한빛사논문
- 조회1,534
Young Sun Choi1,2,3, Hyeonha Jang1,2, Biki Gupta4,5, Ji-Hak Jeong2,4, Yun Ge1,4, Chul Soon Yong6, Jong Oh Kim6, Jong-Sup Bae1,4, Im-Sook Song1,2,4, In-San Kim7 and You Mie Lee1,4,2,*
1BK21 Plus KNU Multi-Omics Creative Drug Research Team, Daegu, Republic of Korea. 2 Department of Molecular Pathophysiology, Vessel-Organ Interaction Research Center, VOICE (MRC), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea. 3Nano-Bio Application Team, National Nanofab Center (NNFC), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. 4Research Institute of Pharmaceutical Sciences, Kyungpook National Univ., Daegu, Republic of Korea. 5Present address : Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261, USA. 6College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. 7Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
*Correspondence
Abstract
Background
Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities.
Methods
Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett’s multiple comparison test.
Results
PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in Gα13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway.
Conclusions
Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy.
논문정보
- Research article
- 2020년 09월 (BRIC 등록일 2020-09-24)
- 국내 연구진
- 생명과학 > 노화/암생물학
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