An organotypic model of high-grade serous ovarian cancer to test the anti-metastatic potential of ROR2 targeted Polyion complex nanoparticles.

Joshi, N; Liu, D; Dickson, K-A; Marsh, DJ; Ford, CE; Stenzel, MH

An organotypic model of high-grade serous ovarian cancer to test the anti-metastatic potential of ROR2 targeted Polyion complex nanoparticles.

Joshi, N Liu, D Dickson, K-A Marsh, DJ Ford, CE Stenzel, MH

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Publisher:: Royal Society of Chemistry (RSC)
Publication Type:: Journal Article
Citation:: J Mater Chem B, 2021
Issue Date:: 2021-10-22

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Field	Value	Language
dc.contributor.author	Joshi, N
dc.contributor.author	Liu, D
dc.contributor.author	Dickson, K-A
dc.contributor.author	Marsh, DJ
dc.contributor.author	Ford, CE
dc.contributor.author	Stenzel, MH
dc.date.accessioned	2021-11-01T08:24:54Z
dc.date.available	2021-11-01T08:24:54Z
dc.date.issued	2021-10-22
dc.identifier.citation	J Mater Chem B, 2021
dc.identifier.issn	2050-750X
dc.identifier.issn	2050-7518
dc.identifier.uri	http://hdl.handle.net/10453/151295
dc.description.abstract	High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy. Most patients are diagnosed at late stages when the tumour has metastasised throughout the peritoneal cavity. The Wnt receptor ROR2 has been identified as a promising therapeutic target in HGSOC, with limited targeting therapeutic options currently available. Small interfering RNA (siRNA)-based therapeutics hold great potential for inhibiting the function of specific biomarkers, however major challenges remain in efficient delivery and stability. The aim of this study was to investigate the ability of nanoparticles to deliver ROR2 siRNA into HGSOC cells, including platinum resistant models, and estimate the anti-metastatic effect via a 3D organotypic model for ovarian cancer. The nanoparticles were generated by conjugating poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) of various chain length to bovine serum albumin (BSA), followed by the condensation of ROR2 siRNA into polyplexes, also termed polyion complex (PIC) nanoparticles. The toxicity and uptake of ROR2 siRNA PIC nanoparticles in two HGSOC cell lines, CaOV3 as well as its cisplatin resistant pair (CaOV3CisR), in addition to primary cells used for the 3D organotypic model were investigated. ROR2 knockdown at both transcriptional and translational levels were evaluated via real-time PCR and western blot analysis, respectively. Following 24 h incubation with the nanoparticles, functional assays were performed including proliferation (IncuCyte S3), transwell migration and 3D co-cultured transwell invasion assays. The PICs nanoparticles exhibited negligible toxicity in the paired CaOV3 cell lines or primary cells. Treating CaOV3 and CaOV3CisR cells with ROR2 siRNA containing PICs nanoparticles significantly inhibited migration and invasion ability. The biocompatible ROR2 siRNA conjugated PICs nanoparticles provide an innovative therapeutic option. ROR2 targeting therapy shows potential in treating HGSOC including platinum resistant forms.
dc.language	eng
dc.publisher	Royal Society of Chemistry (RSC)
dc.relation.ispartof	J Mater Chem B
dc.relation.isbasedon	10.1039/d1tb01837j
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	0303 Macromolecular and Materials Chemistry, 0903 Biomedical Engineering
dc.title	An organotypic model of high-grade serous ovarian cancer to test the anti-metastatic potential of ROR2 targeted Polyion complex nanoparticles.
dc.type	Journal Article
utslib.location.activity	England
utslib.for	0303 Macromolecular and Materials Chemistry
utslib.for	0903 Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2022-10-31T00:00:00+1000Z
dc.date.updated	2021-11-01T08:24:53Z
pubs.publication-status	Published online

Abstract:

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy. Most patients are diagnosed at late stages when the tumour has metastasised throughout the peritoneal cavity. The Wnt receptor ROR2 has been identified as a promising therapeutic target in HGSOC, with limited targeting therapeutic options currently available. Small interfering RNA (siRNA)-based therapeutics hold great potential for inhibiting the function of specific biomarkers, however major challenges remain in efficient delivery and stability. The aim of this study was to investigate the ability of nanoparticles to deliver ROR2 siRNA into HGSOC cells, including platinum resistant models, and estimate the anti-metastatic effect via a 3D organotypic model for ovarian cancer. The nanoparticles were generated by conjugating poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) of various chain length to bovine serum albumin (BSA), followed by the condensation of ROR2 siRNA into polyplexes, also termed polyion complex (PIC) nanoparticles. The toxicity and uptake of ROR2 siRNA PIC nanoparticles in two HGSOC cell lines, CaOV3 as well as its cisplatin resistant pair (CaOV3CisR), in addition to primary cells used for the 3D organotypic model were investigated. ROR2 knockdown at both transcriptional and translational levels were evaluated via real-time PCR and western blot analysis, respectively. Following 24 h incubation with the nanoparticles, functional assays were performed including proliferation (IncuCyte S3), transwell migration and 3D co-cultured transwell invasion assays. The PICs nanoparticles exhibited negligible toxicity in the paired CaOV3 cell lines or primary cells. Treating CaOV3 and CaOV3CisR cells with ROR2 siRNA containing PICs nanoparticles significantly inhibited migration and invasion ability. The biocompatible ROR2 siRNA conjugated PICs nanoparticles provide an innovative therapeutic option. ROR2 targeting therapy shows potential in treating HGSOC including platinum resistant forms.

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http://hdl.handle.net/10453/151295