Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we...Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.展开更多
Rheumatoid arthritis(RA)is a chronic inflammatory and destructive arthropathy with a high deformity rate.Despite numerous studies and clinical trials,no curative treatment is available for large weight-bearing joints....Rheumatoid arthritis(RA)is a chronic inflammatory and destructive arthropathy with a high deformity rate.Despite numerous studies and clinical trials,no curative treatment is available for large weight-bearing joints.Intra-articular(IA)injections could deliver high concentrations of drug to the afflicted joint and improve the drug efficacy while reducing systemic toxicity.However,free drugs are rapidly cleared from synovial fluid and do not significantly halt the progression of joint disease.Herein,a phospholipids-based controlledrelease gel was prepared for sustained IA delivery of celastrol(CEL)and the therapeutic efficiencywas evaluated in a rheumatoid arthritis rabbitmodel.The CEL-loaded gel(CEL-gel)contained up to 70%phospholipids yetwas easy to inject.After injecting into the joint cavity,CEL-gel achieved sol to gel phase transition without special stimuli and gelling agent.In vitro release and in vivo pharmacokinetic studies evidenced the stable and sustained release action of CEL-gel.A single IA injection of CEL-gel could maintain therapeutic efficiency for about 25 d and showed much better anti-arthritic efficacy compared to repeated injections of free drug solution(CEL-sol).Furthermore,the IA injection of CEL-gel greatly reduced the systemic toxicity of CEL.With good biocompatibility and biodegradability,CEL-gel might be a promising IA drug delivery system.展开更多
Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the m...Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.展开更多
Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has re...Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.展开更多
Nitric oxide(NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogen...Nitric oxide(NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogenous and exogenous stimuli. Then the application of NO donors, which was the main aim of the review, was discussed in detailed according to their functions, including inducing tumor cell apoptosis, reversing tumor multidrug resistance, inhibiting tumor metastasis and improving drug delivery.展开更多
Chondroitin sulfate-mediated albumin corona nanoparticles were readily prepared without any chemical reaction,and their active tumor targeting and therapeutic effects were examined.Negatively charged chondroitin sulfa...Chondroitin sulfate-mediated albumin corona nanoparticles were readily prepared without any chemical reaction,and their active tumor targeting and therapeutic effects were examined.Negatively charged chondroitin sulfate(CS)and positively charged doxorubicin(DOX)self-assembled into nanoparticles(CS-DOX-NPs)via electrostatic interactions.Bovine serum albumin(BSA)was then adsorbed on the surface of CS-DOX-NPs to form albumin corona nanoparticles(BC-DOX-NPs)protected from endogenous proteins.Due to the dual effect of BSA and CS,BC-DOX-NPs interacted with the gp60,SPARC and CD44 receptors on tumor cells,facilitating their rapid and efficient transcytosis and improving their accumulation and uptake within tumor tissues.The simultaneous presence of BSA and CS also allowed BC-DOX-NPs to target CD44 efficiently,leading to greater cellular uptake and cytotoxicity against 4 T1 cells than CS-DOX-NPs or free DOX.Intravenous injection of BCDOX-NPs into orthotopic 4 T1 tumor-bearing mice led to greater drug accumulation at the tumor site than with CS-DOX-NPs or free DOX,resulting in significant inhibition of tumor growth and lower exposure of major organs to the drug.展开更多
Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous i...Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.展开更多
Decades have passed since the first nanoparticles-base medicine was approved for human cancer treatment, and the research and development of nanoparticles for drug delivery are always undergoing.Nowadays, the signific...Decades have passed since the first nanoparticles-base medicine was approved for human cancer treatment, and the research and development of nanoparticles for drug delivery are always undergoing.Nowadays, the significant advances complicate nanoparticles’ branches, including liposomes, solid lipid nanoparticles, inorganic nanoparticles, micelles, nanovaccines and nano-antibodies, etc. These nanoparticles show numerous capabilities in treatment and diagnosis of stubborn diseases like cancer and neurodegenerative diseases, emerging as novel drug carriers or therapeutic agents in future. In this review, the complicated branches of nanoparticles are classified and summarized, with their property and functions concluded. Besides, there are also some delivery strategies that make nanoparticles smarter and more efficient in drug delivery, and frontiers in these strategies are also summarized in this review. Except these excellent works in newly-produced drug delivery nanoparticles, some points of view and future expectations are made in the end.展开更多
