, such as sucrose and maltose. Others include cavitands and cryptophanes as well as crown ethers, crown ethers and dendrimers.

?Small molecule,? As used herein, small molecules are those with a molecular mass of less than 2000 g/mol. More preferably, less than 1500 g/mol. Most preferably, less than 1200 g/mol.

?Hydrogel,? “?Hydrogel” is a water-swellable, polymeric matrix made from a three-dimensional network macromolecules linked together by crosslinks. It can absorb substantial amounts of water (by weight), to form a gel.

?Hydrodynamic radius? The radius of a particle is, as used in this article, the radius of a hard, perfectly spherical object with the same mass as the particle and the same rate for diffusion. It may also be called the Stokes radius, or the Stokes-Einstein radius. The radius is usually twice the diameter.

A nanoparticle, as it is used herein, refers to a particle with a diameter of about 10 nm and up to, but without including, about 1 mm. Preferably, the diameter ranges from 100 nm to around 1 micron. Any shape is possible for the particles. The term “nanospheres” is used to refer to nanoparticles with a spherical form.

?Molecular weight? “Molecular weight” is, as used herein generally, the average chain length for the bulk polymer. Molecular weight can be measured or characterized by a variety of methods, including capillary viscometry (GPC), or gel permeationchromatography (GPC). GPC molecular masses are reported as the molecular mass (Mw) rather than the number-average (Mn) molecular weight. Capillary viscometry is a method of estimating molecular weight by measuring the inherent viscosity of a solution of dilute polymers under a specific set of temperature, concentration, and solvent conditions.

Mean particle size?” As used herein, the statistical mean size of the particles (or the diameter) in a population is generally referred to as the particle’s statistical mean size. A spherical particle’s diameter may be referred to its physical or hydrodynamic dimension. Hydrodynamic diameter may be the preferred definition of the diameter of non-spherical particles. The diameter of a nonspherical particle could refer to the longest linear distance between two points on its surface. Dynamic light scattering, a method that measures the mean particle size, is used in measuring it.

?Monodisperse? “?Monodisperse?” and “homogeneous size distribution?” are interchangeable terms that refer to a population or microparticles with the same or almost identical size. A monodisperse distribution is a distribution of particle distributions that are within 15% of the median size of the particle, more preferably within 10%, and most preferably within 5%.

As used herein, “Active Agent” refers to any physiologically or pharmaceutically active substance that acts in the body both locally and/or systemsically. Active agents are substances that are administered to patients for treatment (e.g. therapeutic agent), prevention (e.g. prophylactic agent) or diagnosis (e.g. diagnostic agent).

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