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Extracellular vesicles are recognized as a kind of membranous vesicle derived from endosomes and cell membranes that play important roles in intercellular communication. Strict biogenesis pathways dictate that extracellular vesicles have a wide range of origins and specific parental characteristics, while complex contents and surface proteins facilitate their recognition by receptor cells. Extracellular vesicles are considered a promising drug delivery system due to their natural biocompatibility and vesicle structure, where more functional biomolecules can be accommodated. The classification, biological functions, and characteristics of extracellular vesicles in different types of drug delivery were introduced. The application of extracellular vesicles in disease therapy and the clinical transformation and challenges of the extracellular vesicle delivery system were discussed.
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Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.
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Exosome is a kind of extracellular vesicles secreted by cells to the outside. Biogenesis mainly involves two invaginations of the cytoplasmic membrane, the formation of multivesicular bodies, and the release of exosomes. Exosomes have abundant and diverse inclusions—including landmark membrane proteins, soluble proteins, various RNA molecules and DNA fragments, etc. Cells can achieve intercellular signal communication by secreting and receiving exosomes. Through interaction of ligand molecules on the exosome membrane with receptors on the surface of other cytoplasmic membranes, exosomes can activate cell signal transduction or fuse with the cell membrane to release its contents into the cytoplasm to exert regulatory functions. In the central nervous system, exosomes secreted by neurons and various glial cells can mediate wired synaptic signal transmission, but mainly play a role similar to neuromodulator by way of volume transmission. In this paper, the biogenesis of exosomes and important functional components are described in detail, and the characteristics of neural exosomes in the biogenesis, content sorting and controlled release are compared with those of synaptic vesicles. We further review the research progress on the physiological functions of neural exosomes on the central nervous system and their roles in the occurrence and development of neurodegenerative diseases and major depressive disorder. We also prospect the application of exosomes in the early diagnosis and targeted therapy of nervous system diseases.
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Nanotechnology has shown obvious advantages in the field of medical treatment and diagnosis. Through the encapsulation of nano carriers, drugs not only enhance the therapeutic effect and reduce toxic and side effects, but also become intelligent responsive targeted drug systems through the modification on the surface of nano carriers. However, due to the obstacles in relevant basic research, production conditions, cost, clinical trials, and the lack of pharmacokinetic research on various drug loading systems, few nano systems have been used in therapy. In order to solve the above problems, this paper reviewed and analyzed the research progress of nano carriers in drug delivery, including their auxiliary role and characteristics, types and functions, pharmacokinetics, application prospects and challenges.
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Neutrophils are the first to reach the site of infection as they are the most numerous and dominant pathogen-killing cells in the circulatory system. They are both involved in initial immunity and act as effector cells in destructive inflammatory responses. The abundance of neutrophils in the human body and their inherent properties give them the ability to target inflammatory sites for drug delivery, and their important role in the inflammatory response has led to increasing attention to the therapeutic potential of neutrophils. In this review paper, the research progress in neutrophil-mediated drug delivery systems is reviewed, including the use of neutrophils as carriers, neutrophil exosomes as carriers, and in vivo targeted delivery of drugs using neutrophil properties.
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@#Immunotherapy cytokine preparations have important clinical value in anti-infection,anti-tumor,anti-rejection,autoimmune diseases and tissue repair,while their clinical application is limited due to the adverse reactions caused by short half-life,non-specific and adverse biodistribution of early cytokine preparations. With the in-depth understanding of the principle of cytokine-receptor interaction and cytokine-mediated signaling pathways,cytokine engineering for modification has become an effective cytokine design route. This paper mainly summarized the engineering design technology of cytokines,such as the design,targeting and delivery of recombinant cytokines,mRNA expression and cell technology,as well as the possible development directions of cytokine engineering in the future and the challenges in the process of clinical transformation,aiming to provide relevant technical references for the research and development of cytokine genetic engineering technology.
