Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.How...Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.展开更多
Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs wi...Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.展开更多
Pancreatic cancer is one of the leading causes of cancer death worldwide.Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival...Pancreatic cancer is one of the leading causes of cancer death worldwide.Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival of patients with this disease. However, the optimal chemotherapeutic regimen remains controversial. Recently, Conroy et al demonstrated the impressive benefits of modified FOLFIRINOX over gemcitabine alone in the multicenter Partenariat de Recherche en Oncologie Digestive 24(PRODIGE-24) trial. The remarkable results mark a new milestone in treating resectable pancreatic cancer and have now changed the standard of care for this patient population. In this commentary, we discuss an issue of difference of tumor grade between the PRODIGE-24 trial and previous phase III trials. We also discuss potential biomarkers predicting therapeutic response to modified FOLFIRINOX. Finally,we summarize several ongoing clinical trials of replacing part of the FOLFIRINOX regimen with Xeloda/S-1/nanoliposomal irinotecan for pancreatic cancer.展开更多
Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between ...Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovectorbased anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma.展开更多
Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot synd...Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.展开更多
The objective of this study is to compare the targeting ability of activated carbon nanoparticles and nanoliposomes,which are used as carriers for delivering docetaxel(DTX)to the metastatic lymph nodes.In this study,w...The objective of this study is to compare the targeting ability of activated carbon nanoparticles and nanoliposomes,which are used as carriers for delivering docetaxel(DTX)to the metastatic lymph nodes.In this study,we first prepared the DTX-loaded activated carbon nanoparticles(DTX-AC-NPs)by modifying the activated carbon with nitric acid oxidation and absorbing DTX in the concentrated nitro-oxide nanocarbon.We then prepared DTX-loaded nanoliposomes(DTX-LPs)by the proliposome method.The physiochemical properties of DTX-AC-NPs and DTX-LPs were carefully evaluated in vitro.The metastatic lymph node uptake and the injection site retention were investigated by analyzing the DTX concentration in metastatic lymph nodes and injection sites.The result showed that DTX-AC-NPs and DTX-LPs with suitable and stable physicochemical properties could be used for in vivo lymph node targeting studies.DTX-AC-NPs significantly increased DTX-AUC_((0-24)) and prolonged DTX-retention in metastatic lymph nodes compared to DTX-LPs and non-modified activate carbon in vivo.This study demonstrated activated carbon nanoparticles may be potential intralymphatic drug delivery system to preferentially target regional metastatic lymph nodes.展开更多
Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by...Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.展开更多
Catechin(CTC)is a phenolic active compound with multiple biological activities.However,CTC is relatively unstable,easily oxidized and poorly soluble in water,showing limited bioavailability,which is a challenge for it...Catechin(CTC)is a phenolic active compound with multiple biological activities.However,CTC is relatively unstable,easily oxidized and poorly soluble in water,showing limited bioavailability,which is a challenge for its application in the pharmaceutical and food industry.The purpose of this study was to promote the controlled release of CTC in the simulated gastrointestinal(GI)tract by using biopolymer-coupled nanoliposomes(NL).The nanoliposome was characterized by multifunctional polycrystalline X-ray diffraction(XRD),and Fourier transform infrared spectroscopy(FTIR).The results exhibited that the size of the nanocarrier was in the range of 87-178 nm,the encapsulation efficiency of CTC was 93.5%,and the combination of chitosan(CS)and alginate(ALG)was better than that of monopolymer.In vitro digestion studies showed that ALG-CS-NL significantly controlled the release of CTC by the diffusion,dissolution,and slow release mechanism and retained about 33%-37%of CTC under the GI condition.These results demonstrated that ALG-CS-NL could increase the stability of CTC,which may be important for the development of nutraceutical-enriched functional foods.展开更多
Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport.For their clinical application,nanoliposomes must b...Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport.For their clinical application,nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects.Therefore,responsive drug-release strategies for inflammation treatment have been explored;however,no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation.Herein,we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes(R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate,RC-NL@DMF)that pre-cisely release encapsulated anti-pyroptotic drugs into pyroptotic cells.The activated key pyroptotic protein,the N-terminal domain of gasdermin E,selectively integrates with the cardiolipin of liposomes,thus forming pores for controlled drug release,pyroptosis,and inflammation inhibition.Therefore,RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice.Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery,suppressing pyroptosis and treating autoimmune inflammatory diseases.展开更多
Crocetin displays strong antioxidant,anti-inflammatory and anti-depression activity which is promising to relieve symptoms of fatigue.As a carotenoid,crocetin is difficult to dissolve in water and highly unstable agai...Crocetin displays strong antioxidant,anti-inflammatory and anti-depression activity which is promising to relieve symptoms of fatigue.As a carotenoid,crocetin is difficult to dissolve in water and highly unstable against many environmental factors.Nanoliposome is used to encapsulate crocetin to improve its water dispersion.In the present study,the antifatigue activities and potential mechanism of crocetin loaded nanoliposome(CLN)was extensively investigated.The potential antifatigue pathway of CLN was analyzed.Furthermore,impact of CLN on the gut microbiota structure was examined which contributes to its antifatigue functions.CLN significantly increases exhaustive swimming time of fatigue mice,decreases the blood contents of lactic,blood urea nitrogen(BUN)and malondialdehyde(MDA).At the same time,CLN improves the activity of glutathione peroxidase(GSH-Px)and succinate dehydrogenase(SDH)enzyme,attenuates the oxidant stress in mice.CLN activates the adenosine monophosphate-activated kinase(AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)signaling pathway of fatigue mice,increases the mRNA expression of ATP synthase.It also increases mRNA expression of mitochondrial transcription factor A(TFAM)which promotes mitochondrial biogenesis.Additionally,CLN ameliorates the gut microbiota structure by increasing the abundance of genus such as Lactobacillus in fatigue mice.In summary,CLN exerts strong anti-fatigue properties by decreasing the oxidant stress and the contents of harmful metabolites,augmenting the production of ATP,and potentially ameliorating the gut microbiota structure.展开更多
Skeletal muscle disorders have posed great threats to health.Selective delivery of drugs and oligonucleotides to skeletal muscle is challenging.Aptamers can improve targeting efficacy.In this study,for the first time,...Skeletal muscle disorders have posed great threats to health.Selective delivery of drugs and oligonucleotides to skeletal muscle is challenging.Aptamers can improve targeting efficacy.In this study,for the first time,the human skeletal muscle-specific ssDNA aptamers(HSM01,etc.)were selected and identified with Systematic Evolution of Ligands by Exponential Enrichment(SELEX).The HSM01 ssDNA aptamer preferentially interacted with human skeletal muscle cells in vitro.The in vivo study using tree shrews showed that the HSM01 ssDNA aptamer specifically targeted human skeletal muscle cells.Furthermore,the ability of HSM01 ssDNA aptamer to target skeletal muscle cells was not affected by the formation of a disulfide bond with nanoliposomes in vitro or in vivo,suggesting a potential new approach for targeted drug delivery to skeletal muscles via liposomes.Therefore,this newly identified ssDNA aptamer and nanoliposome modification could be used for the treatment of human skeletal muscle diseases.展开更多
Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years.However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug rele...Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years.However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissuepenetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond directly.The aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin(DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.展开更多
Effective and precise neural modulation with real-time detection in the brain is of great importance and represents a significant challenge.Nanoliposome-encapsulated light-sensitive compounds have excellent characteri...Effective and precise neural modulation with real-time detection in the brain is of great importance and represents a significant challenge.Nanoliposome-encapsulated light-sensitive compounds have excellent characteristics such as high temporal and spatial resolution,delayed drug clearance,and restricted drug biodistribution for neural modulation.In this study,we developed a nanoliposome-based delivery system for ruthenium-based caged GABA compounds(Nanolipo-Ru)to modulate neural activity and allow for real-time monitoring using the microelectrode arrays(MEAs).The Nanolipo-Ru nanoparticles had an average size of 134.10±4.30 nm and exhibited excellent stability for seven weeks.For the in vivo experiment in the rat,release of GABA by Nanolipo-Ru under blue light illumination resulted in an average firing rate reduction in interneurons and pyramidal neurons in the same brain region of 79.4%and 81.6%,respectively.Simultaneously,the average power of local field potentials in the 0–15 Hz range degraded from 4.34 to 0.85 mW.In addition,the Nanolipo-Ru nanoparticles have the potential to provide more flexible timing of modulation than unencapsulated RuBi-GABA in the experiments.These results indicated that Nanolipo-Ru could be an effective platform for regulating neuronal electrophysiology.Furthermore,nanoliposomes with appropriate modifications would render promising utilities for targeting of specific types of neurons in the future.展开更多
