The subject invention provides materials and methods for intracellular deliver of molecules and/or therapeutic agents. The subject invention also provides methods for synthesizing polymeric systems and nanomaterials that enhance or assist the passage of molecules and/or therapeutic agents across biological membranes. The compound, polymer or nanoparticle of the subject invention comprises a modified guanidine moiety in a plurality of repeating units of a polymer or on the surface of a nanoparticle where the guanidine moiety comprises, for example, a carbamoyl or thiourea modification. The polymer or nanoparticle can be used in a cancer treatment formulation.

In various embodiments tolerogenic nanoparticles are provided that induce immune tolerance to one or more desired antigen(s) and/or that reduce an immune response to those antigen(s). In certain embodiments the tolerogenic nanoparticle comprises a nanoparticle comprising a biocompatible polymer; an antigen disposed within or attached to said biocompatible polymer where said antigen comprises an antigen to which immune tolerance is to be induced by administration of said tolerogenic nanoparticle to a mammal; and a first targeting moiety that binds to a scavenger receptor in the liver, and/or a second targeting moiety that binds to a mannose receptor in the liver, and/or a third targeting moiety that binds to hepatocytes, wherein said first and/or second and/or third targeting moiety are attached to the surface of said nanoparticle.

The present invention describes novel nanoparticle compositions, and systems and methods utilizing them for treating disorders and/or conditions. Methods generally involve administering nanoparticle compositions (e.g., nanoparticle compositions comprising at least one known therapeutic agent and/or independently active biologically active agent; and/or empty nanoparticle compositions) to a subject in need thereof.

The present invention relates to cell delivery systems. The present invention specifically relates to new methods of intracellular delivery by endocytosis routing sequence peptides having the sequence of WYKYV or analogues thereof, by caveloar/lipid raft-mediated endocytosis and uses of such peptides. The invention also relates to conjugates comprising said peptides and uses thereof in therapies wherein intracellular delivery of a therapeutically active molecule is required.

Methods of treating subjects having G4C2 dipeptide repeat expansion in the gene C9ORF72, including subjects having amyotrophic lateral sclerosis or frontotemporal degeneration (ALS/FTD), are provided. Compounds directed at reducing the toxicity of G4C2 dipeptide repeat expansion in the gene C9ORF72 are described.

Provided are methods for treating a disease, disorder, or condition associated with an acid ceramidase (AC) biological activity. The methods include administering to a subject in need thereof a composition including an AC inhibitor and at least one additional active agent, such as a C6-ceramide nanoliposome (CNL); an inhibitor of a Bcl-2 family protein; a hypomethylating agent; an intensive chemotherapeutic agent such as cytarabine (AraC) and/or daunorubicin; a Hedgehog pathway inhibitor; a targeted agent, such as a FLT2 inhibitor or a EDH1/2 inhibitor; and/or an antibody drug conjugate that targets, for example, CD-33. The composition can include N-[(2S,3R)-1,3-dihydroxyoctadecan-2-yl]2-chloroacetamide (SACLAC) or a pharmaceutically acceptable salt thereof and at least one additional active agent. The disease, disorder, or condition associated with the AC biological activity can be a cancer, such as acute myeloid leukemia (AML).

The present disclosure describes compounds of Formula (I) or a pharmaceutically acceptable salt thereof:

##STR00001##

wherein: R.sup.1 and R.sup.2 are each independently (CH.sub.3(CH.sub.2).sub.m).sub.2CH—, (CH.sub.3(CH.sub.2).sub.m)(CH.sub.3(CH.sub.2).sub.m-1)CH, (CH.sub.3(CH.sub.2).sub.m)(CH.sub.3(CH.sub.2).sub.m-2)CH, (CH.sub.3(CH.sub.2).sub.m).sub.2CHCH.sub.2—, or (CH.sub.3(CH.sub.2).sub.m)(CH.sub.3(CH.sub.2).sub.m-1)CHCH.sub.2—, wherein m is 4-11; L.sup.1 and L.sup.2 are each independently absent, a linear C.sub.1-5 alkylene, or (CH.sub.2).sub.p—O—(CH.sub.2).sub.q, wherein p and q are each independently 1-3; R.sup.3 is a linear C.sub.2-5 alkylene optionally substituted with one or two methyl groups; R.sup.4 and R.sup.5 are each independently H or C.sub.1-6 alkyl; X is O or S; and n is 0-2.

A system is disclosed for delivery of a therapeutic agent to a site in mucosal tissue or to the skin of a patient. The system includes a porous mucoadhesive, freeze-dried matrix formed by a composition including chitosan in an aqueous salt solution of a chloride salt of a monovalent cation. The system further includes a plurality of chitosan microparticles having an average diameter between 500 nm and 2000 nm and comprising a therapeutic agent.

The present disclosure relates to degradable polymers which contain a hydrophobic and hydrophilic segment which is sensitive to pH. In some aspects, the polymers form a micelle which is sensitive to pH and have backbones which are capable of undergoing degradation in vivo. In some aspects, the disclosure also provides methods of using these degradable polymers for the delivery of a drug.

The disclosure provides a hybrid membrane camouflaged nanomedicine loaded with oxidative phosphorylation inhibitor and preparation method thereof. The nanomedicine comprises an inner core and an outer shell coated on the periphery of the inner core. The inner core is a ROS-responsive drug-loaded nanoparticle, and the drug loaded by the ROS-responsive nanocarrier is an oxidative phosphorylation inhibitor. The outer shell is a hybrid membrane of mitochondrial membrane and cancer cell membrane. The nanomedicines can cross the BBB and reach tumor sites by the homologous targeting of cancer cell membrane, and then they can homologously target and enter mitochondria by the mitochondrial membrane. Subsequently, under the high-level ROS environment of the mitochondria, the ROS responsive drug-loaded nanoparticle releases the oxidative phosphorylation inhibitor due to the swell and degradation of the inner core, so that the safe and efficient targeted GBM therapy is achieved.