Bioengineered adipose-derived stem cells for targeted enzyme-prodrug therapy of ovarian cancer intraperitoneal metastasis.
Adipose Tissue
/ cytology
Animals
Antineoplastic Agents
/ administration & dosage
Bioengineering
Carboxylesterase
/ genetics
Cell Line, Tumor
Cisplatin
/ administration & dosage
Drug Resistance, Neoplasm
Enzyme Therapy
Female
Irinotecan
/ administration & dosage
Mice, Nude
Molecular Targeted Therapy
Ovarian Neoplasms
/ drug therapy
Paclitaxel
/ administration & dosage
Peritoneal Neoplasms
/ drug therapy
Prodrugs
/ administration & dosage
Stem Cells
Adipose derived mesenchymal stem cells
Enzyme prodrug systems
Ovarian cancer
Suicide gene therapy
Targeted therapy
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
06
05
2019
revised:
05
08
2019
accepted:
05
09
2019
pubmed:
10
9
2019
medline:
22
10
2020
entrez:
10
9
2019
Statut:
ppublish
Résumé
The objective of this study was to develop a stem cell-based system for targeted suicide gene therapy of recurrent, metastatic, and unresectable ovarian cancer. Malignant cells were obtained from the ascites of a patient with advanced recurrent epithelial ovarian cancer (named OVASC-1). Cancer cells were characterized to determine the percentages of drug-resistant ALDH+ cells, MDR-1/ABCG2 overexpressing cells, and cancer stem-like cells. The sensitivity and resistance of the OVASC-1 cells and spheroids to the metabolites of three different enzyme/prodrug systems were assessed, and the most effective one was selected. Adipose-derived stem cells (ASCs) were genetically engineered to express recombinant secretory human carboxylesterase-2 and nanoluciferase genes for simultaneous disease therapy and quantitative imaging. Bioluminescent imaging, magnetic resonance imaging and immuno/histochemistry results show that the engineered ASCs actively targeted and localized at both tumor stroma and necrotic regions. This created the unique opportunity to deliver drugs to not only tumor supporting cells in the stroma, but also to cancer stem-like cells in necrotic/hypoxic regions. The statistical analysis of intraperitoneal OVASC-1 tumor burden and survival rates in mice shows that the administration of the bioengineered ASCs in combination with irinotecan prodrug in the designed sequence and timeline eradicated all intraperitoneal tumors and provided survival benefits. In contrast, treatment of the drug-resistant OVASC-1 tumors with cisplatin/paclitaxel (standard-of-care) did not have any statistically significant benefit. The histopathology and hematology results do not show any toxicity to major peritoneal organs. Our toxicity data in combination with efficacy outcomes delineate a nonsurgical and targeted stem cell-based approach to overcoming drug resistance in recurrent metastatic ovarian cancer.
Identifiants
pubmed: 31499084
pii: S0168-3659(19)30539-5
doi: 10.1016/j.jconrel.2019.09.006
pmc: PMC6884134
mid: NIHMS1544133
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Prodrugs
0
Irinotecan
7673326042
CES2 protein, human
EC 3.1.1.1
Carboxylesterase
EC 3.1.1.1
Paclitaxel
P88XT4IS4D
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
273-287Subventions
Organisme : NCI NIH HHS
ID : R01 CA175318
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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