Neglected tropical diseases(NTDs)refer to infectious diseases caused by multiple pathogens that are prevalent in hot,humid climates in tropical areas.With the global economic growth and the improvement of public healt...Neglected tropical diseases(NTDs)refer to infectious diseases caused by multiple pathogens that are prevalent in hot,humid climates in tropical areas.With the global economic growth and the improvement of public health status,eliminating neglected tropical diseases will be of great significance to the healthy development of human beings.However,the number of drugs and vaccines for NTDs treatment is extremely limited,so it is urgent to develop new drugs.Since most NTDs are caused by parasites,this paper selected parasitic diseases with high morbidity and mortality,and focused on new effective therapeutic targets and excellent lead compounds for these diseases.Schistosomiasis,human African trypanosomiasis(HAT),Chagas disease,leishmaniasis,filariasis and toxoplasmosis correspond to a series targets such as smHDAC8,thioredoxin glutathione reductase(TGR),T.cruzi glucokinase(TcGlcK),phosphofructokinase(PFK),type IB topoisomerase,cell division cycle-2-related Kinase,sterolmethyl transferase,calumenin,dihydrofolate reductase(DHFR)and Toxoplasma gondii farnesyl-diphosphate synthase(TgFPPs).In this paper,the pharmacological effects of typical lead compounds corresponding to each disease,the structural characteristics of the mother nucleus and the pharmacological activities of the substituent.In addition,the binding patterns of some involved targets(such as smHDAC8)with corresponding lead compounds(such as compound 13)and the signaling pathways associated with gluconeogenesis,glycolysis,and pentose phosphate pathways are analyzed in detail.In this paper,the interaction mechanism between the lead compounds and the target were thoroughly discussed,in order to provide the research ideas of potential anti-parasite compounds,and further improve the understanding and prevention ability of such diseases of NTDs.展开更多
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor respon...Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.展开更多
Although progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency,nanoparticl...Although progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency,nanoparticles need to change size so as to fully utilize the enhanced permeability and retention(EPR) effect of solid tumor, which is the golden principle of nanoparticles used for cancer treatment. Herein, we employed cationic small-sized red emission bovine serum albumin(BSA) protected gold nanocluster(Au NC@CBSA,21.06 nm) to both load indocyanine green(ICG) and act as imaging probe to realize theranostic. Then Au NC@CBSA-ICG was fabricated with negatively charged hyaluronic acid(HA) to form Au NC@CBSAICG@HA, which was about 200 nm to easily retain at tumor site and could be degraded by tumor-specific hyaluronidase into small nanoparticles for deep tumor penetration. The HA shell also endowed Au NC@CBSA-ICG@HA with actively targeting ability and hyaluronidase-dependent drug release. Furthermore, the quenching and recovery of fluorescence revealed the interaction between ICG and carrier, which was essential for the investigation of pharmacokinetic profiles. No matter in vitro or in vivo, Au NC@CBSAICG@HA showed markedly anti-tumor effect, and could suppress 95.0% of tumor growth on mice breast cancer model. All results demonstrated Au NC@CBSA-ICG@HA was potential for breast cancer therapy.展开更多
Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we su...Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we summarize recent advances in design of aggregatable nanoparticles by different stimuli.Internal(pH and enzyme)and external(light,temperature and ROS)stimuli are introduced for a comprehensive description.Moreover,the aggregated nanoparticles usually exhibit photothermal,photoacoustic,PET and enhanced MRI contrast,which is also described.In the end,we discuss about the potential applications and challenges for the future clinical translation.展开更多