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Malignant tumors are major diseases that endanger human health. Due to their complex and variable microenvironment, most anti-tumor drugs cannot precisely reach the focal tissue and be released in a controlled manner. Intelligent responsive nano carriers have become a hot spot in the field of anti-tumor drug delivery systems. As an excellent nano material, mesoporous silica has the advantages of non-toxic, stable, adjustable pore volume and pore diameter, and easy functional modification on the surface. By virtue of its perceptive response to the tumor microenvironment or physiological changes, it can achieve the targeted drug release or controlled drug release of the drug delivery system in the tissue, making it an ideal carrier for intelligent response drug delivery system. In this paper, we review the design strategies and current research status of smart responsive anti-tumor drug delivery systems based on mesoporous silica, in order to provide a reference for the development of anti-tumor drug nanoformulations.
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Small-molecule anticancer drugs inhibited tumor growth based on targeted inhibition of specific proteins, while most of oncogenic proteins are "undruggable". Proteolysis targeting chimeras (PROTAC) is an attractive and general strategy for treating cancer based on targeted degradation of oncogenic proteins. This review briefly describes the peptide-based PTOTAC and small molecule-based PROTAC. Subsequently, we summarize the development of targeted delivery of PROTAC, such as targeting molecule-mediated targeted delivery of PROTAC, nanomaterial-mediated targeted delivery of PROTAC and controllable activation of small-molecular PROTAC prodrug. Such strategies show potential application in improving tumor selectivity, overcoming off-target effect and reducing biotoxicity. At the end, the druggability of PROTAC is prospected.
الموضوعات
Humans , Proteolysis Targeting Chimera , Nanostructures , Neoplasms/drug therapy , Proteolysisالملخص
Exosome is an excellent vesicle for in vivo delivery of therapeutics, including RNAi and chemical drugs. The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping. However, being composed of a lipid-bilayer membrane without specific recognition capacity for aimed-cells, the entry into nonspecific cells can lead to potential side-effects and toxicity. Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable. Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands. RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface. The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion, thus lowering the side-effect and toxicity. In this review, we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands, small peptides or RNA aptamers, for specific cancer targeting to deliver anticancer therapeutics, highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks. Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.
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Central nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are essential causes of death and long-term disability and are difficult to cure, mainly due to the limited neuron regeneration and the glial scar formation. Herein, we apply extracellular vesicles (EVs) secreted by M2 microglia to improve the differentiation of neural stem cells (NSCs) at the injured site, and simultaneously modify them with the injured vascular targeting peptide (DA7R) and the stem cell recruiting factor (SDF-1) on their surface via copper-free click chemistry to recruit NSCs, inducing their neuronal differentiation, and serving as the nanocarriers at the injured site (Dual-EV). Results prove that the Dual-EV could target human umbilical vascular endothelial cells (HUVECs), recruit NSCs, and promote the neuronal differentiation of NSCs in vitro. Furthermore, 10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis, and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs, miR30b-3p, miR-222-3p, miR-129-5p, and miR-155-5p may exert effect of inducing NSC to differentiate into neurons. In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice, potentiate NSCs recruitment, and increase neurogenesis. This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells, and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.
