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Publication Number
US-12263215-B2
Publication Date
2025-04-01
Expiration Date
Abstract
The present invention relates to particles comprising RNA, in which the RNA is associated with a cationic polymer or lipid or with both a cationic polymer and lipid, wherein the RNA comprises a cytotoxic nucleotide or cytotoxic nucleotide analog and/or the RNA is covalently attached to a cytotoxin, pharmaceutical compositions containing said particles and pharmaceutical uses of the particles and pharmaceutical compositions. The particles of the present invention are particularly useful as an immunostimulating medicament capable to block proliferation or induce death in dividing cells such as tumor cells.
Core Innovation
The invention relates to immunostimulating cytotoxic RNA particles comprising single stranded RNA (ssRNA) associated with a cationic polymer and/or lipid. The ssRNA includes fluorouridine and one or more other types of cytotoxic nucleotides or cytotoxic nucleotide analogs, and the resulting particles are presented as immunostimulating cytotoxic (mtiRNA) particles.
The particles provide a dual activity anticancer medicament by inducing an immune response while simultaneously exerting toxicity to dividing or tumor cells. The immune response is described in terms of type I interferon induction, including IFN-alpha, associated with pathways including TLR3/7/8 and RIG-I.
A representative embodiment described is Protamine-associated mtiRNA nanoparticles, including a defined particle size of about 107 nm and a Protamine:mRNA mass ratio range. The document also reports induction of IFN-alpha in PBMCs and in BALB/c mice after IV administration.
Claims Coverage
The claim set centers on one independent particle claim and one independent cancer treatment claim, with multiple inventive features. The particle claim covers ssRNA with fluorouridine and one or more other cytotoxic nucleotides or cytotoxic nucleotide analogs, associated with a cationic polymer and/or lipid; dependent claims add specific cytotoxic nucleotide types, modification coverage, a minimum fraction of modified nucleotides, and selectable cationic polymers including Protamine.
Single stranded RNA with fluorouridine and other cytotoxic nucleotides
A particle comprising single stranded RNA (ssRNA), wherein the ssRNA comprises fluorouridine and one or more other types of cytotoxic nucleotides or cytotoxic nucleotide analogs.
SsRNA associated with cationic polymer or lipid
The ssRNA is associated with a cationic polymer or lipid or with both a cationic polymer and lipid.
Other cytotoxic nucleotides or cytotoxic nucleotide analogs include modifications
The ssRNA includes one or more other types of cytotoxic nucleotides or cytotoxic nucleotide analogs, each having at least one modification on the base moiety and/or the sugar moiety.
Specified types of cytotoxic nucleotides or cytotoxic nucleotide analogs
Each additional type of cytotoxic nucleotide or cytotoxic nucleotide analog includes a moiety selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, nelarabine, pentostatin, azathioprine, carmofur, mercaptopurine, tegafur, tioguanine, or combinations thereof.
Minimum fraction of modified nucleotides in ssRNA
The ssRNA includes at least 20% modified nucleotides.
Cationic polymer selected from specified options
The particle includes a cationic polymer selected from Protamine, polyethyleneimine, poly-L-lysine, poly-L-arginine, or histone.
Cancer treatment by inducing immune response and cytotoxicity
A method for treating cancer by administering an effective amount of the particle to a cancer-bearing subject to induce an immune response and cytotoxicity, thereby treating the cancer.
Overall, the claims define ssRNA particles containing fluorouridine and additional cytotoxic nucleotides or analogs, associated with a cationic polymer and/or lipid. The scope is further refined by specific nucleotide or analog types, modification content, cationic polymer options including Protamine, and therapeutic use in cancer treatment through immune response and cytotoxicity.
Stated Advantages
Dual activity anticancer medicament that induces immune response and exerts toxicity to dividing or tumor cells.
Induction of type I interferon (IFN-alpha) associated with TLR3/7/8 and RIG-I pathways.
Tumor cell proliferation blockade and cytotoxicity behavior observed using LDH-based cytotoxicity.
Induction of IFN-alpha in PBMCs and in BALB/c mice after IV administration.
Documented Applications
Treating cancer by administering an effective amount of the particle to a cancer-bearing subject to induce an immune response and cytotoxicity.
Induction of IFN-alpha after IV administration in BALB/c mice.
Induction of IFN-alpha in PBMCs.
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