The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavail...The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.展开更多
Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), p...Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), palmitoyl Danshensu(PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL^(-1), its solubility in Fa SSIF and Fe SSIF reached 4.68 and 9.08 mg·mL^(-1), respectively. Octanol-water partition coefficient(log P) was increased from-2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL^(-1) for PDSS and 0.81 ± 0.06 μg·m L-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.展开更多
The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At...The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.展开更多
Cells and exosomes derived from them are extensively used as biological carrier systems.Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins,wh...Cells and exosomes derived from them are extensively used as biological carrier systems.Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins,while exosomes,due to their small size,cross barriers and penetrate tumors efficiently.However,challenges remain,cells’large size restricts tissue penetration,and exosomes have limited targeting accuracy and short circulation times.To address these challenges,we developed a novel concept termed exosomal spheres.This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine(PS)and linked via pH-sensitive bonds for drug delivery applications.The study demonstrated that,compared with exosomes,the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine,thereby minimizing immune clearance.Moreover,the increased expression of P-selectin promoted adhesion to circulating tumor cells,thereby enhancing targeting efficiency.Upon reaching the tumor site,the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment,leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets.These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.展开更多
Dental,oral,and craniofacial diseases can substantially impact the quality of human life,thereby posing a serious public health concern.Although conventional therapies such as surgery have solved these problems largel...Dental,oral,and craniofacial diseases can substantially impact the quality of human life,thereby posing a serious public health concern.Although conventional therapies such as surgery have solved these problems largely,the prognosis of patients is not always satisfactory.Cell membrane-coated nanoparticles(CMCNPs)carry nanodrugs with the help of natural cell membranes,therefore utilizing their remarkable ability to interface and interact with their surrounding environment.These nanoparticles have demonstrated substantial advantages in drug targeting,prolonging blood circulation time,penetrating biofilms,and immune escape.With the assistance of CMCNPs,the therapeutic effects of dental,oral,and craniofacial diseases can reach a higher level.CMCNPs have been applied for dental,oral,and craniofacial diseases for various conditions such as head and neck cancer,periodontal disease,and oral biosignal detection.For the therapies of head and neck cancer,CMCNPs have been widely utilized as a tool of chemotherapy,phototherapy,and immunotherapy,while yet to be exploited in imaging technique.In the end,we summarized the challenges and prospectives of CMCNPs for dental,oral,and craniofacial diseases:large-scale production with uniform standards and high quantity,extensive application directions in dental,oral,and craniofacial regions(implant,endodontics),and the promotion of its clinical application.展开更多
Objective： To objectively assess the effect of Qiming Granule （芪明颗粒） in the treatment of diabetic retinopathy （DR） by fluorescence fundus angiography （FFA）. Methods： In a multi-center, randomized, parallel...Objective： To objectively assess the effect of Qiming Granule （芪明颗粒） in the treatment of diabetic retinopathy （DR） by fluorescence fundus angiography （FFA）. Methods： In a multi-center, randomized, parallel controlled clinical trial, patients with DR were randomly assigned to the control group （calcium dobesilate capsule） and the test group （Qiming Granule）. Changes in the retinal blood circulation time were recorded by FFA after 3 months of medication. Results： Significant reduction was observed in the retinal arterio-venous circulation time （AVCT） in both groups （P〈0.01）, the value was 7.635 ± 3.149 s before treatment and 5.165 ±3.382 s after treatment in the treated group, and 7.737±3.413 s and 5.313±3.472 s in the control group respectively. Qiming Granule also reduced the arm-to-retinal circulation time （ARCT, P〈0.05）. The value was 17.867± 3.872 s before treatment and 15.643 ± 4.648 s after treatment in the treated group, and 17.217 ± 3.833 s and 16.312± 3.613 s in the control group （P〉0.05） respectively. The ARCT in the tested group was reduced, with a statistically significant difference post-medication （P〈0.01）. Conclusion： As a Chinese medicine complex prescription, Qiming Granule may alleviate retinal hypoxia and ischemia by increasing retinal blood flow and improving the blood circulation.展开更多
