ABSTRACT
In recent years, the use of the body's immune system for anti-tumor immunotherapy has received extensive attention. However, the immunosuppressive tumor microenvironment (TME) limits the effect of immunotherapy. Therefore, overcoming the limitations of TME and immunosuppressive cells plays an important role in tumor immunotherapy. Nano agents have great potential to reprogram the immunosuppressive microenvironment and provide an effective strategy for immunotherapy. With the continuous development of active targeting nano carrier technology and the deepening of the research on drug action sites, subcellular organ targeting nano carrier materials with more accurate active targeting function have also attracted more and more attention. This review will briefly introduce the relationship between subcellular organelles and tumor, summarize the design strategy and research progress of targeted nano drug delivery system based on the characteristics of acidity, reactive oxygen species (ROS) activity, immunogenicity, and TME of immunosuppressive cells, to provide reference for the construction of subcellular pathway targeted drug delivery system in tumor immunotherapy.
ABSTRACT
There are two serious obstacles to tumor immunotherapy. Firstly, the immune response of the tumor is seriously reduced due to immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumor. The second obstacle is the dense and complex heterogeneous structures, which seriously prevent the nanoparticles (NPs) from penetrating deeper into tumor tissue. Immunogenic cell death (ICD) induced by doxorubicin (DOX) is an effective method to enhance tumor immune activity. However, interferon-γ (IFN-γ) secreted by cytotoxic T lymphocytes (CTL) after ICD induction would increase the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and enhance ITM. IDO1 siRNA would reduce the expression of IDO1 protein, regulate the tumor immunosuppressive microenvironment and regulate ITM, so as to enhance the ICD effect of DOX. In this paper, a novel charge conversional, particle size reduction and highly penetrable NPs based on a pH sensitive copolymer poly(ethylene glycol)-poly-L-lysine-2,3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLD) and polyamidoamine (PAMAM) dendrimers to achieve deep delivery of tumor tissue. DOX and IDO1 siRNA were encapsulated to achieve efficient tumor immunotherapy. Preparation and cell level experiments showed that PLD material had significant pH sensitivity. Results of 3D tumor penetrable experiment in vitro showed that adding the pH sensitive material PLD significantly improved the permeability of the preparation. In addition, 4T1 tumor model was established for BALB/c mice and all animal experiments were displayed in according with the requirements of the Animal Experiment Ethics Committee of Shenyang Pharmaceutical University. The results of in vivo efficacy experiments and tissue experiments evaluated that IDO1 siRNA significantly improved the ICD effect owing to DOX, so as to significantly inhibit tumor growth.
ABSTRACT
<p><b>OBJECTIVE</b>To discuss the value of Gemstone Spectrum Imaging (GSI) CT anterior spinal artery angiography in the patients with cervical spinal cord injury, and to evaluate the correlation between the change of the blood flow of the anterior spinal artery and the postoperative recovery of nerve function.</p><p><b>METHODS</b>From January 2014 to June 2016, thirty patients who underwent cervical open door laminoplasty for spinal cord injury were retrospective analyzed and included 21 males and 9 females with an average age of (46.4±9.7) years old ranging from 33 to 59 years. Within 2 weeks after injury, open door laminoplasty was performed through cervical posterior approach. Among them, there were 8 cases of 3 segments of open door decompression, 18 cases of 4 segments, 4 cases of 5 segments. GSI CT were performed at 3 days before operation and 5 days after operation. The anterior spinal artery was reconstructed and evaluated the improvement of blood flow after operation. The cervical JOA score was calculated at 1 day before operation, 5 days after operation and 1, 6 and 12 months after operation, and the JOA score improvement rate of the corresponding follow-up points was calculated.</p><p><b>RESULTS</b>All patients were followed up for 12 to 30 months with an average of (17.4±7.6) months. The iodine content ratio (ASA/VA) of the anterior spinal artery before and after operation was 0.75±0.20 and 0.89±0.02 respectively, the postoperative improvement was significantly higher than that before operation(<0.01). The average ASA/VA improvement rate was(21.05±12.45)% after operation. There was a positive linear correlation between the improvement of blood flow and the improvement of JOA score at 1, 6 and 12 months after operation.</p><p><b>CONCLUSIONS</b>GSI CT anterior spinal artery angiography is safe and feasible, the imaging is satisfactory, it can quantitatively evaluated the blood flow of the anterior spinal artery. There was a positive linear correlation between the improvement of blood flow in anterior spinal artery and the recovery of neurological function. Early postoperative improvement of blood flow in the anterior spinal artery can be used as a reference index for predicting the recovery of neurological function in patients.</p>