Abstract
Small interfering RNAs, depending on their structure, delivery system and sequence, can stimulate innate and adaptive immunity. The aim of this study was to investigate the antitumor and antimetastatic effects of immunostimulatory 19-bp dsRNA with 3’- trinucleotide overhangs (isRNA) on melanoma B16 in C57Bl/6 mice. Recently developed novel cationic liposomes 2X3-DOPE were used for the in vivo delivery of isRNA. Administration of isRNA/2X3-DOPE complexes significantly inhibits melanoma tumor growth and metastasis. Histopathological analysis of spleen cross sections showed hyperplasia of the lymphoid white pulp and formation of large germinal centers after isRNA/2X3-DOPE administration, indicating activation of the immune system. The treatment of melanoma-bearing mice with isRNA/2X3-DOPE decreases the destructive changes in the liver parenchyma. Thus, the developed isRNA displays pronounced immunostimulatory, antitumor and antimetastatic properties against melanoma B16 and may be considered a potential agent in the immunotherapy of melanoma.
Highlights
Malignant melanoma is one of the most aggressive forms of skin cancer and is responsible for 80% of mortality from skin tumors [1]
We applied cationic liposomes (2X3-DOPE) consisting of the recently created polycationic lipid 2X3, built from two cholesterol residues linked with spermine, and lipid-helper DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) for the functional delivery of immunostimulatory 19-bp dsRNA with 3’- trinucleotide overhangs (isRNA) in vivo
We treated the mice with complexes composed of 10 μg isRNA and liposomes 2X3-DOPE at concentration corresponding to phosphate to nitrogen ratio (P/N) ratio 1/4
Summary
Malignant melanoma is one of the most aggressive forms of skin cancer and is responsible for 80% of mortality from skin tumors [1]. Recombinant interferon-α (IFN-α) is the basic therapy approved currently for use either alone or as a part of the combined therapy in the treatment of a range of tumors including malignant melanoma [3,4,5], but this treatment is associated with significant toxicity and the risk of autoimmune reactions [6]. The innate and adaptive immune response can be activated by exogenic nucleic acids (e.g. bacterial, viral and fungal nucleic acids) via several families of pattern recognition receptors, such as endosomal and cell surface Toll-like receptors 3/7/8/9 (TLRs) [7]. TLR ligands are PLOS ONE | DOI:10.1371/journal.pone.0150751 March 16, 2016
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