The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various ...The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.展开更多
Localized delivery,comparing to systemic drug administration,offers a unique alternative to enhance efficacy,lower dosage,and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the...Localized delivery,comparing to systemic drug administration,offers a unique alternative to enhance efficacy,lower dosage,and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests.Herein,a localized drug delivery platform ("plum?pudding"structure) with controlled release and long-acting features is developed through an injectable hydrogel ("pudding") crosslinked via self-assembled triblock polymeric micelles ("plum") to help reduce renal interstitial fibrosis.This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice.Following a single injection,local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFb antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-k B signaling pathway or neutralizing TGF-b1 locally.Importantly,the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity,which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.展开更多
Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines...Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.展开更多
An asymmetric total synthesis of(+)-21-epi-eburnamonine has been achieved.Key features of the synthesis include a visible-light photocatalytic intra-/intramolecular radical cascade reaction to assemble the tetracyclic...An asymmetric total synthesis of(+)-21-epi-eburnamonine has been achieved.Key features of the synthesis include a visible-light photocatalytic intra-/intramolecular radical cascade reaction to assemble the tetracyclic ABCD ring system,and a highly diastereoselective Johnson-Claisen rearrangement to establish the C20 all-carbon quaternary stereocenter.展开更多
Many studies have shown the influence of protein corona(PC)on the active targeting capability of ligand-modified nanoparticles;however,the influence of clinical status on PC composition and targeting capacity is rarel...Many studies have shown the influence of protein corona(PC)on the active targeting capability of ligand-modified nanoparticles;however,the influence of clinical status on PC composition and targeting capacity is rarely discussed.In this study,when transferrinmodified PEGylated polystyrene nanoparticles(Tf-PNs)is intravenously injected into mice with non-small cell lung cancer(NSCLC)comorbid with type 2 diabetes mellitus(T2DM),more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice.This indicated that PC derived fromdifferent states of disease changed the active targeting ability of Tf-PNs.To explain the occurrence of this phenomenon,our analysis of PC from different disease states revealed that Tf(transferrin)modification had no significant effect on the formation of PC,and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin.This work demonstrates the impacts of comorbidity,such as with T2DM,on the active targeting capability of ligand-modified nanoparticles,and the results promote the application of nanoparticles for precision medicine.展开更多
The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictab...The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.展开更多
Protein corona(PC)has been identified to impede the transportation of intravenously injected nanoparticles(NPs)from blood circulation to their targeted sites.However,how intestinal PC(IPC)affects the delivery of orall...Protein corona(PC)has been identified to impede the transportation of intravenously injected nanoparticles(NPs)from blood circulation to their targeted sites.However,how intestinal PC(IPC)affects the delivery of orally administered NPs are still needed to be elucidated.Here,we found that IPC exerted“positive effect”or“negative effect”depending on different pathological conditions in the gastrointestinal tract.We prepared polystyrene nanoparticles(PS)adsorbed with different IPC derived from the intestinal tract of healthy,diabetic,and colitis rats(H-IPC@PS,D-IPC@PS,C-IPC@PS).Proteomics analysis revealed that,compared with healthy IPC,the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine.Consequently,both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking,which increased the transcytosis from the epithelium.Together,disease-specific IPC endowed NPs with higher intestinal absorption.D-IPC@PS posed“positive effect”on intestinal absorption into blood circulation for diabetic therapy.Conversely,CIPC@PS had“negative effect”on colitis treatment because of unfavorable absorption in the intestine before arriving colon.These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.展开更多
