Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer

Ga Hee Kim; Ji Eun Won; Yeongseon Byeon; Min Gi Kim; Tae In Wi; Jae Myeong Lee; Yun-Yong Park; Jeong-Won Lee; Tae Heung Kang; In Duk Jung; Byung Cheol Shin; Hyung Jun Ahn; Young Joo Lee; Anil K Sood; Hee Dong Han; Yeong-Min Park

doi:10.1080/10717544.2018.1480672

Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer

Drug Deliv. 2018 Nov;25(1):1394-1402. doi: 10.1080/10717544.2018.1480672.

Authors

Ga Hee Kim¹, Ji Eun Won¹, Yeongseon Byeon¹, Min Gi Kim¹, Tae In Wi¹, Jae Myeong Lee¹, Yun-Yong Park^{2

3}, Jeong-Won Lee⁴, Tae Heung Kang¹, In Duk Jung¹, Byung Cheol Shin⁵, Hyung Jun Ahn⁶, Young Joo Lee⁷, Anil K Sood^{8

9

10}, Hee Dong Han¹, Yeong-Min Park¹

Affiliations

¹ a Department of Immunology School of Medicine , Konkuk University , Chungju , South Korea.
² b Asan Institute for Life Sciences, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Republic of Korea.
³ c Department of Convergence Medicine, University of Ulsan College of Medicine , Seoul , Republic of Korea.
⁴ d Department of Obstetrics and Gynecology , Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Republic of Korea.
⁵ e Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology , Daejeon , Republic of Korea.
⁶ f Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , Seoul, Republic of Korea.
⁷ g Department of Bioscience and Biotechnology , Sejong University , Kwang-Jin-Gu , Seoul , Republic of Korea.
⁸ h Department of Gynecologic Oncology and Reproductive Medicine , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
⁹ i Department of Cancer Biology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
¹⁰ j Center for RNA Interference and Non-coding RNA , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Abstract

Angiogenesis plays an essential role in the growth and metastasis of tumor cells, and the modulation of angiogenesis can be an effective approach for cancer therapy. We focused on silencing the angiogenic gene PLXDC1 as an important factor for anti-angiogenesis tumor therapy. Herein, we developed PLXDC1 small interfering siRNA (siRNA)-incorporated chitosan nanoparticle (CH-NP/siRNA) coated with hyaluronic acid (HA) to target the CD44 receptor on tumor endothelial cells. This study aimed to improve targeted delivery and enhance therapeutic efficacy for tumor anti-angiogenesis. The HA-CH-NP/siRNA was 200 ± 10 nm in size with a zeta potential of 26.4 mV. The loading efficiency of siRNA to the HA-CH-NP/siRNA was up to 60%. The selective binding of HA-CH-NP/siRNA to CD44-positive tumor endothelial cells increased by 2.1-fold compared with that of the CD44 nontargeted CH-NP/siRNA. PLXDC1 silencing by the HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor-bearing mice compared with that in the control group (p < .01), and mRNA expression of PLXDC1 was significantly reduced in the HA-CH-NP/siRNA-treated group. Furthermore, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p < .001), reduced microvessel density (p < .001), and increased cell apoptosis (p < .001). This study demonstrates that HA-CH-NP/siRNA is a highly selective delivery platform for siRNA, and has broad potential to be used in anti-angiogenesis tumor therapy.

Keywords: Chitosan nanoparticles; PLXDC1 siRNA; angiogenesis tumor therapy; epithelial ovarian cancer; targeted delivery.

MeSH terms

Angiogenesis Inhibitors / administration & dosage*
Animals
Antineoplastic Agents / administration & dosage
Apoptosis / drug effects
Carcinoma, Ovarian Epithelial
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Chitosan / chemistry*
Drug Delivery Systems / methods
Endothelial Cells / drug effects*
Female
Gene Silencing / drug effects
Human Umbilical Vein Endothelial Cells
Humans
Hyaluronan Receptors / genetics*
Hyaluronic Acid / chemistry
Mice
Mice, Inbred BALB C
Mice, Nude
Nanoparticles / administration & dosage
Nanoparticles / chemistry*
Neoplasm Proteins / genetics*
Neoplasms, Glandular and Epithelial / drug therapy*
Ovarian Neoplasms / drug therapy*
Particle Size
RNA, Messenger / genetics
RNA, Small Interfering / administration & dosage*
Receptors, Cell Surface / genetics*
Xenograft Model Antitumor Assays / methods

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
CD44 protein, human
Hyaluronan Receptors
Neoplasm Proteins
PLXDC1 protein, human
RNA, Messenger
RNA, Small Interfering
Receptors, Cell Surface
Hyaluronic Acid
Chitosan

Grants and funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2016R1A5A2012284, NRF-2016R1A2B2007327, and NRF-2015R1A2A2A04003620 to Y.-M.P., H.D.H., and Y.J.L.). This work was also supported by Basic Research Laboratory Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (No. 2013R1A4A1069575, to H.D.H., T.H.K., and I.D.J.) and a grant from the National R&D program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (1520100 to H.D.H., H.J.A., and J.-W.L.).