Nowadays,tremendous researches have been focused on the core-shell lipid-polymer nanoparticles(LPNs) due to the advantages of both liposomes and polymer nanoparticles.In this work,LPNs were applied to encapsulate brin...Nowadays,tremendous researches have been focused on the core-shell lipid-polymer nanoparticles(LPNs) due to the advantages of both liposomes and polymer nanoparticles.In this work,LPNs were applied to encapsulate brinzolamide(Brz-LPNs) for achieving sustained drug release,improving drug corneal permeation and enhancing drug topical therapeutic effect.The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid(PLGA) nanocore which encapsulated Brz(Brz-NPs) and lipid shell around the core.Brz-LPNs were prepared by a modified thin-film dispersion method.With the parameters optimization of Brz-LPNs,optimal Brz-LPNs showed an average particle size of151.23±1.64 nm with a high encapsulation efficiency(EE) of 86.7%±2.28%.The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy(TEM).Fourier transformed infrared spectra(FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs.Brz-LPNs exhibited obvious sustained release of Brz,compared with AZOPT^■ and Brz-LPs.Furthermore,the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation(AZOPT^■) in vitro.Moreover,Brz-LPNs(1 mg/mL Brz) showed a more sustained and effective intraocular pressure(IOP) reduction than Brz-LPs(1 mg/mL) and AZOPT^■(10 mg/mL Brz) in vivo.In conclusion,Brz-LPNs,as promising ocular drug delivery systems,are well worth developing in the future for glaucoma treatment.展开更多
Hypertension is the leading risk factor for death and disability, and hypertensive patients always need long-term oral antihypertensive drugs. Some bioactive peptides that extracted from animals or plants have shown e...Hypertension is the leading risk factor for death and disability, and hypertensive patients always need long-term oral antihypertensive drugs. Some bioactive peptides that extracted from animals or plants have shown excellent advantages on antihypertension. However, the oral delivery of these peptides is always failure on account of instability and poor absorption in the gastrointestinal tract. Herein, we developed a core-shell lipid-polymeric nanoparticle for oral delivery of a highly efficient antihypertensive peptide KY5(KY5-CSs). KY5-CSs had a particle size of 216.7 ± 2.5 nm, with a narrow PDI of 0.07 ± 0.01.The zeta potential was-4.1 ± 0.1 m V. It exhibited good stability in 4 ℃ and possessed a controlled release behavior in gastrointestinal tract. The cellular uptake study proved that the lipid shell imparted unique capability of permeation across the mucus layer and internalization by Caco-2/HT-29 cells. In addition, KY5-CSs enhanced in situ intestinal absorption in SD rats. The pharmacokinetic studies and antihypertensive efficacy showed a superior oral absorption and antihypertensive effect of KY5-CSs than KY5-NPs. In conclusion, the core-shell lipid-polymeric nanoparticles will provide attractive potential for oral delivery of antihypertensive peptides.展开更多
Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceuticalpreparations such as controlled release formulations, parenteral preparations, surgicaltreatment application...Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceuticalpreparations such as controlled release formulations, parenteral preparations, surgicaltreatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticlesfor topical and site targeting delivery of Norfloxacin by emulsification solvent evaporationmethod (ESE). The design of experiment (DOE) was done by using software to optimize the result, andthen a surface plot was generated to compare with the practical results. The surface morphology, particlesize, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized bySEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterizedby DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited anaverage particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution withpolydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymerhybrid nanoparticles were confirmed by zeta potential, showed the value from t23.4 ± 1.5 mVto t41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonasaeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two.Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in24 h. A stability study of the optimized formulation showed the suitable condition for the storage oflipid-polymer hybrid nanoparticles was at 4 ± 2 C/60 ± 5% RH. These results illustrated high potential oflipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.展开更多
Drug resistance presents one of the major causes for the failure of cancer chemotherapy.Cancer stem-like cells(CSCs),a population of self-renewal cells with high tumorigenicity and innate chemoresistance,can survive c...Drug resistance presents one of the major causes for the failure of cancer chemotherapy.Cancer stem-like cells(CSCs),a population of self-renewal cells with high tumorigenicity and innate chemoresistance,can survive conventional chemotherapy and generate increased resistance.Here,we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent,all-trans retinoic acid and the chemotherapeutic drug,doxorubicin to overcome the CSC-associated chemoresistance.The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation.In the hypoxic CSCs,ATRA is released to induce differentiation of the CSCs,and in the differentiating CSCs with decreased chemoresistance,DOX is released upon elevation of reactive oxygen species to cause subsequent cell death.In the bulk tumor cells,the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect.This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism.We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.展开更多