Breast cancer and metastasis remain great challenges in clinical therapy.Compared with monotherapy,combination therapy,especially mediated by nanomedicine delivery strategy,significantly improves the therapeutic effic...Breast cancer and metastasis remain great challenges in clinical therapy.Compared with monotherapy,combination therapy,especially mediated by nanomedicine delivery strategy,significantly improves the therapeutic efficacy and reduces undesired toxicity.Cyclooxygenase-2(COX-2)inhibitors are widely used for adjuvant chemotherapy because COX-2 is overexpressed in virtually all cancer cell lines to regulate tumor progression by catalyzing prostaglandin E2(PGE2)synthesis.This drug combination strategy is still required to be improved due to some unsatisfactory clinical trial results.Intricate processes of tumor growth and metastasis are orchestrated by multiple proteins in addition to COX-2,which are modified and transported by Golgi apparatus.Hence,disrupting the structure and function of Golgi apparatus can inhibit the secretion of tumor-related proteins and further suppress carcinoma progression and metastasis.Since COX-2 is also enriched within Golgi apparatus in tumor cells,COX-2 inhibitors and Golgi disrupting agents can be co-delivered to Golgi apparatus to maximize the synergy.In this work,we developed a human serum albumin(HSA)nanoparticle encapsulating pirarubicin(THP),retinoic acid(RA),and indomethacin(IMC),called TIR-HSA,which was observed to be localized in Golgi complex of 4T1 cells.Owing to the synergistic effect of these three drugs,TIR-HSA inhibited the proliferation,migration,and invasion of tumor cells,enhanced the apoptotic rate,and improved the immunosuppressive tumor microenvironment,which remarkably regressed the tumor growth and metastasis and prolonged the survival period of 4T1-bearing mice.展开更多
基金The authors gratefully acknowledge financial support from National Natural Science Foundation of China(81872818)National Key R&D Program of China(2021YFE0115200).
文摘Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.
基金financially supported by the National Natural Science Foundation of China (Nos. 82173758, China)Sichuan major science and technology project on biotechnology and medicine (2018SZDZX0018, China)
文摘Rheumatoid arthritis(RA)is a chronic inflammatory and destructive arthropathy with a high deformity rate.Despite numerous studies and clinical trials,no curative treatment is available for large weight-bearing joints.Intra-articular(IA)injections could deliver high concentrations of drug to the afflicted joint and improve the drug efficacy while reducing systemic toxicity.However,free drugs are rapidly cleared from synovial fluid and do not significantly halt the progression of joint disease.Herein,a phospholipids-based controlledrelease gel was prepared for sustained IA delivery of celastrol(CEL)and the therapeutic efficiencywas evaluated in a rheumatoid arthritis rabbitmodel.The CEL-loaded gel(CEL-gel)contained up to 70%phospholipids yetwas easy to inject.After injecting into the joint cavity,CEL-gel achieved sol to gel phase transition without special stimuli and gelling agent.In vitro release and in vivo pharmacokinetic studies evidenced the stable and sustained release action of CEL-gel.A single IA injection of CEL-gel could maintain therapeutic efficiency for about 25 d and showed much better anti-arthritic efficacy compared to repeated injections of free drug solution(CEL-sol).Furthermore,the IA injection of CEL-gel greatly reduced the systemic toxicity of CEL.With good biocompatibility and biodegradability,CEL-gel might be a promising IA drug delivery system.
基金funded by the National Natural Science Foundation of China(82003879)Project of Science and Technology Department of Sichuan Province(2023NSFSC1928,2023NSFSC1992)+3 种基金Young Elite Scientists Sponsorship Program China Association for Science and Technology(CACM-2020-QNRC1-01)Project of State Administration of Traditional Chinese Medicine of China(ZYYCXTD-D-202209)Project of Undergraduate Training Programs for Innovation and Entrepreneurship(S202310610637)the Open Research Fund of State Key Laboratory of Southwestern Chinese Medicine Resources(SKLTCM202205).
文摘Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.