Polymer chain architectures play a crucial role in the physical properties of polymers and this unique phenomenon has been recognized as the topological effects.As one of the most representative architectures,macrocyc...Polymer chain architectures play a crucial role in the physical properties of polymers and this unique phenomenon has been recognized as the topological effects.As one of the most representative architectures,macrocyclic polymers characterized by the endless topology have received extensive attention due to their distinct physical properties as compared to the linear counterparts.To understand these differences and unravel the underlying mechanisms,there is a long pursuit to efficiently fabricate macrocyclic polymers.To date,both ring-closing and ring-expansion strategies have been developed,which drastically elevates the accessibility of macrocyclic polymers.The improved availability of macrocyclic polymers enables the further investigation of the biomedical applications and the preliminary results suggest that macrocyclic polymers outperform their linear analogs in terms of improving gene delivery efficiency,elevating blood circulation time,and enhancing colloidal stability of nanoparticles.展开更多
PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformu...PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG,which limits their therapeutic effect.To this end,we designed and prepared two kinds of poly(L-glutamic acid)-cisplatin(PLG-CDDP)nanoformulations with detachable PEG,which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.The extracellular pH(pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride(CDM)-derived amide bond and matrix metalloproteinases-2/9(MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG,yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG.The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin(CDDP).The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt,respectively.Upon reaching tumor tissue,PEG on the surface of nanomedicines was detached as triggered by pHe or MMP,which increased intratumoral CDDP retention,enhanced cell uptake,and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer(HGSOC)mouse model,indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.展开更多
基金supported by Military Medical Innovation Project(16CXZ032)National Science and Technology Major Projects for“Major New Drugs Innovation and Development”(No.2018ZX09J18107-03,2018ZX09721003-005-009)。
文摘The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.
基金supported by the National Natural Science Foundation of China(No.31371014)
文摘Danshensu [3-(3, 4-dihydroxyphenyl) lactic acid, DSS], one of the significant cardioprotective components, is extracted from the root of Salvia miltiorrhiza. In the present study, an ester prodrug of Danshensu(DSS), palmitoyl Danshensu(PDSS), was synthesized with the aim to improve its oral bioavailability and prolong its half-life. The in vitro experiments were carried out to evaluate the physicochemical properties and stability of PDSS. Although the solubility of PDSS in water was only 0.055 mg·mL^(-1), its solubility in Fa SSIF and Fe SSIF reached 4.68 and 9.08 mg·mL^(-1), respectively. Octanol-water partition coefficient(log P) was increased from-2.48 of DSS to 1.90 of PDSS. PDSS was relatively stable in the aqueous solution in pH range from 5.6 to 7.4. Furthermore, the pharmacokinetics in rats was evaluated after oral administration of PDSS and DSS. AUC and t1/2 of PDSS were enhanced up to 9.8-fold and 2.2-fold, respectively, compared to that of DSS. Cmax was 1.67 ± 0.11 μg·mL^(-1) for PDSS and 0.81 ± 0.06 μg·m L-1 for DSS. Thus, these results demonstrated that PDSS had much higher oral bioavailability and longer circulation time than its parent drug.
基金the National Natural Science Foundation of China(Grant No.81373334).
文摘The properties of modified biomaterial are gaining more and more importance in drug delivery systems.Sialic acid(SA)and polysialic acid(PSA)serve as endogenous substances,which are non-immunogenic and biodegradable.At the same time,SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain;PSA modifi-cation can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood,thus achieving active targeting effect.These properties offer a variety of opportunities for applications in drug delivery systems.This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs,proteins and carriers in drug delivery systems.
基金support from National Key R&D Program of China(No.2022YFE0111600)National Natural Science Foundation of China(No.82273874)Liaoning Revitalization Talents Program(No.XLYC22202019,China).
文摘Cells and exosomes derived from them are extensively used as biological carrier systems.Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins,while exosomes,due to their small size,cross barriers and penetrate tumors efficiently.However,challenges remain,cells’large size restricts tissue penetration,and exosomes have limited targeting accuracy and short circulation times.To address these challenges,we developed a novel concept termed exosomal spheres.This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine(PS)and linked via pH-sensitive bonds for drug delivery applications.The study demonstrated that,compared with exosomes,the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine,thereby minimizing immune clearance.Moreover,the increased expression of P-selectin promoted adhesion to circulating tumor cells,thereby enhancing targeting efficiency.Upon reaching the tumor site,the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment,leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets.These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.
基金supported by the Fundamental Research Funds for the Central Universities(Wuhan University,Clinical Medicine+X,2042024YXB017)Hubei Province Chinese Medicine Research Project(ZY2023Q015)+1 种基金Natural Science Foundation of Hubei Province(2023AFB665)Medical Young Talents Program of Hubei Province,Wuhan Young Medical Talents Training Project to L-L.B.