The epidermal growth factor receptor(EGFR)pathway plays an important role in the progression of colorectal cancer(CRC).Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the ce...The epidermal growth factor receptor(EGFR)pathway plays an important role in the progression of colorectal cancer(CRC).Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway.However,the majority of CRC patients will inevitably develop drug-resistance during anti-EGFR drug treatment,which is mainly caused by a point mutation in the KRAS oncogene.We developed a nanoliposomal(NL)particle containing the Cas9 protein and a single-guide RNA(sgRNA)complex(Cas9-RNP),for genomic editing of the KRAS mutation.The NL particle is composed of bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP.By modifying the NL particle to include the appropriate antibody,it can specifically recognize EGFR expressing CRC and effectively deliver the gene-editing complexes.The conditions of NL treatment were optimized using a KRAS mutated CRC in vivo mouse model.Mice with KRAS-mutated CRC showed drug resistance against cetuximab,a therapeutic antibody drug.After treating the mice with the KRAS gene-editing NL particles,the implanted tumors showed a dramatic decrease in size.Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for the treatment of drug-resistant cancer caused by a point mutation.展开更多
Aim:Despite the huge advancements in cancer therapies and treatments over the past decade,most patients with metastasized melanoma still die from the disease.This poor prognosis largely results from resistance to conv...Aim:Despite the huge advancements in cancer therapies and treatments over the past decade,most patients with metastasized melanoma still die from the disease.This poor prognosis largely results from resistance to conventional chemotherapies and other cytotoxic drugs.We have previously identified 6 antigenic peptides derived from melanomas that have proven efficacious for activating CD4+T cells in clinical trials for melanoma.Our aim was to improve pharmacodynamics,pharmacokinetic and toxicological parameters by individually encapsulating each of the 6 melanoma helper peptides within their own immunogenic nanoliposomes.Methods:We modified these liposomes as necessary to account for differences in the peptides’chemical properties,resulting in 3 distinct formulations.To further enhance immunogenicity,we also incorporated KDO2,a TLR4 agonist,into the lipid bilayer of all nanoliposome formulations.We then conducted in vivo imaging studies in mice and ex vivo cell studies from 2 patient samples who both strongly expressed one of the identified peptides.Results:We demonstrate that these liposomes,loaded with the different melanoma helper peptides,can be readily mixed together and simultaneously delivered without toxicity in vivo.These liposomes are capable of being diffused to the secondary lymphoid organs very quickly and for at least 6 days.In addition,we show that these immunogenic liposomes enhance immune responses to specific peptides ex vivo.Conclusion:Lipid-based delivery systems,including nanoliposomes and lipid nanoparticles,have now been validated for pharmacological(small molecules,bioactive lipids)and molecular(mRNA,siRNA)therapeutic approaches.However,the utility of these formulations as cancer vaccines,delivering antigenic peptides,has not yet achieved the same degree of commercial success.Here,we describe the novel and successful development of a nanoliposome-based cancer vaccine for melanoma.These vaccines help to circumvent drug resistance by increasing a patient’s T cell response,making them more susceptible to checkpoint blockade therapy.展开更多
基金financially supported by Shenzhen Sanming Project of Medicine and Health, No. SZSM201612049 (to KJC)the Shenzhen Municipal Basic Research Project for Discipline Layout of China, No. JCYJ20170413161352000 (to YHL)Guangdong Basic Research Project, No. 2020A1515011427 (to ZZW)
文摘Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.
基金supported by Zhejiang Provincial Natural Science Foundation of China under Grant No.LYY21H300001Zhejiang Medical and Health Science and Technology project under Grant No.2021KY906Hangzhou Medical Key Discipline Construction Project under Grant No.[2021]21–39
文摘Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.
