Cytotoxic immunostimulating particles and uses thereof
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.
1. A particle comprising single stranded RNA (ssRNA), in which the ssRNA is associated with a cationic polymer or lipid or with both a cationic polymer and lipid,
wherein the ssRNA comprises at least 20% modified U residues, wherein each modified U residue is a cytotoxic nucleotide or cytotoxic nucleotide analog.
2. The particle of claim 1 , wherein the cytotoxic nucleotide or cytotoxic nucleotide analog is 5 fluoro uridine (5FU).
3. The particle of claim 1 , wherein the ssRNA is an oligonucleotide or is a messenger RNA.
4. The particle of claim 1 , wherein the cationic polymer is selected from the group consisting of Protamine, polyethyleneimine, poly-L-lysine, poly-L-arginine and histone.
5. The particle of claim 4 , wherein the particle comprises ssRNA and Protamine.
6. The particle of claim 5 , wherein the Protamine-ssRNA particle is a Protamine-ssRNA nanoparticle having a size in the range from about 10 nm to about 990 nm.
7. The particle of claim 6 , wherein the Protamine-sRNA nanoparticle has a Protamine:ssRNA mass ratio in the range from about 16:1 to about 1:2.
8. A pharmaceutical composition comprising the particle of claim 1 , and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8 , further comprising an antigen and/or an adjuvant.
10. A method for treating cancer, comprising administering to a subject having cancer an amount effective of the particle of claim 1 to induce an immune response and induce cytotoxicity, thereby treating the cancer.
11. The particle of claim 1 , wherein the sRNA is an oligonucleotide or is a messenger RNA, and wherein the cationic polymer is Protamine.
12. The method of claim 10 , wherein each cytotoxic nucleotide or cytotoxic nucleotide analog is 5 fluoro uridine (5FU).
13. The method of claim 11 , wherein each cytotoxic nucleotide or cytotoxic nucleotide analog is 5 fluoro uridine (5FU).