pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microsc...pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.展开更多
Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been som...Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection.However,significant barriers still exist on the road to clinical applications of siRNA drugs,including poor cellular uptake,instability under physiological conditions,off-target effects and possible immunogenicity.The successful application of siRNA for cancer therapy requires the development of clinically suitable,safe and effective drug delivery systems.Herein,we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy,including chemical modifications,lipidbased nanovectors,polymer-mediated delivery systems,conjugate delivery systems,and others.展开更多
Small interfering RNAs （siRNA） have enormous potential as therapeutics to target and treat various bone disor- ders such as osteoporosis and cancer bone metastases. However, effective and specific delivery of siRNA ...Small interfering RNAs （siRNA） have enormous potential as therapeutics to target and treat various bone disor- ders such as osteoporosis and cancer bone metastases. However, effective and specific delivery of siRNA therapeu- tics to bone and bone-specific cells in vivo is very challenging. To realize the full therapeutic potential of siRNA in treating bone disorders, a safe and efficient, tissue- and cell-specific delivery system must be developed. This review focuses on recent advances in bone site-specific delivery of siRNA at the tissue or cellular level. Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates, oligopeptides （Asp）8 and （AspSerSer）6, and aptamers are highlighted. Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specific cell types residing in bone tissue. It also provides a means for bone-formation surface-, bone-resorption surface-, or osteoblast- specific targeting and transportation of siRNA therapeutics. The discussion mainly focuses on systemic and local bone-specific delivery of siRNA in osteoporosis and bone metastasis preclinical models.展开更多
How to effectively transform the pro-oncogenic tumor microenvironments(TME)surrounding a tumor into an anti-tumoral never fails to attract people to study.Small interfering RNA(siRNA)is considered one of the most note...How to effectively transform the pro-oncogenic tumor microenvironments(TME)surrounding a tumor into an anti-tumoral never fails to attract people to study.Small interfering RNA(siRNA)is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference(RNAi).The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years.Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions.However,the manufacture of a siRNA delivery system faces three major obstacles,i.e.,appropriate cargo protection,accurately targeted delivery,and site-specific cargo release.In the following review,we summarized the pharmacological actions of siRNA drugs in remolding TME.In addition,the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed.In the meanwhile,the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented.Ultimately,we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy.This summary offers a thorough analysis and roadmap for general readers working in the field.展开更多
Upon the discovery of RNA interference(RNAi),canonical small interfering RNA(si RNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of si RNAs as potential new drugs,there are ob...Upon the discovery of RNA interference(RNAi),canonical small interfering RNA(si RNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of si RNAs as potential new drugs,there are obstacles still to be overcome,including off-target effects and immune stimulation. More recently,Dicer substrate si RNA(Dsi RNA) has been introduced as an alternative to si RNA. Similarly,it also is proving to be potent and target-specific,while rendering less immune stimulation. Dsi RNA is 25–30 nucleotides in length,and is further cleaved and processed by the Dicer enzyme. As with si RNA,it is crucial to design and develop a stable,safe,and efficient system for the delivery of Dsi RNA into the cytoplasm of targeted cells. Several polymeric nanoparticle systems have been well established to load Dsi RNA for in vitro and in vivo delivery,thereby overcoming a major hurdle in the therapeutic uses of Dsi RNA. The present review focuses on a comparison of si RNA and Dsi RNA on the basis of their design,mechanism,in vitro and in vivo delivery,and therapeutics.展开更多
Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate si...Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel(PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA) and glucose(Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCopolyethyleneimine(FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu(NPsB) and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.展开更多
