The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HE...The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer treatment.However,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application.Herein,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic therapy.The photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the body.Significantly,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser irradiation.The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix.In addition,the drug release rate and the releasing degree are also sensitive to the pH.In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells.In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites.The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.展开更多
Transdermal drug delivery systems have overcome many limitations of other drug administration routes,such as injection pain and first-pass metabolism following oral route,although transdermal drug delivery systems are...Transdermal drug delivery systems have overcome many limitations of other drug administration routes,such as injection pain and first-pass metabolism following oral route,although transdermal drug delivery systems are limited to drugs with low molecular weight.Hence,new emerging technology allowing high molecular weight drug delivery across the skin—known as‘microneedles’—has been developed,which creates microchannels that facilitate drug delivery.In this report,drug-loaded degradable conic microneedles are modeled to characterize the degradation rate and drug release profile.Since a lot of data are available for polylactic acid-co-glycolic acid(PLGA)degradation in the literature,PLGA of various molecular weights-as a biodegradable polymer in the polyester family-is used for modeling and verification of the drug delivery in themicroneedles.The main reaction occurring during polyester degradation is hydrolysis of steric bonds,leading to molecular weight reduction.The acid produced in the degradation has a catalytic effect on the reaction.Changes in water,acid and steric bond concentrations over time and for different radii of microneedles are investigated.To solve the partial and ordinary differential equations simultaneously,finite difference and Runge–Kutta methods are employed,respectively,with the aid of MATLAB.Correlation of the polymer degradation rate with its molecular weight and molecular weight changes versus time are illustrated.Also,drug diffusivity is related to matrix molecular weight.The molecular weight reduction and accumulative drug release within the system are predicted.In order to validate and assess the proposed model,data series of the hydrolytic degradation of aspirin(180.16 Da)-and albumin(66,000 Da)-loaded PLGA(1:1 molar ratio)are used for comparison.The proposed model is in good agreement with experimental data from the literature.Considering diffusion as themain phenomena and autocatalytic effects in the reaction,the drug release profile is predicted.Based on our results for a microneedle containing drug,we are able to estimate drug release rates before fabrication.展开更多
In this work,hollow manganese dioxide/gold nanoparticle(MnO2/GNPs)hybrid drug nanocarriers were prepared by coupling the gold nanoparticles(GNPs)with hollow structure manganese dioxide(MnO2).Among them,GNPs have been ...In this work,hollow manganese dioxide/gold nanoparticle(MnO2/GNPs)hybrid drug nanocarriers were prepared by coupling the gold nanoparticles(GNPs)with hollow structure manganese dioxide(MnO2).Among them,GNPs have been used as near-infrared(NIR)-responsive element for photothermal effect under NIR laser irradiation.The glutathione(GSH)-responsive and p H-responsive performances of drug release were derived from hollow MnO2.Particularly,Doxorubicin hydrochloride(DOX)can be loaded into hollow MnO2/GNPs with the drug loading efficiency up to 82.0%.Moreover,the photothermal effect and GSH-/pH-responsive properties of hollow MnO2/GNPs were investigated.The hollow MnO2/GNPs possessed satisfactory drug release efficiency(ca.87.4%of loaded drug released in 12 h)and have high photothermal conversion efficiency,multiresponsive properties,and degradability.Finally,the kinetics of drug release was discussed in detail.Thus,our finding highlights that the multiresponsive nanocarriers are of great potential in the field of drug controlled release.展开更多
Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and he...Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.展开更多
基金support from the National Natural Science Foundation of China (Nos.52101287 and U1806219)the Shenzhen Fundamental Research Program (No.JCYJ20190807092803583)+1 种基金the Natural Science Foundation of Jiangsu Province (No.BK20190205)supported by the Special Funding in the Project of the Taishan Scholar Construction Engineering and the Program of Jinan Science and Technology Bureau (No.2020GXRC019)as well as New Material Demonstration Platform Construction Project from the Ministry of Industry and Information Technology (No.2020-370104-34-03-043952-01-11).
文摘The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer treatment.However,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application.Herein,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic therapy.The photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the body.Significantly,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser irradiation.The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix.In addition,the drug release rate and the releasing degree are also sensitive to the pH.In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells.In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites.The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.