基金the National Natural Science Foundation of China (Grants 82170844 and 82270613)the Sichuan Science and Technology Program (Grants 2022YFH0045 and 2022YFH0102)+5 种基金the 111 Project (Grant B18035)the 1·3·5 project for Disciplines of Excellence at West China Hospital, Sichuan University (Grant ZYGD22007 and ZYJC21004)Ningbo Top Medical and Health Research Program (No.2023030514)Ningbo Medical and Health Brand Discipline (Grant No.PPXK2018–02)Ningbo Clinical Research Center for Otolaryngology Head and Neck Disease (Grant No.2022L005)the Ministry of Education, Singapore, (Grant MOE-000395-00) to LYC.
文摘Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.
基金supported by National Natural Science Foundation of China (31571016,81872806)
文摘Nitric oxide(NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogenous and exogenous stimuli. Then the application of NO donors, which was the main aim of the review, was discussed in detailed according to their functions, including inducing tumor cell apoptosis, reversing tumor multidrug resistance, inhibiting tumor metastasis and improving drug delivery.
基金financially supported by grants from the National Natural Science Foundation of China(No.81673359)Sichuan Major Science and Technology Project on Biotechnology and Medicine(No.2018SZDZX0018)。
文摘Chondroitin sulfate-mediated albumin corona nanoparticles were readily prepared without any chemical reaction,and their active tumor targeting and therapeutic effects were examined.Negatively charged chondroitin sulfate(CS)and positively charged doxorubicin(DOX)self-assembled into nanoparticles(CS-DOX-NPs)via electrostatic interactions.Bovine serum albumin(BSA)was then adsorbed on the surface of CS-DOX-NPs to form albumin corona nanoparticles(BC-DOX-NPs)protected from endogenous proteins.Due to the dual effect of BSA and CS,BC-DOX-NPs interacted with the gp60,SPARC and CD44 receptors on tumor cells,facilitating their rapid and efficient transcytosis and improving their accumulation and uptake within tumor tissues.The simultaneous presence of BSA and CS also allowed BC-DOX-NPs to target CD44 efficiently,leading to greater cellular uptake and cytotoxicity against 4 T1 cells than CS-DOX-NPs or free DOX.Intravenous injection of BCDOX-NPs into orthotopic 4 T1 tumor-bearing mice led to greater drug accumulation at the tumor site than with CS-DOX-NPs or free DOX,resulting in significant inhibition of tumor growth and lower exposure of major organs to the drug.
基金financial support from National Natural Science Foundation of China (81872818)National Key R&D Program of China (2021YFE0115200)
文摘Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.
基金supported by National Natural Science Foundation of China (No. 81961138009)111 Project (No. B18035)the Key Research and Development Program of Science and Technology Department of Sichuan Province (No. 2020YFS0570)。
文摘Decades have passed since the first nanoparticles-base medicine was approved for human cancer treatment, and the research and development of nanoparticles for drug delivery are always undergoing.Nowadays, the significant advances complicate nanoparticles’ branches, including liposomes, solid lipid nanoparticles, inorganic nanoparticles, micelles, nanovaccines and nano-antibodies, etc. These nanoparticles show numerous capabilities in treatment and diagnosis of stubborn diseases like cancer and neurodegenerative diseases, emerging as novel drug carriers or therapeutic agents in future. In this review, the complicated branches of nanoparticles are classified and summarized, with their property and functions concluded. Besides, there are also some delivery strategies that make nanoparticles smarter and more efficient in drug delivery, and frontiers in these strategies are also summarized in this review. Except these excellent works in newly-produced drug delivery nanoparticles, some points of view and future expectations are made in the end.