Graphene oxide(GO) has emerged as a potential drug delivery vector. For siRNA delivery, GO should be modified to endow it with gene delivery ability and targeting effect. However, the cationic materials used previousl...Graphene oxide(GO) has emerged as a potential drug delivery vector. For siRNA delivery, GO should be modified to endow it with gene delivery ability and targeting effect. However, the cationic materials used previously usually had greater toxicity. In this study, GO was modified with a non-toxicity cationic material(chitosan) and a tumor specific monoclonal antibody(anti-EpCAM) for the delivery of survivin-siRNA(GCE/siRNA). And the vector(GCE) prepared was proved with excellent biosafety and tumor targeting effect. The GCE exhibited superior performance in loading si RNA, maintained stability in different solutions and showed excellent protection effect for survivin-siRNA in vitro. The gene silencing results in vitro showed that the m RNA level and protein level were down-regulated by 48.24% ± 2.50% and 44.12% ± 3.03%, respectively, which was equal with positive control( P > 0.05). It was also demonstrated that GCE/siRNA had a strong antitumor effect in vitro, which was attributed to the efficient antiproliferation, and migration and invasion inhibition effect of GCE/siRNA. The results in vivo indicated that GCE could accumulate siRNA in tumor tissues. The tumor inhibition rate of GCE/siRNA 54.74% ± 5.51% was significantly higher than control 4.87% ±8.49%. Moreover, GCE/siRNA showed no toxicity for blood and main organs, suggesting that it is a biosafety carrier for gene delivery. Taken together, this study provides a novel design strategy for gene delivery system and siRNA formulation.展开更多
Gene therapy using siRNA molecules is nowadays considered as a promising approach. For successful therapy, development of a stable and reliable vector for siRNA is crucial. Non-viral and non-organic vectors like mesop...Gene therapy using siRNA molecules is nowadays considered as a promising approach. For successful therapy, development of a stable and reliable vector for siRNA is crucial. Non-viral and non-organic vectors like mesoporous silica nanoparticles(MSN) are associated with lack of most viral vector drawbacks, such as toxicity, immunogenicity, but also generally a low nucleic acid carrying capacity. To overcome this hurdle, we here modified the pore walls of MSNs with surface-hyperbranching polymerized poly(ethyleneimine)(hbPEI), which provides an abundance of amino-groups for loading of a larger amount of siRNA molecules via electrostatic adsorption. After loading, the particles were covered with a second layer of pre-polymerized PEI to provide better protection of siRNA inside the pores, more effective cellular uptake and endosomal escape. To test the transfection efficiency of PEI covered si RNA/MSNs, MDA-MB 231 breast cancer cells stably expressing GFP were used. We demonstrate that PEI-coated si RNA/MSN complexes provide more effective delivery of si RNAs compared to unmodified MSNs. Thus, it can be concluded that appropriately surface-modified MSNs can be considered as prospective vectors for therapeutic siRNA delivery.展开更多
Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion n...Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.展开更多
Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined...Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.展开更多
基金Funded by the National Key R&D Program of China(No.2023YFC2412300)the Natural Science Foundation of Hubei Province(No.2022CFB386)the National Natural Science Foundation of China(No.52073222)。
文摘pH-responsive charge reversal loaded miRNA nanocomposite was prepared by electrostatic self-assembly.The morphology,particle size and zeta potential of the nanocomposites were analyzed by transmission electron microscopy and dynamic light scattering.The synthesis of the polymer was analyzed by^(1)H-NMR.The zeta-potential changes and cellular uptake effects of the nanocomplexes under different pH environments were investigated.The experimental results show that the surface morphology of the nanocomposite is spherical,and the average particle size is about 135 nm.As the pH value of the solution gradually decreases,the surface charge of the nanocomposite reverses from negative charge to positive charge(from-9.4 to+17.1 mV).Cellular uptake mediated by pH-responsive nanocomposite is selective for tumor cells,and the cellular uptake effect in tumor cells at pH 6.5 was approximately 3 times higher than that at pH 7.4.This pH responsive charge reversal nanocomposite has promising application prospects for gene delivery in the weak acid environment of tumors.