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OBJECTIVES@#Glioma is the most common primary intracranial tumor and there is still no ideal treatment at present. Gene therapy, as one of the new methods for treating glioma, has attracted attention in recent years. But its application in treating glioma is very limited due to lack of effective delivery vectors. This study aims to investigate the feasibility of biomimetic nanomaterials made from glioma cells-derived extracellular vesicles (EV) for targeted delivery of signal transducers and activators of transcription 3 (STAT3)-small interfering RNA (siRNA) in treating glioma.@*METHODS@#First, U251 glioma cells-derived extracellular vessel (EVU251) was extracted by ultra-centrifugal method. Nanoparticle tracking analysis was used to characterize the particle size distribution, the transmission electron microscope was used to analyze the morphology, and Western blotting was used to verify the expression of srface characteristic protein. The homing ability was verified by cell uptake assay after labeling EVU251 with membrane dye kit PKH67; the EVU251 contents were removed by a low permeability method and then EVMU251 was prepared through a microporous membrane. Finally, the biomimetic nanomaterials EVMU251@STAT3-siRNA were prepared by loading STAT3-SiRNA with electro-dyeing method. The real-time quantitative PCR was used to quantify the successful encapsulation of siRNA, and the encapsulation and drug loading rate was calculated; then Cy5-labeled siRNA was used to evaluate the ability of biomimetic nanomaterials (EVMU251@CY5-siRNA) to target U251 cells. Lysosomal escape ability of the biomimetic nanomaterial was evaluated by lysosomal dye lyso-tracker green. At last, the ability of EVMU251@STAT3-siRNA to knock down STAT3 gene and selective killing of U251 cells was detected by cell experiments in vitro.@*RESULTS@#The size of EVU251 ranged from 50 nm to 200 nm with a natural disc shape. The expression of extracellular vesicle marker proteins could be detected on the membrane of EVU251. The cell uptake assay demonstrated that it had homing ability to target U251 cells. After EVU251 was prepared as EVMU251@STAT3-siRNA, the particle size was (177.9±5.0) nm, the siRNA loading rate was (33.5±2.2)% and the drug loading rate was (3.24±0.21)%. The biomimetic nanomaterial EVMU251@STAT3-siRNA still had the ability to target U251 cells and successfully deliver siRNA to the cytoplasm without lysosomal degradation. The EVMU251@STAT3-siRNA can effectively knock down the expression of STAT3 gene and produce selective killing ability in U251 cells.@*CONCLUSIONS@#The biomimetic nanomaterials EVMU251@STAT3-siRNA made from glioma U251 cells-derived extracellular vesicles can knock down STAT3 gene of U251 cells and produce selective killing effect, which can provide a new idea for the treatment of glioma.
الموضوعات
Humans , RNA, Small Interfering/genetics , Biomimetics , Cell Line, Tumor , Glioma/therapy , Nanostructures , Cell Proliferation , STAT3 Transcription Factor/metabolismالملخص
BACKGROUND: Super-paramagnetic iron oxide nanoparticles (SPION) contain a chemotherapeutic drug and are regarded as a promising technique for improving targeted delivery into cancer cells. RESULTS: In this study, the fabrication of 5-fluorouracil (5-FU) was investigated with loaded Dextran (DEXSPION) using the co-precipitation technique and conjugated by folate (FA). These nanoparticles (NPs) were employed as carriers and anticancer compounds against liver cancer cells in vitro. Structural, magnetic, morphological characterization, size, and drug loading activities of the obtained FA-DEX-5-FUSPION NPs were checked using FTIR, VSM, FESEM, TEM, DLS, and zeta potential techniques. The cellular toxicity effect of FA-DEX-5-FU-SPION NPs was evaluated using the MTT test on liver cancer (SNU-423) and healthy cells (LO2). Furthermore, the apoptosis measurement and the expression levels of NF-1, Her-2/neu, c-Raf-1, and Wnt-1 genes were evaluated post-treatment using flow cytometry and RT-PCR, respectively. The obtained NPs were spherical with a suitable dispersity without noticeable aggregation. The size of the NPs, polydispersity, and zeta were 74 ± 13 nm, 0.080 and 45 mV, respectively. The results of the encapsulation efficiency of the nano-compound showed highly colloidal stability and proper drug maintenance. The results indicated that FA-DEX-5-FU-SPION demonstrated a sustained release profile of 5-FU in both phosphate and citrate buffer solutions separately, with higher cytotoxicity against SNU-423 cells than against other cells types. These findings suggest that FA-DEX-SPION NPs exert synergistic effects for targeting intracellular delivery of 5-FU, apoptosis induction, and gene expression stimulation. CONCLUSIONS: The findings proved that FA-DEX-5-FU-SPION presented remarkable antitumor properties; no adverse subsequences were revealed against normal cells.