文摘Dental,oral,and craniofacial diseases can substantially impact the quality of human life,thereby posing a serious public health concern.Although conventional therapies such as surgery have solved these problems largely,the prognosis of patients is not always satisfactory.Cell membrane-coated nanoparticles(CMCNPs)carry nanodrugs with the help of natural cell membranes,therefore utilizing their remarkable ability to interface and interact with their surrounding environment.These nanoparticles have demonstrated substantial advantages in drug targeting,prolonging blood circulation time,penetrating biofilms,and immune escape.With the assistance of CMCNPs,the therapeutic effects of dental,oral,and craniofacial diseases can reach a higher level.CMCNPs have been applied for dental,oral,and craniofacial diseases for various conditions such as head and neck cancer,periodontal disease,and oral biosignal detection.For the therapies of head and neck cancer,CMCNPs have been widely utilized as a tool of chemotherapy,phototherapy,and immunotherapy,while yet to be exploited in imaging technique.In the end,we summarized the challenges and prospectives of CMCNPs for dental,oral,and craniofacial diseases:large-scale production with uniform standards and high quantity,extensive application directions in dental,oral,and craniofacial regions(implant,endodontics),and the promotion of its clinical application.
基金Supported by the National Key Technologies R&D Programme for the 10th Five-year Plan(No.2001BA701A13a)
文摘Objective： To objectively assess the effect of Qiming Granule （芪明颗粒） in the treatment of diabetic retinopathy （DR） by fluorescence fundus angiography （FFA）. Methods： In a multi-center, randomized, parallel controlled clinical trial, patients with DR were randomly assigned to the control group （calcium dobesilate capsule） and the test group （Qiming Granule）. Changes in the retinal blood circulation time were recorded by FFA after 3 months of medication. Results： Significant reduction was observed in the retinal arterio-venous circulation time （AVCT） in both groups （P〈0.01）, the value was 7.635 ± 3.149 s before treatment and 5.165 ±3.382 s after treatment in the treated group, and 7.737±3.413 s and 5.313±3.472 s in the control group respectively. Qiming Granule also reduced the arm-to-retinal circulation time （ARCT, P〈0.05）. The value was 17.867± 3.872 s before treatment and 15.643 ± 4.648 s after treatment in the treated group, and 17.217 ± 3.833 s and 16.312± 3.613 s in the control group （P〉0.05） respectively. The ARCT in the tested group was reduced, with a statistically significant difference post-medication （P〈0.01）. Conclusion： As a Chinese medicine complex prescription, Qiming Granule may alleviate retinal hypoxia and ischemia by increasing retinal blood flow and improving the blood circulation.
基金supported by the National Natural Science Foundation of China(51690150,51690154,21674103,51673179)International S&T Cooperation Program of China of MOST(2016YFE0129700)
文摘Polymer chain architectures play a crucial role in the physical properties of polymers and this unique phenomenon has been recognized as the topological effects.As one of the most representative architectures,macrocyclic polymers characterized by the endless topology have received extensive attention due to their distinct physical properties as compared to the linear counterparts.To understand these differences and unravel the underlying mechanisms,there is a long pursuit to efficiently fabricate macrocyclic polymers.To date,both ring-closing and ring-expansion strategies have been developed,which drastically elevates the accessibility of macrocyclic polymers.The improved availability of macrocyclic polymers enables the further investigation of the biomedical applications and the preliminary results suggest that macrocyclic polymers outperform their linear analogs in terms of improving gene delivery efficiency,elevating blood circulation time,and enhancing colloidal stability of nanoparticles.
基金The study was financially supported by the National Natural Science Foundation of China(Grant Nos.52073280,51973216,and 51673187).
文摘PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect,which consequently improves the intratumoral accumulation.However,cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG,which limits their therapeutic effect.To this end,we designed and prepared two kinds of poly(L-glutamic acid)-cisplatin(PLG-CDDP)nanoformulations with detachable PEG,which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.The extracellular pH(pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride(CDM)-derived amide bond and matrix metalloproteinases-2/9(MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG,yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG.The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin(CDDP).The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt,respectively.Upon reaching tumor tissue,PEG on the surface of nanomedicines was detached as triggered by pHe or MMP,which increased intratumoral CDDP retention,enhanced cell uptake,and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer(HGSOC)mouse model,indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.
