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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.

SUBMITTER: Oh Y

PROVIDER: S-EPMC4688186 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.

Oh Yumin Y Swierczewska Magdalena M Kim Tae Hyung TH Lim Sung Mook SM Eom Ha Na HN Park Jae Hyung JH Na Dong Hee DH Kim Kwangmeyung K Lee Kang Choon KC Pomper Martin G MG Lee Seulki S

Journal of controlled release : official journal of the Controlled Release Society 20150914 Pt B

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-re ...[more]

PMID: 26381901

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Project description:Background:Local photothermal therapy (PTT) provides an easily applicable, noninvasive adjunctive therapy for colorectal cancer (CRC), especially when multidrug resistance (MDR) occurs. However, using PTT alone does not result in complete tumor ablation in many cases, thus resulting in tumor recurrence and metastasis. Materials and methods:In this study, we aim to develop a personalized local therapeutic platform combining PTT with long-acting chemotherapy for the treatment of MDR CRC. The platform consists of polyethylene glycol (PEG)-coated gold nanorods (PEG-GNRs) and D-alpha-tocopheryl PEG 1000 succinate (TPGS)-coated paclitaxel (PTX) nanocrystals (TPGS-PTX NC), followed by the incorporation into an in situ hydrogel (gel) system (GNRs-TPGS-PTX NC-gel) before injection. After administration, PEG-GNRs can exert quick and efficient local photothermal response under near-infrared laser irradiation to shrink tumor; TPGS-PTX NC then provides a long-acting chemotherapy due to the sustained release of PTX along with the P-glycoprotein inhibitor TPGS to reverse the drug resistance. Results:The cytotoxicity studies showed that the IC50 of GNRs-TPGS-PTX NC-gel with laser irradiation decreased to ~178-folds compared with PTX alone in drug-resistant SW620 AD300 cells. In the in vivo efficacy test, after laser irradiation, the GNRs-TPGS-PTX NC-gel showed similar tumor volume inhibition compared with GNRs-gel at the beginning. However, after 14 days, the tumor volume of the mice treated with GNRs-gel quickly increased, while that of the mice treated with GNRs-TPGS-PTX NC-gel remained controllable due to the long-term chemotherapeutic effect of TPGS-PTX NC. The mice treated with GNRs-TPGS-PTX NC-gel also showed no weight loss and obvious organ damages and lesions during the treatment, indicating a low systemic side effect profile and a good biocompatibility. Conclusion:Overall, the nano-complex may serve as a promising local therapeutic patch against MDR CRC with one-time dosing to achieve a long-term tumor control. The doses of PEG-GNRs and TPGS-PTX NC can be easily adjusted before use according to patient-specific characteristics potentially making it a personalized therapeutic platform.

Dataset Information

Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.

Publications

Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors.

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