| RRC ID |
76474
|
| 著者 |
Sakamoto K, Kittikulsuth W, Miyako E, Steeve A, Ishimura R, Nakagawa S, Ago Y, Nishiyama A.
|
| タイトル |
The VIPR2-selective antagonist KS-133 changes macrophage polarization and exerts potent anti-tumor effects as a single agent and in combination with an anti-PD-1 antibody.
|
| ジャーナル |
PLoS One
|
| Abstract |
We have previously demonstrated that KS-133 is a specific and potent antagonist of vasoactive intestinal peptide receptor 2 (VIPR2). We have also shown that vasoactive intestinal peptide-VIPR2 signaling affects the polarity and activation of tumor-associated macrophages, which is another strategy for cancer immunotherapy apart from the activation of effector T cells. In this study, we aimed to examine whether the selective blockade of VIPR2 by KS-133 changes the polarization of macrophages and induces anti-tumor effects. In the presence of KS-133, genetic markers indicative of tumor-aggressive M1-type macrophages were upregulated, and conversely, those of tumor-supportive M2-type macrophages were downregulated. Daily subcutaneous administration of KS-133 tended to suppress the growth of CT26 tumors (murine colorectal cancer-derived cells) implanted subcutaneously in Balb/c mice. To improve the pharmacological efficacy and reduce the number of doses, we examined a nanoformulation of KS-133 using the US Food and Drug Administration-approved pharmaceutical additive surfactant Cremophor® EL. KS-133 nanoparticles (NPs) were approximately 15 nm in size and stable at 4°C after preparation. Meanwhile, KS-133 was gradually released from the NPs as the temperature was increased. Subcutaneous administration of KS-133 NPs once every 3 days had stronger anti-tumor effects than daily subcutaneous administration of KS-133. Furthermore, KS-133 NPs significantly enhanced the pharmacological efficacy of an immune checkpoint-inhibiting anti-PD-1 antibody. A pharmacokinetic study suggested that the enhancement of anti-tumor activity was associated with improvement of the pharmacokinetic profile of KS-133 upon nanoformulation. Our data have revealed that specific blockade of VIPR2 by KS-133 has therapeutic potential for cancer both alone and in combination with immune checkpoint inhibitors.
|
| 巻・号 |
18(7)
|
| ページ |
e0286651
|
| 公開日 |
2023-1-1
|
| DOI |
10.1371/journal.pone.0286651
|
| PII |
PONE-D-23-03312
|
| PMID |
37405999
|
| PMC |
PMC10321640
|
| MeSH |
Animals
Cell Line, Tumor
Immunotherapy
Macrophages
Mice
Neoplasms*
Receptors, Vasoactive Intestinal Peptide, Type II*
Tumor Microenvironment
|
| IF |
2.74
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