الموضوعات
Humans , Carcinoma, Hepatocellular/drug therapy , Fluorouracil/administration & dosage , Liver Neoplasms/drug therapy , Polymers , Gene Expression/drug effects , Drug Delivery Systems , Apoptosis/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Delayed-Action Preparations , Nanoparticles/administration & dosage , Magnetite Nanoparticles , Flow Cytometryالملخص
@#To improve the therapeutic effect of cisplatin and reduce its side effects, a multifunctional drug delivery system with targeted and chemo-photothermal effect was constructed.Using polyethylene glycol polylactic acid block copolymer as a carrier, nanoparticles loaded with antitumor drug cisplatin and photosensitizer indocyanine green were prepared by ultrasonic emulsification, and the surface was then modified by cetuximab to prepare cetuximab-decorated and near-infrared (NIR)-activated nanoparticles (CPINPs).The physicochemical properties were characterized by mean particle size, Zeta potential, mAb conjugating rate and photothermal effect; the in vitro cell uptake was measured by laser confocal microscopy; and the in vitro antitumor activity was evaluated by CCK8 assay.The results indicated that CPINPs had mean particle diameter of (263.9 ± 3.73) nm, polydispersity index of 0.18 ± 0.03, Zeta potential of -(23.43 ± 0.42) mV, and cetuximab conjugating rate of (44.0 ± 1.72)%.The in vitro photothermal experiments showed that CPINPs upon NIR irradiation induced a photothermal effect, thus destroying the tumor cells. The in vitro cell uptake experiments demonstrated that NIR irradiation could promote cell uptake, and that more CPINPs were effectively internalized into A549 cells. The in vitro cytotoxicity test indicated that CPINPs treated with NIR irradiation had the effect of combined chemo-photothermal therapy, leading to higher cytotoxicity than that of free cisplatin or treatment without NIR, with IC50 values being (8.67 ± 0.04) μmol/L for 24 h incubation.To sumup the multifunctional drug delivery system constructed in the current work expected to be a more efficient targeted therapy strategy for lung cancer.
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Nucleic acid aptamers, broad-spectrum target-specific single-stranded oligonucleotides, serve as molecules in targeted therapy, targeted delivery and disease diagnosis for the treatment of tumor or microbial infection and clinical detection. Due to the existence of components in the use of traditional Chinese medicine(TCM), the target is difficult to concentrate and the specificity of treatment is poor. The effective components of TCM are toxic components, so a highly sensitive detection method is urgently needed to reduce the toxicity problem at the same time. The combined application of TCM and modern medical treatment strategy are difficult and cannot improve the therapeutic effect. Aptamers, advantageous in biosensors, aptamer-nanoparticles for targeted drug delivery, and aptamer-siRNA chimeras, are expected to connect Chinese medicinals with nanotechnology, diagnostic technology and combined therapies. We summarized the preparation, screening, and modification techniques of nucleic acid aptamers and the biomedical applications and advantages in therapy, targeting, and diagnosis, aiming at providing a reference for the in-depth research and development in TCM.
الموضوعات
Aptamers, Nucleotide , Drug Delivery Systems , Medicine, Chinese Traditional , Nucleic Acids , RNA, Small Interferingالملخص
Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.
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Blood-brain barrier (BBB) is the most challengeable obstacle for brain-targeted drug delivery. The combination of focused ultrasound (FUS) and microbubbles provides a new way for brain-targeted drug delivery across BBB based on the cavitation effect. This review briefly described the recent research of FUS combined with microbubbles to enhance the BBB permeability for brain-targeted drug delivery. The contents included the FUS mechanism, the types of the commercial microbubbles, shell materials, inner gas and preparation techniques of microbubbles, the opening mechanism of FUS with microbubbles, and the safety consideration. FUS combined with microbubbles may be the effective strategy to improve the BBB permeability for brain-targeted delivery, which could provide references for the clinical applications.