文摘Transdermal drug delivery systems have overcome many limitations of other drug administration routes,such as injection pain and first-pass metabolism following oral route,although transdermal drug delivery systems are limited to drugs with low molecular weight.Hence,new emerging technology allowing high molecular weight drug delivery across the skin—known as‘microneedles’—has been developed,which creates microchannels that facilitate drug delivery.In this report,drug-loaded degradable conic microneedles are modeled to characterize the degradation rate and drug release profile.Since a lot of data are available for polylactic acid-co-glycolic acid(PLGA)degradation in the literature,PLGA of various molecular weights-as a biodegradable polymer in the polyester family-is used for modeling and verification of the drug delivery in themicroneedles.The main reaction occurring during polyester degradation is hydrolysis of steric bonds,leading to molecular weight reduction.The acid produced in the degradation has a catalytic effect on the reaction.Changes in water,acid and steric bond concentrations over time and for different radii of microneedles are investigated.To solve the partial and ordinary differential equations simultaneously,finite difference and Runge–Kutta methods are employed,respectively,with the aid of MATLAB.Correlation of the polymer degradation rate with its molecular weight and molecular weight changes versus time are illustrated.Also,drug diffusivity is related to matrix molecular weight.The molecular weight reduction and accumulative drug release within the system are predicted.In order to validate and assess the proposed model,data series of the hydrolytic degradation of aspirin(180.16 Da)-and albumin(66,000 Da)-loaded PLGA(1:1 molar ratio)are used for comparison.The proposed model is in good agreement with experimental data from the literature.Considering diffusion as themain phenomena and autocatalytic effects in the reaction,the drug release profile is predicted.Based on our results for a microneedle containing drug,we are able to estimate drug release rates before fabrication.
基金supported by the National Natural Science Foundation of China(Grant Nos.:21776046,21606043)the Six Talent Peaks Project in Jiangsu Province(Grant No.:XCL-079)+2 种基金the Fundamental Research Funds for the Central Universities(Grant No.:2242019K40145)the Cooperative Research Project between Southeast University and China Pharmaceutical Universitythe Recruitment Program for Young Professionals(the Thousand Youth Talents Plan)。
文摘In this work,hollow manganese dioxide/gold nanoparticle(MnO2/GNPs)hybrid drug nanocarriers were prepared by coupling the gold nanoparticles(GNPs)with hollow structure manganese dioxide(MnO2).Among them,GNPs have been used as near-infrared(NIR)-responsive element for photothermal effect under NIR laser irradiation.The glutathione(GSH)-responsive and p H-responsive performances of drug release were derived from hollow MnO2.Particularly,Doxorubicin hydrochloride(DOX)can be loaded into hollow MnO2/GNPs with the drug loading efficiency up to 82.0%.Moreover,the photothermal effect and GSH-/pH-responsive properties of hollow MnO2/GNPs were investigated.The hollow MnO2/GNPs possessed satisfactory drug release efficiency(ca.87.4%of loaded drug released in 12 h)and have high photothermal conversion efficiency,multiresponsive properties,and degradability.Finally,the kinetics of drug release was discussed in detail.Thus,our finding highlights that the multiresponsive nanocarriers are of great potential in the field of drug controlled release.
基金supported in part by an Ontario Research Fund-Research Excellence(ORF-RE)grant(Ontario,Canada)in partnership with Patheon by Thermo Fisher Scientific,Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery Grant and Equipment Grants to Xiao Yu Wu,University of Toronto(Canada),Leslie Dan Faculty of Pharmacy Dean's Fund to Jamie Anne Lugtu-Pe,University of Toronto(Canada),Mitacs Accelerate Internship sponsored by Candoo Pharmatech Company Inc.to Xuning Zhang(Canada),NSERC CREATE ContRoL program support to Sako Mirzaie and Hao Han R.Chang(Canada),Ontario Graduate Scholarship(OGS)to Hao Han R.Chang(Canada),and Pharmaceutical Sciences graduate department scholarships to Hao Han R.Chang and Kuan Chen,University of Toronto(Canada).
文摘Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.