基金funded by the National Natural Science Foundation of China(No.82073311)the National Key Research and Development Program of China(No.2020YFC2005500)+8 种基金the Natural Science Foundation of Sichuan Province(No.2022JDTD0025)Science and Technology Project in Chengdu of Sichuan Province of China(No.2022-YF05-01620-SN)the Key Research and Development Program of Science and Technology Department of Sichuan Province(No.2019YFS0514)the Clinical Research and Transformation Fund of Sichuan Provincial People’s Hospital(No.2021LZ03)Open Fund of the State Key Laboratory of Traditional Chinese Medicine Resources in Southwest China(No.2021HX026)the State Administration of Traditional Chinese Medicine(No.JDZX2015210)the Open Research Fund of Chengdu University of Traditional Chinese Medicine Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China(No.2018GZ2011005)Screening and evaluation of anti-hepatic fibrosis varieties in traditional Chinese medicine formula granules(No.2022HX006)the Special Fund of Sichuan Provincial Administration of Traditional Chinese Medicine(No.2021MS_(2)76).
文摘Neglected tropical diseases(NTDs)refer to infectious diseases caused by multiple pathogens that are prevalent in hot,humid climates in tropical areas.With the global economic growth and the improvement of public health status,eliminating neglected tropical diseases will be of great significance to the healthy development of human beings.However,the number of drugs and vaccines for NTDs treatment is extremely limited,so it is urgent to develop new drugs.Since most NTDs are caused by parasites,this paper selected parasitic diseases with high morbidity and mortality,and focused on new effective therapeutic targets and excellent lead compounds for these diseases.Schistosomiasis,human African trypanosomiasis(HAT),Chagas disease,leishmaniasis,filariasis and toxoplasmosis correspond to a series targets such as smHDAC8,thioredoxin glutathione reductase(TGR),T.cruzi glucokinase(TcGlcK),phosphofructokinase(PFK),type IB topoisomerase,cell division cycle-2-related Kinase,sterolmethyl transferase,calumenin,dihydrofolate reductase(DHFR)and Toxoplasma gondii farnesyl-diphosphate synthase(TgFPPs).In this paper,the pharmacological effects of typical lead compounds corresponding to each disease,the structural characteristics of the mother nucleus and the pharmacological activities of the substituent.In addition,the binding patterns of some involved targets(such as smHDAC8)with corresponding lead compounds(such as compound 13)and the signaling pathways associated with gluconeogenesis,glycolysis,and pentose phosphate pathways are analyzed in detail.In this paper,the interaction mechanism between the lead compounds and the target were thoroughly discussed,in order to provide the research ideas of potential anti-parasite compounds,and further improve the understanding and prevention ability of such diseases of NTDs.
基金This study was supported by National Natural Science Foundation of China(Grant Nos.81925036,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(Grant No.2020YFS0570,China)111 project(Grant No.B18035,China).
文摘Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
基金supported by National Natural Science Foundation of China(No.81872806 and 31571016)
文摘Although progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency,nanoparticles need to change size so as to fully utilize the enhanced permeability and retention(EPR) effect of solid tumor, which is the golden principle of nanoparticles used for cancer treatment. Herein, we employed cationic small-sized red emission bovine serum albumin(BSA) protected gold nanocluster(Au NC@CBSA,21.06 nm) to both load indocyanine green(ICG) and act as imaging probe to realize theranostic. Then Au NC@CBSA-ICG was fabricated with negatively charged hyaluronic acid(HA) to form Au NC@CBSAICG@HA, which was about 200 nm to easily retain at tumor site and could be degraded by tumor-specific hyaluronidase into small nanoparticles for deep tumor penetration. The HA shell also endowed Au NC@CBSA-ICG@HA with actively targeting ability and hyaluronidase-dependent drug release. Furthermore, the quenching and recovery of fluorescence revealed the interaction between ICG and carrier, which was essential for the investigation of pharmacokinetic profiles. No matter in vitro or in vivo, Au NC@CBSAICG@HA showed markedly anti-tumor effect, and could suppress 95.0% of tumor growth on mice breast cancer model. All results demonstrated Au NC@CBSA-ICG@HA was potential for breast cancer therapy.