基金Supported by the National Key R&D Program of China,No.2017YFC1308604
文摘Pancreatic cancer is one of the leading causes of cancer death worldwide.Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival of patients with this disease. However, the optimal chemotherapeutic regimen remains controversial. Recently, Conroy et al demonstrated the impressive benefits of modified FOLFIRINOX over gemcitabine alone in the multicenter Partenariat de Recherche en Oncologie Digestive 24(PRODIGE-24) trial. The remarkable results mark a new milestone in treating resectable pancreatic cancer and have now changed the standard of care for this patient population. In this commentary, we discuss an issue of difference of tumor grade between the PRODIGE-24 trial and previous phase III trials. We also discuss potential biomarkers predicting therapeutic response to modified FOLFIRINOX. Finally,we summarize several ongoing clinical trials of replacing part of the FOLFIRINOX regimen with Xeloda/S-1/nanoliposomal irinotecan for pancreatic cancer.
文摘Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovectorbased anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma.
基金the Career Development Program for Yong and Middle-aged Teachers in Shenyang Pharmaceutical University。
文摘Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.
基金the support of Pharmacy Laboratory Centre and Animal Centre of Shenyang Pharmaceutical Universitysupported by the State Key Laboratory(Long-acting and Targeting Drug Delivery System)the Special Construction Project(Taishan ScholarePharmacy Specially Recruited Experts).
文摘The objective of this study is to compare the targeting ability of activated carbon nanoparticles and nanoliposomes,which are used as carriers for delivering docetaxel(DTX)to the metastatic lymph nodes.In this study,we first prepared the DTX-loaded activated carbon nanoparticles(DTX-AC-NPs)by modifying the activated carbon with nitric acid oxidation and absorbing DTX in the concentrated nitro-oxide nanocarbon.We then prepared DTX-loaded nanoliposomes(DTX-LPs)by the proliposome method.The physiochemical properties of DTX-AC-NPs and DTX-LPs were carefully evaluated in vitro.The metastatic lymph node uptake and the injection site retention were investigated by analyzing the DTX concentration in metastatic lymph nodes and injection sites.The result showed that DTX-AC-NPs and DTX-LPs with suitable and stable physicochemical properties could be used for in vivo lymph node targeting studies.DTX-AC-NPs significantly increased DTX-AUC_((0-24)) and prolonged DTX-retention in metastatic lymph nodes compared to DTX-LPs and non-modified activate carbon in vivo.This study demonstrated activated carbon nanoparticles may be potential intralymphatic drug delivery system to preferentially target regional metastatic lymph nodes.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81770268)the National Basic Research Program of China(No.2015CB932100).
文摘Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.
文摘Catechin(CTC)is a phenolic active compound with multiple biological activities.However,CTC is relatively unstable,easily oxidized and poorly soluble in water,showing limited bioavailability,which is a challenge for its application in the pharmaceutical and food industry.The purpose of this study was to promote the controlled release of CTC in the simulated gastrointestinal(GI)tract by using biopolymer-coupled nanoliposomes(NL).The nanoliposome was characterized by multifunctional polycrystalline X-ray diffraction(XRD),and Fourier transform infrared spectroscopy(FTIR).The results exhibited that the size of the nanocarrier was in the range of 87-178 nm,the encapsulation efficiency of CTC was 93.5%,and the combination of chitosan(CS)and alginate(ALG)was better than that of monopolymer.In vitro digestion studies showed that ALG-CS-NL significantly controlled the release of CTC by the diffusion,dissolution,and slow release mechanism and retained about 33%-37%of CTC under the GI condition.These results demonstrated that ALG-CS-NL could increase the stability of CTC,which may be important for the development of nutraceutical-enriched functional foods.
基金sustained by the National Natural Science Foundation of China(82072512,52273152,22161132027)Zhejiang Provincial Natural Science Foundation of China(LY23H060013,LY21H070001,LY20H160044,LBY21H060003).
