Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing.
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ABSTRACT:
SUBMITTER: Tzeng SY
PROVIDER: S-EPMC5365091 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is an attractive cancer therapeutic because of its ability to induce apoptosis in tumor cells while having a negligible effect on normal cells. However, the short serum half-life of TRAIL and lack of efficient in vivo administration approaches have largely hindered its clinical use. Using nanoparticles (NPs) as carriers in gene therapy is considered as an alternative approach to increase TRAIL delivery to tumors as transfected cells would be induced to secrete TRAIL into the tumor microenvironment. To enable effective delivery of plasmid DNA encoding TRAIL into glioblastoma (GBM), we developed a targeted iron oxide NP coated with chitosan-polyethylene glycol-polyethyleneimine copolymer and chlorotoxin (CTX) and evaluated its effect in delivering TRAIL in vitro and in vivo. NP-TRAIL successfully delivers TRAIL into human T98G GBM cells and induces secretion of 40 pg mL(-1) of TRAIL in vitro. Transfected cells show threefold increased apoptosis as compared to the control DNA bound NPs. Systemic administration of NP-TRAIL-CTX to mice bearing T98G-derived flank xenografts results in near-zero tumor growth and induces apoptosis in tumor tissue. Our results suggest that NP-TRAIL-CTX can potentially serve as a targeted anticancer therapeutic for more efficient TRAIL delivery to GBM.
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Project description:Nanoparticles (NPs) have been widely investigated in the nanomedicine field. One of the main challenges is to accurately predict the NP distribution and fate after administration. Microfluidic platforms acquired huge importance as tools to model the in vivo environment. In this study, we leveraged a microfluidic platform to produce FITC-labeled poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) NPs with defined sizes of 30, 50, and 70 nm. The study aimed to compare the ability of NPs with differences of 20 nm in size to cross an endothelial barrier using static (Transwell inserts) and dynamic (microfluidic perfusion device) in vitro models. Our results evidence a size-dependent NP crossing in both models (30 > 50 > 70 nm) and highlight the bias deriving from the static model, which does not involve shear stresses. The permeation of each NP size was significantly higher in the static system than in the dynamic model at the earliest stages. However, it gradually decreased to levels comparable with those of the dynamic model. Overall, this work highlights clear differences in NP distribution over time in static versus dynamic conditions and distinct size-dependent patterns. These findings reinforce the need for accurate in vitro screening models that allow for more accurate predictions of in vivo performance.
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Project description:IntroductionImmunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention.MethodsHere, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1-7 (Ang(1-7)) to reduce vascular compression and deposition of extracellular matrix in mice.ResultsOur results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1-7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization.DiscussionTogether, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.
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