文摘Since the discovery of the Nobel prize-winning mechanism of RNA interference(RNAi)ten years ago,it has become a promising drug target for the treatment of multiple diseases,including cancer.There have already been some successful applications of siRNA drugs in the treatment of age-related macular degeneration and respiratory syncytial virus infection.However,significant barriers still exist on the road to clinical applications of siRNA drugs,including poor cellular uptake,instability under physiological conditions,off-target effects and possible immunogenicity.The successful application of siRNA for cancer therapy requires the development of clinically suitable,safe and effective drug delivery systems.Herein,we review the design criteria for siRNA delivery systems and potential siRNA drug delivery systems for cancer therapy,including chemical modifications,lipidbased nanovectors,polymer-mediated delivery systems,conjugate delivery systems,and others.
基金supported by the Cancer Prevention Research Institute of Texas(CPRIT,RP 150656,X.L.)National Institute of Health(NIH/NCI,R15CA182769, X.L.)
文摘Small interfering RNAs （siRNA） have enormous potential as therapeutics to target and treat various bone disor- ders such as osteoporosis and cancer bone metastases. However, effective and specific delivery of siRNA therapeu- tics to bone and bone-specific cells in vivo is very challenging. To realize the full therapeutic potential of siRNA in treating bone disorders, a safe and efficient, tissue- and cell-specific delivery system must be developed. This review focuses on recent advances in bone site-specific delivery of siRNA at the tissue or cellular level. Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates, oligopeptides （Asp）8 and （AspSerSer）6, and aptamers are highlighted. Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specific cell types residing in bone tissue. It also provides a means for bone-formation surface-, bone-resorption surface-, or osteoblast- specific targeting and transportation of siRNA therapeutics. The discussion mainly focuses on systemic and local bone-specific delivery of siRNA in osteoporosis and bone metastasis preclinical models.
基金supported by the Natural Science Foundation of China(U2230123,81870683,82121003 and 82201234)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-032)the Department of Science and Technology of Sichuan Province,China(22ZYZYTS0159,2022YFS0606,2023YFS0125,2023YFS0131,2023NSFSC0033,and 22ZYZYTS0151)
文摘How to effectively transform the pro-oncogenic tumor microenvironments(TME)surrounding a tumor into an anti-tumoral never fails to attract people to study.Small interfering RNA(siRNA)is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference(RNAi).The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years.Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions.However,the manufacture of a siRNA delivery system faces three major obstacles,i.e.,appropriate cargo protection,accurately targeted delivery,and site-specific cargo release.In the following review,we summarized the pharmacological actions of siRNA drugs in remolding TME.In addition,the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed.In the meanwhile,the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented.Ultimately,we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy.This summary offers a thorough analysis and roadmap for general readers working in the field.
基金financial support received from Centre of Research and Instrumentation (CRIM), Universiti Kebangsaan Malaysia
文摘Upon the discovery of RNA interference(RNAi),canonical small interfering RNA(si RNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of si RNAs as potential new drugs,there are obstacles still to be overcome,including off-target effects and immune stimulation. More recently,Dicer substrate si RNA(Dsi RNA) has been introduced as an alternative to si RNA. Similarly,it also is proving to be potent and target-specific,while rendering less immune stimulation. Dsi RNA is 25–30 nucleotides in length,and is further cleaved and processed by the Dicer enzyme. As with si RNA,it is crucial to design and develop a stable,safe,and efficient system for the delivery of Dsi RNA into the cytoplasm of targeted cells. Several polymeric nanoparticle systems have been well established to load Dsi RNA for in vitro and in vivo delivery,thereby overcoming a major hurdle in the therapeutic uses of Dsi RNA. The present review focuses on a comparison of si RNA and Dsi RNA on the basis of their design,mechanism,in vitro and in vivo delivery,and therapeutics.
基金supported by the Deputy Research and Technology, Ardabil University of Medical Sciences。
文摘Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel(PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA) and glucose(Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCopolyethyleneimine(FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu(NPsB) and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.