基金supported by the National Natural Science Foundation of China(No.81961138009)the Young Elite Scientists Sponsorship Program by CAST(No.2017QNR001)+1 种基金the Fundamental Research Funds for the Central Universities,111 Project(No.B18035)RFBR and National Natural Science Foundation of China Collaboration Project(No.19-58-55001)。
文摘Recent days,aggregatable nanoparticles,which can specifically respond to certain stimulus,have shown great potential in tumor-targeted drug delivery with prolonged retention and deeper penetration.In this review,we summarize recent advances in design of aggregatable nanoparticles by different stimuli.Internal(pH and enzyme)and external(light,temperature and ROS)stimuli are introduced for a comprehensive description.Moreover,the aggregated nanoparticles usually exhibit photothermal,photoacoustic,PET and enhanced MRI contrast,which is also described.In the end,we discuss about the potential applications and challenges for the future clinical translation.
基金the financial support of the National Natural Science Foundation (82173771)Fundamental Research Funds for the Central Universities and 111 project (B18035)
文摘The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.
基金supported by the National Natural Science Foundation of China (81773654, 81690261, 81503018)SichuanProvincial Science and Technology Department (2019YJ0019,China)+2 种基金National Key Research and Development Plan of China(2017YFC1104601)Sichuan University Fund for Excellent Young Scholars (2017SCU04A23, China)111 Project(B18035, China)。
文摘Localized delivery,comparing to systemic drug administration,offers a unique alternative to enhance efficacy,lower dosage,and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests.Herein,a localized drug delivery platform ("plum?pudding"structure) with controlled release and long-acting features is developed through an injectable hydrogel ("pudding") crosslinked via self-assembled triblock polymeric micelles ("plum") to help reduce renal interstitial fibrosis.This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice.Following a single injection,local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFb antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-k B signaling pathway or neutralizing TGF-b1 locally.Importantly,the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity,which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.
基金supported by National Natural Science Foundation of China (Grant Nos. 81925036 & 82003684)China Postdoctoral Science Foundation Grant (2019M663534, China)+3 种基金the Key Research and Development Program of Science and Technology Department of Sichuan Province (No. 2020YFS0570, China)Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System (CARS-SVDIP, China)the Fundamental Research Funds for the Central UniversitiesSichuan University Postdoctoral Interdisciplinary Innovation Fund。
文摘Mucosal vaccines that stimulate both mucosal and systemic immune responses are desirable,as they could prevent the invading pathogens at their initial infection sites in a convenient and userfriendly way. Nanovaccines are receiving increasing attention for mucosal vaccination due to their merits in overcoming mucosal immune barriers and in enhancing immunogenicity of the encapsulated antigens.Herein, we summarized several nanovaccine strategies that have been reported for enhancing mucosal immune responses, including designing nanovaccines that have superior mucoadhesion and mucus penetration capacity, designing nanovaccines with better targeting efficiency to M cells or antigen-presenting cells, and co-delivering adjuvants by using nanovaccines. The reported applications of mucosal nanovaccines were also briefly discussed, including prevention of infectious diseases, and treatment of tumors and autoimmune diseases. Future research progresses in mucosal nanovaccines may promote the clinical translation and application of mucosal vaccines.
基金surpport from National Natural Science Foundation of China(21921002 and 21991114)National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(2018ZX09711003-015 and 2018ZX09711001-005-004).
文摘An asymmetric total synthesis of(+)-21-epi-eburnamonine has been achieved.Key features of the synthesis include a visible-light photocatalytic intra-/intramolecular radical cascade reaction to assemble the tetracyclic ABCD ring system,and a highly diastereoselective Johnson-Claisen rearrangement to establish the C20 all-carbon quaternary stereocenter.
基金supported by the Key Research and Development Program of Science and Technology Department of the Sichuan Province 111 Project(B18035).
