The disclosure relates generally to polyglutamated antifolates, formulations containing liposomes filled with alpha or D-gamma polyglutamated antifolates, methods of making the polyglutamated antifolates and liposome containing formulations, and methods of using polyglutamated antifolates and liposome containing formulations to treat hyerproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).

Methods for designing bivalent compounds which selectively degrade/disrupt EZH2 and compositions and methods of using such degraders/disruptors to treat EZH2-mediated cancer are provided.

The present invention relates to a novel compound and application thereof in the inhibition of HBV gene expression. The structure of the compound comprises an interfering nucleic acid for inhibiting HBV gene expression, transition points, and delivery chains of the interfering nucleic acid. By means of the delivery chains, two or three N-acetylgalactosamines can be introduced to an antisense strand 3′ end of such siRNA, and two or one N-acetylgalactosamine can be correspondingly introduced to a sense strand 5′ end, the total number of the introduced N-acetylgalactosamines being four. In vitro and in vivo pharmacological experiments prove that such a novel compound can continuously and efficiently inhibit HBV gene expression.

The present invention generally relates to tumor homing statin derivatives (THSD) and their use for therapy, in particular cancer therapy. These THSD comprise three moieties: a statin moiety which comprises a dihydroxyheptanoic acid unit (DHHA) fixated by linkage into its open chain form, a heptamethine carbocyanine dye (HMCD) moiety, and a linker that conjugates the DHHA of the statin to the dye moiety. The linker is linked to the DHHA via an ester bond (ester-linked statin derivative or ELSD), or via an amide bond (amide-linked statin derivative or ALSD). Thus linked to the DHHA, the linker provides a relatively stable link either for essentially no hydrolysis/statin release after administration, or preferably for very slow hydrolysis and statin release, as is the case for the ELSD. Embodiments include methods to provide the desired THSD, in particular the ELSD, with the DHHA in its open chain form. The invention also relates to methods wherein one or more ELSD is administered to a patient in a therapeutically effective amount, and methods wherein an ELSD and an ALSD are co-administered in a coordinated administration schedule. Advantages of the THSD and their use include, among others, improved efficacy and dose-response, and decreased statin-associated side effects.

The invention generally relates to a smart drug delivery system for dual nuclear medical cytotoxic theranostics incorporating either (i) a first compound with the structure CT-L1-Chel-S1-TV or

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or (ii) a second compound with the structure Chel-S-TV and a third compound with the structure CT-L-TV. In the first, second and third compounds Chel is a radical of a chelating agent for complexing a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each linkers; S1, S2 and S are each spacers.

The present disclosure relates to methods of administering, subcutaneously, to a subject, multimeric oligonucleotides having monomeric subunits joined by covalent linkers. The multimeric oligonucleotides have a molecular weight and/or size configured to increase in vivo activity of one or more subunits within the multimeric oligonucleotide relative to in vivo activity of the same subunit when administered in monomeric form of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present disclosure also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.

A conjugate comprising the following topoisomerase inhibitor derivative (A*): with a linker for connecting to a Ligand Unit, wherein the linker is attached in a cleavable manner to the amino residue. The Ligand Unit is preferably an antibody. Also provided is A* with the linking unit attached, and intermediates for their synthesis, as well as the released warhead.

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Compounds, pharmaceutical compositions and methods are provided for reprogramming M2-like macrophages to M1-like macrophages, which reverses the antifibrotic to profibrotic shift observed during the course of fibrotic diseases and certain cancers. The compounds comprise an immune modulator that targets a pattern recognition receptor of a cell and are specific to the cells of interest through the incorporation of a targeting moiety (e.g., folate or a functional fragment or analog thereof). Releasable and/or non-releasable linkers can be included and engineered to facilitate the optimal delivery of the immune modulator. The compounds and compositions can be employed in one or more methods of treatment for fibrotic diseases and/or cancers.

A drug-polymer conjugate having thermoresponsiveness includes at least one drug conjugated to at least one end portion of at least one thermoresponsive polymer segment having a lower critical solution temperature. The drug-polymer conjugate is capable of forming a micellular aggregate in an aqueous medium at temperatures equal to or above the lower critical solution temperature. The drug-polymer conjugate or the micellular aggregate thereof may be administered to and absorbed in the lungs.

The present invention discloses a compound of general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof, a composition comprising the compound of general formula I, and use of the compound of general formula I, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof for preparing a medicament for treating a disease associated with the serine/threonine kinase family (MAP4Ks), and preferably for preparing a medicament for treating a disease associated with hematopoietic progenitor kinase 1 (HPK1).

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