Oh, Yumin Swierczewska, Magdalena Kim, Tae Hyung Lim, Sung Mook Eom, Ha Na Park, Jae Hyung Na, Dong Hee Kim, Kwangmeyung Lee, Kang Choon Pomper, Martin G. Lee, Seulki 2024-01-20T05:30:44Z 2024-01-20T05:30:44Z 2021-09-03 2015-12-28 0168-3659 https://pubs.kist.re.kr/handle/201004/124607 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 (TRAIL(PEG)) and (2) concentrating a TRAIL sensitizer, selected from in vitro screening, in tumors via tumor-homing nanoparticles. Antitumor efficacy of TRAIL(PEG) 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 TRAIL(PEG) 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 TRAIL(PEG), 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 TRAIL(PEG) (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 TRAIL(PEG). (C) 2015 Elsevier B.V. All rights reserved. English ELSEVIER SCIENCE BV APOPTOSIS-INDUCING LIGAND PEGYLATED HYALURONIC-ACID COLON-CANCER CELLS DEATH RECEPTOR 5 IN-VIVO ANTITUMOR-ACTIVITY PHASE-II COMBINATION PHARMACOKINETICS NANOPARTICLES Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors Article 10.1016/j.jconrel.2015.09.014 1 JOURNAL OF CONTROLLED RELEASE, v.220, pp.671 - 681 JOURNAL OF CONTROLLED RELEASE 220 671 681 scie scopus 000368021100013 2-s2.0-84949490107 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article; Proceedings Paper APOPTOSIS-INDUCING LIGAND PEGYLATED HYALURONIC-ACID COLON-CANCER CELLS DEATH RECEPTOR 5 IN-VIVO ANTITUMOR-ACTIVITY PHASE-II COMBINATION PHARMACOKINETICS NANOPARTICLES Apoptosis Death receptors Nanomedicine TRAIL TRAIL sensitizers