Abstract
Polypod-like structured nucleic acids (polypodnas), which are nanostructured DNAs, are useful for delivering cytosine-phosphate guanine oligodeoxynucleotides (CpG ODNs) to antigen-presenting cells (APCs) expressing Toll-like receptor 9 (TLR9) for immune stimulation. Lipid modification is another approach to deliver ODNs to lymph nodes, where TLR9-positive APCs are abundant, by binding to serum albumin. The combination of these two methods can be useful for delivering CpG ODNs to lymph nodes in vivo. In the present study, CpG1668, a phosphodiester-type CpG ODN, was modified with stearic acid (SA) to obtain SA-CpG1668. Tripodna, a polypodna with three pods, was selected as the nanostructured DNA. Tripodnas loaded with CpG1668 or SA-CpG1668 were obtained in high yields. SA-CpG1668/tripodna bound more efficiently to plasma proteins than CpG1668/tripodna and was more efficiently taken up by macrophage-like RAW264.7 cells than CpG1668/tripodna, whereas the levels of tumor necrosis factor-α released from the cells were comparable between the two. After subcutaneous injection into mice, SA-CpG1668/tripodna induced significantly higher interleukin (IL)-12 p40 production in the draining lymph nodes than SA-CpG1668 or CpG1668/tripodna, with reduced IL-6 levels in plasma. These results indicate that the combination of SA modification and nanostructurization is a useful approach for the targeted delivery of CpG ODNs to lymph nodes.
Highlights
The development of oligonucleotide therapeutics has recently accelerated, and the number of approved oligonucleotide therapeutics has been increasing
The delivery to the inguinal lymph node can be explained by the fact that the administration site was in the caudal region close to the inguinal lymph node
The injection sites may possibly be slightly shifted to the left, which could explain the biased delivery of stearic acid (SA)-CpG1668/tripodna to the lymph nodes on the left side
Summary
The development of oligonucleotide therapeutics has recently accelerated, and the number of approved oligonucleotide therapeutics has been increasing. The classes of oligonucleotide therapeutics that have been approved include antisense oligonucleotide, small interfering RNAs, nucleic acid aptamers, and unmethylated cytosine-phosphateguanine (CpG) oligodeoxynucleotides (ODNs). CpG ODNs stimulate innate immunity by being taken up by these cells and binding to TLR9 in endosomes [4,5,6]. The first CpG ODN approved for clinical use was CpG 1018, which is included as an adjuvant for a licensed vaccine for hepatitis B [7,8]. Despite the clinical development of PS-modified CpG ODNs, several challenges still remain, including the inefficient delivery of CpG ODNs to TLR9-positive cells, limited cellular uptake, and hepatic and renal toxicity [9]
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