Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer

Conventional chemotherapy of ovarian cancer often fails because of initiation of drug resistance and/or side effects and trace of untouched remaining cancerous cells. This highlights an urgent need for advanced targeted therapies for effective remediation of the disease using a cytotoxic agent with...

Full description

Bibliographic Details
Main Authors:	Matthaiou, Efthymia-Iliana, Barar, Jaleh, Sandaltzopoulos, Raphael, Li, Chunsheng, Coukos, George, Omidi, Yadollah
Format:	Online
Language:	English
Published:	Dove Medical Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998853/

id	pubmed-3998853
recordtype	oai_dc
spelling	pubmed-39988532014-04-30 Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer Matthaiou, Efthymia-Iliana Barar, Jaleh Sandaltzopoulos, Raphael Li, Chunsheng Coukos, George Omidi, Yadollah Original Research Conventional chemotherapy of ovarian cancer often fails because of initiation of drug resistance and/or side effects and trace of untouched remaining cancerous cells. This highlights an urgent need for advanced targeted therapies for effective remediation of the disease using a cytotoxic agent with immunomodulatory effects, such as shikonin (SHK). Based on preliminary experiments, we found SHK to be profoundly toxic in ovarian epithelial cancer cells (OVCAR-5 and ID8 cells) as well as in normal ovarian IOSE-398 cells, endothelial MS1 cells, and lymphocytes. To limit its cytotoxic impact solely to tumor cells within the tumor microenvironment (TME), we aimed to engineer SHK as polymeric nanoparticles (NPs) with targeting moiety toward tumor microvasculature. To this end, using single/double emulsion solvent evaporation/diffusion technique with sonication, we formulated biodegradable NPs of poly(lactic-co-glycolic acid) (PLGA) loaded with SHK. The surface of NPs was further decorated with solubilizing agent polyethylene glycol (PEG) and tumor endothelial marker 1 (TEM1)/endosialin-targeting antibody (Ab) through carbodiimide/N-hydroxysuccinimide chemistry. Having characterized the physicochemical and morphological properties of NPs, we studied their drug-release profiles using various kinetic models. The biological impact of NPs was also evaluated in tumor-associated endothelial MS1 cells, primary lymphocytes, and epithelial ovarian cancer OVCAR-5 cells. Based on particle size analysis and electron microscopy, the engineered NPs showed a smooth spherical shape with size range of 120 to 250 nm and zeta potential value of −30 to −40 mV. Drug entrapment efficiency was ~80%–90%, which was reduced to ~50%–60% upon surface decoration with PEG and Ab. The liberation of SHK from NPs showed a sustained-release profile that was best fitted with Wagner log-probability model. Fluorescence microscopy and flow cytometry analysis showed active interaction of Ab-armed NPs with TEM1-positive MS1 cells, but not with TEM1-negative MS1 cells. While exposure of the PEGylated NPs for 2 hours was not toxic to lymphocytes, long-term exposure of the Ab-armed and PEGylated NPs was significantly toxic to TEM1-positive MS1 cells and OVCAR-5 cells. Based on these findings, we propose SHK-loaded Ab-armed PEGylated PLGA NPs as a novel nanomedicine for targeted therapy of solid tumors. Dove Medical Press 2014-04-15 /pmc/articles/PMC3998853/ /pubmed/24790428 http://dx.doi.org/10.2147/IJN.S51880 Text en © 2014 Matthaiou et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Matthaiou, Efthymia-Iliana Barar, Jaleh Sandaltzopoulos, Raphael Li, Chunsheng Coukos, George Omidi, Yadollah
spellingShingle	Matthaiou, Efthymia-Iliana Barar, Jaleh Sandaltzopoulos, Raphael Li, Chunsheng Coukos, George Omidi, Yadollah Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
author_facet	Matthaiou, Efthymia-Iliana Barar, Jaleh Sandaltzopoulos, Raphael Li, Chunsheng Coukos, George Omidi, Yadollah
author_sort	Matthaiou, Efthymia-Iliana
title	Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
title_short	Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
title_full	Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
title_fullStr	Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
title_full_unstemmed	Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
title_sort	shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer
description	Conventional chemotherapy of ovarian cancer often fails because of initiation of drug resistance and/or side effects and trace of untouched remaining cancerous cells. This highlights an urgent need for advanced targeted therapies for effective remediation of the disease using a cytotoxic agent with immunomodulatory effects, such as shikonin (SHK). Based on preliminary experiments, we found SHK to be profoundly toxic in ovarian epithelial cancer cells (OVCAR-5 and ID8 cells) as well as in normal ovarian IOSE-398 cells, endothelial MS1 cells, and lymphocytes. To limit its cytotoxic impact solely to tumor cells within the tumor microenvironment (TME), we aimed to engineer SHK as polymeric nanoparticles (NPs) with targeting moiety toward tumor microvasculature. To this end, using single/double emulsion solvent evaporation/diffusion technique with sonication, we formulated biodegradable NPs of poly(lactic-co-glycolic acid) (PLGA) loaded with SHK. The surface of NPs was further decorated with solubilizing agent polyethylene glycol (PEG) and tumor endothelial marker 1 (TEM1)/endosialin-targeting antibody (Ab) through carbodiimide/N-hydroxysuccinimide chemistry. Having characterized the physicochemical and morphological properties of NPs, we studied their drug-release profiles using various kinetic models. The biological impact of NPs was also evaluated in tumor-associated endothelial MS1 cells, primary lymphocytes, and epithelial ovarian cancer OVCAR-5 cells. Based on particle size analysis and electron microscopy, the engineered NPs showed a smooth spherical shape with size range of 120 to 250 nm and zeta potential value of −30 to −40 mV. Drug entrapment efficiency was ~80%–90%, which was reduced to ~50%–60% upon surface decoration with PEG and Ab. The liberation of SHK from NPs showed a sustained-release profile that was best fitted with Wagner log-probability model. Fluorescence microscopy and flow cytometry analysis showed active interaction of Ab-armed NPs with TEM1-positive MS1 cells, but not with TEM1-negative MS1 cells. While exposure of the PEGylated NPs for 2 hours was not toxic to lymphocytes, long-term exposure of the Ab-armed and PEGylated NPs was significantly toxic to TEM1-positive MS1 cells and OVCAR-5 cells. Based on these findings, we propose SHK-loaded Ab-armed PEGylated PLGA NPs as a novel nanomedicine for targeted therapy of solid tumors.
publisher	Dove Medical Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998853/
_version_	1612082194652594176

Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer

Similar Items