目的了解注射用纳米制剂的研究进展,为其进一步开发提供参考和新思路。方法通过检索PubMed、Web of Science等数据库,筛选近20年发表的相关文献,对注射用纳米制剂的研究进展进行综述。结果临床常用的注射用纳米制剂包括脂质体、聚合物...目的了解注射用纳米制剂的研究进展,为其进一步开发提供参考和新思路。方法通过检索PubMed、Web of Science等数据库,筛选近20年发表的相关文献,对注射用纳米制剂的研究进展进行综述。结果临床常用的注射用纳米制剂包括脂质体、聚合物纳米粒、纳米晶,主要用于肿瘤、感染、精神分裂症的治疗,同时还可用于造影检查。目前,纳米制剂受到医药界的广泛关注和重视,注射用纳米药物因其长效、缓释、靶向等优点,在临床受到密切关注。结论近年来,注射用纳米药物的发展成为新型药物递送系统研发的热点。展开更多
The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformat...The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.展开更多
For cancer immunotherapy,triggering toll-like receptors(TLRs)in dendritic cells(DCs)can potentiate antigen-based immune responses.Nevertheless,to generate robust and long-lived immune responses,a well-designed nanovac...For cancer immunotherapy,triggering toll-like receptors(TLRs)in dendritic cells(DCs)can potentiate antigen-based immune responses.Nevertheless,to generate robust and long-lived immune responses,a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity.Herein,we fabricated lipid-polymer hybrid nanoparticles(LPNPs)to spatio-temporally deliver model antigen ovalbumin(OVA)on the surface of the lipid layer,TLR4 agonist monophosphoryl lipid A(MPLA)within the lipid layer,and TLR7 agonist imiquimod(IMQ)in the polymer core to synergistically activate DCs by both extra-and intra-cellular TLRs for enhancing adaptive immune responses.LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of−2.36 mV,showed a high OVA loading(around 70.83μg/mg)and IMQ encapsulation efficiency(88.04%).Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization,thereby promoting DCs maturation and cytokines production.Compared to Free OVA,OVA-LPNPs promoted antigen uptake,lysosome escape,depot effect and migration to secondary lymphatic organs.In vivo immunization showed that IMQ-MPLA-OVA-LPNPs with dual agonists induced more powerful cellular and humoral immune responses.Moreover,prophylactic vaccination by IMQ-MPLA-OVA-LPNPs effectively suppressed tumor growth and increased survival efficacy.Hence,the nanovaccines we fabricated can effectively co-deliver antigens and different TLR agonists and realize coordinated stimulation of DCs in a spatio-temporal manner for enhanced immune responses,which provides a promising strategy for cancer immunotherapy.展开更多
基金financially supported by Sichuan Province Science and Technology Support Program(Nos.16ZC2698 and 2018JY0582)the National Natural Science Foundation of China(No.81872821)。
文摘Nowadays,tremendous researches have been focused on the core-shell lipid-polymer nanoparticles(LPNs) due to the advantages of both liposomes and polymer nanoparticles.In this work,LPNs were applied to encapsulate brinzolamide(Brz-LPNs) for achieving sustained drug release,improving drug corneal permeation and enhancing drug topical therapeutic effect.The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid(PLGA) nanocore which encapsulated Brz(Brz-NPs) and lipid shell around the core.Brz-LPNs were prepared by a modified thin-film dispersion method.With the parameters optimization of Brz-LPNs,optimal Brz-LPNs showed an average particle size of151.23±1.64 nm with a high encapsulation efficiency(EE) of 86.7%±2.28%.The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy(TEM).Fourier transformed infrared spectra(FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs.Brz-LPNs exhibited obvious sustained release of Brz,compared with AZOPT^■ and Brz-LPs.Furthermore,the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation(AZOPT^■) in vitro.Moreover,Brz-LPNs(1 mg/mL Brz) showed a more sustained and effective intraocular pressure(IOP) reduction than Brz-LPs(1 mg/mL) and AZOPT^■(10 mg/mL Brz) in vivo.In conclusion,Brz-LPNs,as promising ocular drug delivery systems,are well worth developing in the future for glaucoma treatment.
基金supported by the Youth Fund of National Natural Science Foundation of China (No. 82104081)the Science and Technology Project of Shenzhen (No. JCYJ20170413155047512)+2 种基金the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University (No. ZYGD18020/ZYJC18006)the Sichuan Province Science and Technology Support Program (No. 2020JDRC0052)the Science and Technology Project of Xinjiang Production and Construction Corps (No. 2022AB020)。
文摘Hypertension is the leading risk factor for death and disability, and hypertensive patients always need long-term oral antihypertensive drugs. Some bioactive peptides that extracted from animals or plants have shown excellent advantages on antihypertension. However, the oral delivery of these peptides is always failure on account of instability and poor absorption in the gastrointestinal tract. Herein, we developed a core-shell lipid-polymeric nanoparticle for oral delivery of a highly efficient antihypertensive peptide KY5(KY5-CSs). KY5-CSs had a particle size of 216.7 ± 2.5 nm, with a narrow PDI of 0.07 ± 0.01.The zeta potential was-4.1 ± 0.1 m V. It exhibited good stability in 4 ℃ and possessed a controlled release behavior in gastrointestinal tract. The cellular uptake study proved that the lipid shell imparted unique capability of permeation across the mucus layer and internalization by Caco-2/HT-29 cells. In addition, KY5-CSs enhanced in situ intestinal absorption in SD rats. The pharmacokinetic studies and antihypertensive efficacy showed a superior oral absorption and antihypertensive effect of KY5-CSs than KY5-NPs. In conclusion, the core-shell lipid-polymeric nanoparticles will provide attractive potential for oral delivery of antihypertensive peptides.