文摘Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport.For their clinical application,nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects.Therefore,responsive drug-release strategies for inflammation treatment have been explored;however,no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation.Herein,we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes(R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate,RC-NL@DMF)that pre-cisely release encapsulated anti-pyroptotic drugs into pyroptotic cells.The activated key pyroptotic protein,the N-terminal domain of gasdermin E,selectively integrates with the cardiolipin of liposomes,thus forming pores for controlled drug release,pyroptosis,and inflammation inhibition.Therefore,RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice.Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery,suppressing pyroptosis and treating autoimmune inflammatory diseases.
基金supported by National Natural Science Foundation of China(31700015)Health Commission of Hunan Province(C202306017634)Changsha Natural Science Foundation(KQ2208092).
文摘Crocetin displays strong antioxidant,anti-inflammatory and anti-depression activity which is promising to relieve symptoms of fatigue.As a carotenoid,crocetin is difficult to dissolve in water and highly unstable against many environmental factors.Nanoliposome is used to encapsulate crocetin to improve its water dispersion.In the present study,the antifatigue activities and potential mechanism of crocetin loaded nanoliposome(CLN)was extensively investigated.The potential antifatigue pathway of CLN was analyzed.Furthermore,impact of CLN on the gut microbiota structure was examined which contributes to its antifatigue functions.CLN significantly increases exhaustive swimming time of fatigue mice,decreases the blood contents of lactic,blood urea nitrogen(BUN)and malondialdehyde(MDA).At the same time,CLN improves the activity of glutathione peroxidase(GSH-Px)and succinate dehydrogenase(SDH)enzyme,attenuates the oxidant stress in mice.CLN activates the adenosine monophosphate-activated kinase(AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)signaling pathway of fatigue mice,increases the mRNA expression of ATP synthase.It also increases mRNA expression of mitochondrial transcription factor A(TFAM)which promotes mitochondrial biogenesis.Additionally,CLN ameliorates the gut microbiota structure by increasing the abundance of genus such as Lactobacillus in fatigue mice.In summary,CLN exerts strong anti-fatigue properties by decreasing the oxidant stress and the contents of harmful metabolites,augmenting the production of ATP,and potentially ameliorating the gut microbiota structure.
基金supported by the National Key Research and Development Plan(2018YFC2001500)National Natural Science Foundation of China(81972254,82172098).
文摘Skeletal muscle disorders have posed great threats to health.Selective delivery of drugs and oligonucleotides to skeletal muscle is challenging.Aptamers can improve targeting efficacy.In this study,for the first time,the human skeletal muscle-specific ssDNA aptamers(HSM01,etc.)were selected and identified with Systematic Evolution of Ligands by Exponential Enrichment(SELEX).The HSM01 ssDNA aptamer preferentially interacted with human skeletal muscle cells in vitro.The in vivo study using tree shrews showed that the HSM01 ssDNA aptamer specifically targeted human skeletal muscle cells.Furthermore,the ability of HSM01 ssDNA aptamer to target skeletal muscle cells was not affected by the formation of a disulfide bond with nanoliposomes in vitro or in vivo,suggesting a potential new approach for targeted drug delivery to skeletal muscles via liposomes.Therefore,this newly identified ssDNA aptamer and nanoliposome modification could be used for the treatment of human skeletal muscle diseases.
基金supported by the National Natural Science Foundation of China (Nos. 30801441 and 81773278)。
文摘Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years.However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissuepenetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond directly.The aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin(DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.
基金This work was sponsored by the National Key Research and Development Program of nano science and technology of China (No. 2017YFA0205902)the National Natural Science Foundation of China (Nos. 61527815, 61960206012, 61975206, 61775216, 61971400, 61973292 and 61771452)the Key Research Programs (Nos. QYZDJ-SSW-SYS015 and XDA16020902) of Frontier Sciences, CAS.