基金supported by the National Natural Science Foundation(81502688)Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education(KM201810025019)+2 种基金a basic-clinical key research Grant(16JL72,17JL67)from Capital Medical Universitythe Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions(2013–2015)Natural Science Foundation of Capital Medical University(1210020232)。
文摘Graphene oxide(GO) has emerged as a potential drug delivery vector. For siRNA delivery, GO should be modified to endow it with gene delivery ability and targeting effect. However, the cationic materials used previously usually had greater toxicity. In this study, GO was modified with a non-toxicity cationic material(chitosan) and a tumor specific monoclonal antibody(anti-EpCAM) for the delivery of survivin-siRNA(GCE/siRNA). And the vector(GCE) prepared was proved with excellent biosafety and tumor targeting effect. The GCE exhibited superior performance in loading si RNA, maintained stability in different solutions and showed excellent protection effect for survivin-siRNA in vitro. The gene silencing results in vitro showed that the m RNA level and protein level were down-regulated by 48.24% ± 2.50% and 44.12% ± 3.03%, respectively, which was equal with positive control( P > 0.05). It was also demonstrated that GCE/siRNA had a strong antitumor effect in vitro, which was attributed to the efficient antiproliferation, and migration and invasion inhibition effect of GCE/siRNA. The results in vivo indicated that GCE could accumulate siRNA in tumor tissues. The tumor inhibition rate of GCE/siRNA 54.74% ± 5.51% was significantly higher than control 4.87% ±8.49%. Moreover, GCE/siRNA showed no toxicity for blood and main organs, suggesting that it is a biosafety carrier for gene delivery. Taken together, this study provides a novel design strategy for gene delivery system and siRNA formulation.
基金supported in part by Russian Science Founda-tion grant 17-15-01230(biological characterization)Academy of Finland project nos.284542,384542(JMR)+2 种基金Jane and Aatos Erkko Foundation(EC)Anna Egorova is supported by President of Russian Federation scholarship(SP-2162.2015.4)Anna Slita was supported by the scholarship within Saint Pe-tersburg State University bilateral exchange program for study abroad
文摘Gene therapy using siRNA molecules is nowadays considered as a promising approach. For successful therapy, development of a stable and reliable vector for siRNA is crucial. Non-viral and non-organic vectors like mesoporous silica nanoparticles(MSN) are associated with lack of most viral vector drawbacks, such as toxicity, immunogenicity, but also generally a low nucleic acid carrying capacity. To overcome this hurdle, we here modified the pore walls of MSNs with surface-hyperbranching polymerized poly(ethyleneimine)(hbPEI), which provides an abundance of amino-groups for loading of a larger amount of siRNA molecules via electrostatic adsorption. After loading, the particles were covered with a second layer of pre-polymerized PEI to provide better protection of siRNA inside the pores, more effective cellular uptake and endosomal escape. To test the transfection efficiency of PEI covered si RNA/MSNs, MDA-MB 231 breast cancer cells stably expressing GFP were used. We demonstrate that PEI-coated si RNA/MSN complexes provide more effective delivery of si RNAs compared to unmodified MSNs. Thus, it can be concluded that appropriately surface-modified MSNs can be considered as prospective vectors for therapeutic siRNA delivery.
基金supported by the National Key Basic Research Program(973 Project)(Grant Nos.2015CB931802 and 2017FYA0205301)the Special Fund for Science and Technology Innovation of Shanghai Jiao Tong University(Grant Nos.YG2017MS70,YG2015MS62,and AF0300179)+3 种基金the Shanghai Municipal Bureau of Economy and Information Technology(Grant No.XC-ZXSJ-02-2016-05)the National Natural Scientific Foundation of China(Grant Nos.8202010801,81921002,81225010,81028009,and 31170961)the 863 Project of China(Grant No.2014AA020700)and the Shanghai Science and Technology Fund(Grant No.13NM1401500)。
文摘Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.
文摘Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.