文摘Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceuticalpreparations such as controlled release formulations, parenteral preparations, surgicaltreatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticlesfor topical and site targeting delivery of Norfloxacin by emulsification solvent evaporationmethod (ESE). The design of experiment (DOE) was done by using software to optimize the result, andthen a surface plot was generated to compare with the practical results. The surface morphology, particlesize, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized bySEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterizedby DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited anaverage particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution withpolydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymerhybrid nanoparticles were confirmed by zeta potential, showed the value from t23.4 ± 1.5 mVto t41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonasaeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two.Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in24 h. A stability study of the optimized formulation showed the suitable condition for the storage oflipid-polymer hybrid nanoparticles was at 4 ± 2 C/60 ± 5% RH. These results illustrated high potential oflipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.
基金supported by the National Natural Science Foundation of China(82273876,81971730,81673381,82104090)the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China(171028)+2 种基金the Project of State Key Laboratory of Natural Medicines of China Pharmaceutical University(SKLNMZZ202024,China)the Natural Science Foundation of Jiangsu Province(BK20210425,China)the Postdoctoral Research Funding of Jiangsu Province(2021K051A,China).
文摘Drug resistance presents one of the major causes for the failure of cancer chemotherapy.Cancer stem-like cells(CSCs),a population of self-renewal cells with high tumorigenicity and innate chemoresistance,can survive conventional chemotherapy and generate increased resistance.Here,we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent,all-trans retinoic acid and the chemotherapeutic drug,doxorubicin to overcome the CSC-associated chemoresistance.The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation.In the hypoxic CSCs,ATRA is released to induce differentiation of the CSCs,and in the differentiating CSCs with decreased chemoresistance,DOX is released upon elevation of reactive oxygen species to cause subsequent cell death.In the bulk tumor cells,the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect.This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism.We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.
文摘目的了解注射用纳米制剂的研究进展,为其进一步开发提供参考和新思路。方法通过检索PubMed、Web of Science等数据库,筛选近20年发表的相关文献,对注射用纳米制剂的研究进展进行综述。结果临床常用的注射用纳米制剂包括脂质体、聚合物纳米粒、纳米晶,主要用于肿瘤、感染、精神分裂症的治疗,同时还可用于造影检查。目前,纳米制剂受到医药界的广泛关注和重视,注射用纳米药物因其长效、缓释、靶向等优点,在临床受到密切关注。结论近年来,注射用纳米药物的发展成为新型药物递送系统研发的热点。
文摘The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.
基金This work was financially supported by National Natural Science Foundation of China(82072059 and 82172090)CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-058,China)+1 种基金Fundamental Research Funds for the Central Universities(2019PT320028 and 2019-0831-03,China)Tianjin Municipal Natural Science Foundation(20JCYBJC00030,China).
文摘For cancer immunotherapy,triggering toll-like receptors(TLRs)in dendritic cells(DCs)can potentiate antigen-based immune responses.Nevertheless,to generate robust and long-lived immune responses,a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity.Herein,we fabricated lipid-polymer hybrid nanoparticles(LPNPs)to spatio-temporally deliver model antigen ovalbumin(OVA)on the surface of the lipid layer,TLR4 agonist monophosphoryl lipid A(MPLA)within the lipid layer,and TLR7 agonist imiquimod(IMQ)in the polymer core to synergistically activate DCs by both extra-and intra-cellular TLRs for enhancing adaptive immune responses.LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of−2.36 mV,showed a high OVA loading(around 70.83μg/mg)and IMQ encapsulation efficiency(88.04%).Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization,thereby promoting DCs maturation and cytokines production.Compared to Free OVA,OVA-LPNPs promoted antigen uptake,lysosome escape,depot effect and migration to secondary lymphatic organs.In vivo immunization showed that IMQ-MPLA-OVA-LPNPs with dual agonists induced more powerful cellular and humoral immune responses.Moreover,prophylactic vaccination by IMQ-MPLA-OVA-LPNPs effectively suppressed tumor growth and increased survival efficacy.Hence,the nanovaccines we fabricated can effectively co-deliver antigens and different TLR agonists and realize coordinated stimulation of DCs in a spatio-temporal manner for enhanced immune responses,which provides a promising strategy for cancer immunotherapy.