文摘Many studies have shown the influence of protein corona(PC)on the active targeting capability of ligand-modified nanoparticles;however,the influence of clinical status on PC composition and targeting capacity is rarely discussed.In this study,when transferrinmodified PEGylated polystyrene nanoparticles(Tf-PNs)is intravenously injected into mice with non-small cell lung cancer(NSCLC)comorbid with type 2 diabetes mellitus(T2DM),more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice.This indicated that PC derived fromdifferent states of disease changed the active targeting ability of Tf-PNs.To explain the occurrence of this phenomenon,our analysis of PC from different disease states revealed that Tf(transferrin)modification had no significant effect on the formation of PC,and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin.This work demonstrates the impacts of comorbidity,such as with T2DM,on the active targeting capability of ligand-modified nanoparticles,and the results promote the application of nanoparticles for precision medicine.
基金financially supported by the National Natural Science Foundation of China(81925036&81872814)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2020YFS0570,China)+2 种基金Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(CARS-SVDIP)111 project(b18035,China)the Fundamental Research Funds for the Central Universities(China)。
文摘The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.
基金financial support from the National Natural Science Foundation of China(No.81872818)the National Key R&D Program of China(No.2021YFE0115200)。
文摘Protein corona(PC)has been identified to impede the transportation of intravenously injected nanoparticles(NPs)from blood circulation to their targeted sites.However,how intestinal PC(IPC)affects the delivery of orally administered NPs are still needed to be elucidated.Here,we found that IPC exerted“positive effect”or“negative effect”depending on different pathological conditions in the gastrointestinal tract.We prepared polystyrene nanoparticles(PS)adsorbed with different IPC derived from the intestinal tract of healthy,diabetic,and colitis rats(H-IPC@PS,D-IPC@PS,C-IPC@PS).Proteomics analysis revealed that,compared with healthy IPC,the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine.Consequently,both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking,which increased the transcytosis from the epithelium.Together,disease-specific IPC endowed NPs with higher intestinal absorption.D-IPC@PS posed“positive effect”on intestinal absorption into blood circulation for diabetic therapy.Conversely,CIPC@PS had“negative effect”on colitis treatment because of unfavorable absorption in the intestine before arriving colon.These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.
基金supported by grants from the National Natural Science Foundation of China(No.81872804)Sichuan major science and technology project on biotechnology and medicine(No.2018SZDZX0018).
文摘Breast cancer and metastasis remain great challenges in clinical therapy.Compared with monotherapy,combination therapy,especially mediated by nanomedicine delivery strategy,significantly improves the therapeutic efficacy and reduces undesired toxicity.Cyclooxygenase-2(COX-2)inhibitors are widely used for adjuvant chemotherapy because COX-2 is overexpressed in virtually all cancer cell lines to regulate tumor progression by catalyzing prostaglandin E2(PGE2)synthesis.This drug combination strategy is still required to be improved due to some unsatisfactory clinical trial results.Intricate processes of tumor growth and metastasis are orchestrated by multiple proteins in addition to COX-2,which are modified and transported by Golgi apparatus.Hence,disrupting the structure and function of Golgi apparatus can inhibit the secretion of tumor-related proteins and further suppress carcinoma progression and metastasis.Since COX-2 is also enriched within Golgi apparatus in tumor cells,COX-2 inhibitors and Golgi disrupting agents can be co-delivered to Golgi apparatus to maximize the synergy.In this work,we developed a human serum albumin(HSA)nanoparticle encapsulating pirarubicin(THP),retinoic acid(RA),and indomethacin(IMC),called TIR-HSA,which was observed to be localized in Golgi complex of 4T1 cells.Owing to the synergistic effect of these three drugs,TIR-HSA inhibited the proliferation,migration,and invasion of tumor cells,enhanced the apoptotic rate,and improved the immunosuppressive tumor microenvironment,which remarkably regressed the tumor growth and metastasis and prolonged the survival period of 4T1-bearing mice.