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Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2015 Dec 28; Vol. 220 (Pt B), pp. 671-81. Date of Electronic Publication: 2015 Sep 14. - Publication Year :
- 2015
-
Abstract
- Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has attracted great interest as a cancer therapy because it selectively induces death receptor (DR)-mediated apoptosis in cancer cells while sparing normal tissue. However, recombinant human TRAIL demonstrates limited therapeutic efficacy in clinical trials, possibly due to TRAIL-resistance of primary cancers and its inherent short half-life. Here we introduce drug delivery approaches to maximize in vivo potency of TRAIL in TRAIL-resistant tumor xenografts by (1) extending the half-life of the ligand with PEGylated TRAIL (TRAILPEG) and (2) concentrating a TRAIL sensitizer, selected from in vitro screening, in tumors via tumor-homing nanoparticles. Antitumor efficacy of TRAILPEG with tumor-homing sensitizer was evaluated in HCT116 and HT-29 colon xenografts. Western blot, real-time PCR, immunohistochemistry and cell viability assays were employed to investigate mechanisms of action and antitumor efficacy of the combination. We discovered that doxorubicin (DOX) sensitizes TRAIL-resistant HT-29 colon cancer cells to TRAIL by upregulating mRNA expression of DR5 by 60% in vitro. Intravenously administered free DOX does not effectively upregulate DR5 in tumor tissues nor demonstrate synergy with TRAILPEG in HT-29 xenografts, but rather introduces significant systemic toxicity. Alternatively, when DOX was encapsulated in hyaluronic acid-based nanoparticles (HAC/DOX) and intravenously administered with TRAILPEG, DR-mediated apoptosis was potentiated in HT-29 tumors by upregulating DR5 protein expression by 70% and initiating both extrinsic and intrinsic apoptotic pathways with reduced systemic toxicity compared to HAC/DOX or free DOX combined with TRAILPEG (80% vs. 40% survival rate; 75% vs. 34% tumor growth inhibition). This study demonstrates a unique approach to overcome TRAIL-based therapy drawbacks using sequential administration of a tumor-homing TRAIL sensitizer and long-acting TRAILPEG.<br /> (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Apoptosis drug effects
Caspases metabolism
Cell Survival drug effects
Chemistry, Pharmaceutical
Colonic Neoplasms genetics
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Enzyme Activation
HCT116 Cells
HEK293 Cells
HT29 Cells
Half-Life
Humans
Hyaluronic Acid chemistry
Injections, Intravenous
Mice, Inbred BALB C
Mice, Nude
Polyethylene Glycols chemistry
RNA Interference
Receptors, TNF-Related Apoptosis-Inducing Ligand genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
TNF-Related Apoptosis-Inducing Ligand chemistry
TNF-Related Apoptosis-Inducing Ligand pharmacokinetics
Transfection
Xenograft Model Antitumor Assays
Antineoplastic Agents administration & dosage
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Colonic Neoplasms drug therapy
Doxorubicin administration & dosage
Drug Resistance, Neoplasm drug effects
TNF-Related Apoptosis-Inducing Ligand administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 220
- Issue :
- Pt B
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 26381901
- Full Text :
- https://doi.org/10.1016/j.jconrel.2015.09.014