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Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which could result in autophagic cell death (ACD). Though novel combination chemotherapy of autophagy inducers with chemotherapeutic agents is extensively investigated, nanomedicine-based combination therapy for ACD remains in infancy. In attempt to actively trigger ACD for synergistic chemotherapy, here we incorporated autophagy inducer rapamycin (RAP) into 7pep-modified PEG-DSPE polymer micelles (7pep-M-RAP) to specifically target and efficiently priming ACD of MCF-7 human breast cancer cells with high expression of transferrin receptor (TfR). Cytotoxic paclitaxel (PTX)-loaded micelle (7pep-M-PTX) was regarded as chemotherapeutic drug model. We discovered that with superior intracellular uptake and more tumor accumulation of micelles , 7pep-M-RAP exhibited excellent autophagy induction and synergistic antitumor efficacy with 7pep-M-PTX. Mechanism study further revealed that 7pep-M-RAP and 7pep-M-PTX used in combination provided enhanced efficacy through induction of both apoptosis- and mitochondria-associated autophagic cell death. Together, our findings suggested that the targeted excess autophagy may provide a rational strategy to improve therapeutic outcome of breast cancer, and simultaneous induction of ACD and apoptosis may be a promising anticancer modality.
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Cancer stem cells (CSCs) can self-renew to form new tumors and consistently proliferate, which is considered as the root cause of chemotherapy resistance, relapse, and metastasis. Meanwhile, CSCs are resistant to standard chemotherapeutics and radiation therapy. Therefore, effectively eliminating CSCs is the key to curing cancers. Compared with current therapeutics, the agents loaded in nanocarriers can achieve better stability, greater bioavailability and longer circulation time. Nanoparticles can also be applied to hyperthermia and other therapies. Recently, considerable success has been achieved in application of nanotechnology to target CSCs. This review overviews the research on anti-CSCs therapies in chemotherapy, genetic therapy and hyperthermia. Combination therapy and multi-targeted nanomedicine will be effective ways to cure cancer and highlight the promising future in theranostic nanomedicine.
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Charge-reversal nanocarrier was constructed to enhance lysosomal escape and improve an-titumor effect. We synthesized the cholesterol-polyethyleneimine-hexahydrophthalic anhydride (Chol-PEI-HHPA) polymer and characterized by 1H NMR. The charge-reversal liposomes (Lipo-HHPA) were synthesized and the hematoporphyrin monomethyl ether (HMME) was loaded. pH-triggered charge conversion was determined at different pH values. The lysosomal escape and cytotoxicity of the Lipo-HHPA were evaluated in MCF-7 cells. The Lipo-HHPA was uniform with an average particle size of 102 nm. Upon the irradiation of ultrasound, burst release of HMME could be observed. The zeta potential of Lipo-HHPA changed sharply from negative (-23.5 mV) to positive (+21.2 mV) over the pH range of 7.4-4.5. In the cellular uptake experiment, the lysosomal escape of Lipo-HHPA was observed. HMME loaded Lipo-HHPA displayed obviously enhanced cytotoxicity towards MCF-7 cells. These results indicate that the charge-reversal liposomes hold a great potential in improving the cytotoxicity and antitumor effect.
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In the past 20 years, tumor immunotherapy has made a significant progress in tumor inhibition effects in both laboratory studies and clinical trails. In the immune response to tumor, effective antitumor immunity is induced during the tumor progress; long-term monitoring of the tumor would be achieved through the immune memory, reducing the possibility of tumor recurrence. In the immune treatment strategies, a focus is delivery of therapeutic immune regulators with nanocarriers. It has been demonstrated that due to the special physical and chemical properties, nanocarriers are easily internalized by immune cells, which regulate the immune responses and effectively induce anti-tumor immune cascade to achieve the tumor inhibition effect. In this paper, we will discuss the progress of nanocarrier-mediated antitumor immunotherapy in recent years.