title: Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.
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.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Swierczewska
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Sung Mook
authors.initials: SM
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Eom
authors.affiliation: Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Na
authors.affiliation: Center for Theragnosis, Korea Institute of Science of Technology, Seoul, South Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA. Electronic address: seulki@jhmi.edu.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006207:Half-Life; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D007275:Injections, Intravenous; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D011092:Polyethylene Glycols; D004317:Doxorubicin; D006820:Hyaluronic Acid; D020169:Caspases
keywords: Apoptosis; Death receptors; Nanomedicine; TRAIL; TRAIL sensitizers