文摘Effective and precise neural modulation with real-time detection in the brain is of great importance and represents a significant challenge.Nanoliposome-encapsulated light-sensitive compounds have excellent characteristics such as high temporal and spatial resolution,delayed drug clearance,and restricted drug biodistribution for neural modulation.In this study,we developed a nanoliposome-based delivery system for ruthenium-based caged GABA compounds(Nanolipo-Ru)to modulate neural activity and allow for real-time monitoring using the microelectrode arrays(MEAs).The Nanolipo-Ru nanoparticles had an average size of 134.10±4.30 nm and exhibited excellent stability for seven weeks.For the in vivo experiment in the rat,release of GABA by Nanolipo-Ru under blue light illumination resulted in an average firing rate reduction in interneurons and pyramidal neurons in the same brain region of 79.4%and 81.6%,respectively.Simultaneously,the average power of local field potentials in the 0–15 Hz range degraded from 4.34 to 0.85 mW.In addition,the Nanolipo-Ru nanoparticles have the potential to provide more flexible timing of modulation than unencapsulated RuBi-GABA in the experiments.These results indicated that Nanolipo-Ru could be an effective platform for regulating neuronal electrophysiology.Furthermore,nanoliposomes with appropriate modifications would render promising utilities for targeting of specific types of neurons in the future.
基金This work was supported by the Industrial Strategic Technology Development Program(Project No.10047679)of the Ministry of Trade,Industry&Energy(MI,Republic of Korea)+1 种基金partially supported by the GRRC program of Gyeonggi province(GRRC 2016B02,Photonics-Medical Convergence Technology Research Center)was partly supported by grant(No.2019R1F1A1058879)from the National Foundation Research of Korea.
文摘The epidermal growth factor receptor(EGFR)pathway plays an important role in the progression of colorectal cancer(CRC).Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway.However,the majority of CRC patients will inevitably develop drug-resistance during anti-EGFR drug treatment,which is mainly caused by a point mutation in the KRAS oncogene.We developed a nanoliposomal(NL)particle containing the Cas9 protein and a single-guide RNA(sgRNA)complex(Cas9-RNP),for genomic editing of the KRAS mutation.The NL particle is composed of bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP.By modifying the NL particle to include the appropriate antibody,it can specifically recognize EGFR expressing CRC and effectively deliver the gene-editing complexes.The conditions of NL treatment were optimized using a KRAS mutated CRC in vivo mouse model.Mice with KRAS-mutated CRC showed drug resistance against cetuximab,a therapeutic antibody drug.After treating the mice with the KRAS gene-editing NL particles,the implanted tumors showed a dramatic decrease in size.Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for the treatment of drug-resistant cancer caused by a point mutation.
文摘Aim:Despite the huge advancements in cancer therapies and treatments over the past decade,most patients with metastasized melanoma still die from the disease.This poor prognosis largely results from resistance to conventional chemotherapies and other cytotoxic drugs.We have previously identified 6 antigenic peptides derived from melanomas that have proven efficacious for activating CD4+T cells in clinical trials for melanoma.Our aim was to improve pharmacodynamics,pharmacokinetic and toxicological parameters by individually encapsulating each of the 6 melanoma helper peptides within their own immunogenic nanoliposomes.Methods:We modified these liposomes as necessary to account for differences in the peptides’chemical properties,resulting in 3 distinct formulations.To further enhance immunogenicity,we also incorporated KDO2,a TLR4 agonist,into the lipid bilayer of all nanoliposome formulations.We then conducted in vivo imaging studies in mice and ex vivo cell studies from 2 patient samples who both strongly expressed one of the identified peptides.Results:We demonstrate that these liposomes,loaded with the different melanoma helper peptides,can be readily mixed together and simultaneously delivered without toxicity in vivo.These liposomes are capable of being diffused to the secondary lymphoid organs very quickly and for at least 6 days.In addition,we show that these immunogenic liposomes enhance immune responses to specific peptides ex vivo.Conclusion:Lipid-based delivery systems,including nanoliposomes and lipid nanoparticles,have now been validated for pharmacological(small molecules,bioactive lipids)and molecular(mRNA,siRNA)therapeutic approaches.However,the utility of these formulations as cancer vaccines,delivering antigenic peptides,has not yet achieved the same degree of commercial success.Here,we describe the novel and successful development of a nanoliposome-based cancer vaccine for melanoma.These vaccines help to circumvent drug resistance by increasing a patient’s T cell response,making them more susceptible to checkpoint blockade therapy.