TRAIL-coated Nanoparticles Enhance Antitumor Efficacy Via Autophagy-mediated DR5 Upregulation

Cancer is a major threat to human health,causing about million deaths every year worldwide,and the number of new cancer cases is considered to rise in the future.However,substantial research has been made in the cancer,the routinely used form is surgery and it is usually not resectable because of the laggard preoperative diagnosis.Nonetheless,the survival time of most of cancer patients could be significantly prolonged by applying effective pharmaceuticals to inhibit the growth of tumor even kill cancer cells.Apoptosis as a type I programmed cell death plays a critical role in keeping human tissue homeostasis,and its aberration is closely related to the initiation and progression of cancer.Traditional chemotherapy and radiotherapy mainly induce cancer cells apoptosis through intrinsic pathway,however,some serious adverse effects and potential drug resistance occur,even worse,the acquired resistance often causes recurrence,cancer dissemination and death.In contrast,extrinsic pathway controlled by extracellular death ligands is considered as a promising strategy to regulate apoptosis while overcoming the key resistance pathways.Autophagy is a cytoprotective mechanism that help cancer cells survive in nutrition deprivation and chemical therapeutics used in treatment of human cancer.Previous clinical researches have demonstrated that cancer cells are proactively to degrade subcellular organelles to produce new nutrition and energy to sustain cell homeostasis and survival under conditions of TRAIL treatment.Surprisingly,much work has been done to research autophagy,the importance made by autophagy in cell death and survival remains controversial.In some preclinical trials,making full use of autophagy induced DR5 upregulation has shown promising outcomes because it can promote cell death by sensitizing cancer cells to chemotherapeutics.To date,as favorable contrast agents for magnetic resonance imaging and drug carriers in clinical,iron oxide nanoparticles and other ferumoxytol have been approved by the Food and Drug administration(FDA).Furthermore,how to combine with TRAIL with the new theranostics,which can modulate autophagy with sensitizing cancer,cell to TRAIL and be as MRI contrast agent is one of the highlights in this article.Here,we-design a novel polymer-based TRAIL protein delivery strategy and superparamagnetic iron oxide(SPIO)is one of the important components of the nanoparticles.In the first,the cytotoxicity of the nanoparticle was assayed by MTT methods in different cell lines to confirm it is safe.Then,we find that NanoTRAIL can induce autophagy and upregulate DR5 expression at the same time.NanoTRAIL also can bind the DR5 expressed on the surface of cancer cells and induce the cells apoptosis.Accurate diagnostic information of tumor can be obtained by magnetic resonance imaging due to TRAIL protein and nanoparticles complex highly specific accumulation in tumor.Enhancing apoptosis induction is an appealing treatment strategy in clinical applications and laboratory research.TRAIL is a promising biogenetic derivative protein and is proven to successfully trigger apoptosis in a variety of tumor cells,but,-the way to take advantage of TRAIL still deserves consideration.With the development of nanomedicine and nanobiotechnology,the introduction of nanoTRAIL would significantly advance the progression of TRAIL and open up a new avenue for future TRAIL designs.