Resveratrol(RES),a non-flavonoid polyphenol extracted from a wide variety of plants,exhibits neuroprotective activities against Parkinson’s disease(PD).However,undesirable water solubility of RES reduces its oral bio...Resveratrol(RES),a non-flavonoid polyphenol extracted from a wide variety of plants,exhibits neuroprotective activities against Parkinson’s disease(PD).However,undesirable water solubility of RES reduces its oral bioavailability and demonstrates lowefficacy in blood and brain,thus limiting its application.In present study,a nanocrystal formulation of RES(RES-NCs)was developed to enhance its oral bioavailability and delivery into brain for PD treatment.RES-NCs were fabricated with hydroxypropyl methylcellulose(HPMC)stabilizer via antisolvent precipitation approach.The obtained RES-NCs displayed the particle size of 222.54±1.66 nm,the PDI of 0.125±0.035,the zeta potential of−9.41±0.37mV,and a rapid in vitro dissolution rate.Molecular dynamics simulation of RES and HPMC revealed an interaction energy of−68.09 kJ/mol and a binding energy of−30.98±0.388 kJ/mol,indicating that the spontaneous binding between the two molecules is through van der Waals forces.RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES.In addition,RES-NCs were able to protect neurons against cytotoxicity induced by MPP+.Meanwhile,RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae,and did not influence their survival and hatching rates.When orally administered to rats,RES-NCs exhibited more favorable pharmacokinetics than pure RES,with higher plasma and brain concentrations.More importantly,MPTP-induced PD mice showed notable improvements in behavior,attenuated dopamine deficiency,and elevated levels of dopamine and its metabolites after the treatment with RES-NCs.Furthermore,immunoblot analysis revealed that the neuroprotective role of RES-NCsmay be at least partially mediated by Akt/Gsk3βsignaling pathway.Taken altogether,RES-NCs can serve as a potential treatment modality for PD,offering means of improving RES oral bioavailability and brain accumulation.展开更多
Despite extensive use of radiotherapy in nasopharyngeal carcinoma(NPC)treatment because of its high radiosensitivity,there have been huge challenges in further improving therapeutic effect,meanwhile obviously reducing...Despite extensive use of radiotherapy in nasopharyngeal carcinoma(NPC)treatment because of its high radiosensitivity,there have been huge challenges in further improving therapeutic effect,meanwhile obviously reducing radiation damage.To this end,synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy.Here,we developed RGD-targeted platinum-based nanoparticles(RGD-PtNPs,denoted as RPNs)to achieve targeted chemoradiotherapy for NPC.Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum(CDDP)crosslinking core.Taking advantage of RGD,the RPNs may effectively accumulate in tumor,penetrate into tumor tissues and be taken by cancer cells,giving rise to a high delivery efficiency of CDDP.When they are fully enriched in tumor sites,the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents.By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases,RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.展开更多
基金Supported by the Guangdong Provincial Natural Science Foundation of China(2018A030310623)Research Fund of University of Macao(MYRG2018-00207-ICMS and SRG2017-00095-ICMS)+1 种基金National Natural Science Foundation of China(81673627)Guangzhou Science Technology and Innovation Commission Technology Research Projects(201805010005).
文摘Resveratrol(RES),a non-flavonoid polyphenol extracted from a wide variety of plants,exhibits neuroprotective activities against Parkinson’s disease(PD).However,undesirable water solubility of RES reduces its oral bioavailability and demonstrates lowefficacy in blood and brain,thus limiting its application.In present study,a nanocrystal formulation of RES(RES-NCs)was developed to enhance its oral bioavailability and delivery into brain for PD treatment.RES-NCs were fabricated with hydroxypropyl methylcellulose(HPMC)stabilizer via antisolvent precipitation approach.The obtained RES-NCs displayed the particle size of 222.54±1.66 nm,the PDI of 0.125±0.035,the zeta potential of−9.41±0.37mV,and a rapid in vitro dissolution rate.Molecular dynamics simulation of RES and HPMC revealed an interaction energy of−68.09 kJ/mol and a binding energy of−30.98±0.388 kJ/mol,indicating that the spontaneous binding between the two molecules is through van der Waals forces.RES-NCs conferred enhanced cellular uptake as well as improved permeability relative to pure RES.In addition,RES-NCs were able to protect neurons against cytotoxicity induced by MPP+.Meanwhile,RES-NCs exerted no significant toxic effects on zebrafish embryos and larvae,and did not influence their survival and hatching rates.When orally administered to rats,RES-NCs exhibited more favorable pharmacokinetics than pure RES,with higher plasma and brain concentrations.More importantly,MPTP-induced PD mice showed notable improvements in behavior,attenuated dopamine deficiency,and elevated levels of dopamine and its metabolites after the treatment with RES-NCs.Furthermore,immunoblot analysis revealed that the neuroprotective role of RES-NCsmay be at least partially mediated by Akt/Gsk3βsignaling pathway.Taken altogether,RES-NCs can serve as a potential treatment modality for PD,offering means of improving RES oral bioavailability and brain accumulation.
基金We acknowledge the financial support from Guangdong Basic and Applied Basic Research Foundation for Distinguished Young Scholars(2020B1515020027)the grant from Guangzhou Science and Technology Bureau(202002020070,202102010181,202102010007)+7 种基金the Fundamental Research Funds for the Central Universities(19ykpy108,20ykpy93)Guangdong Science and Technology Department(2020B1212060018,2020B1212030004)Shenzhen Key Medical Discipline Construction Fund(SZXK039)the Guangdong Basic and Applied Basic Research Fund Foundation(2019A1515110204,2020A1515010523)the Yat-sen Scientific Research Project(YXQH202018)Shenzhen Innovation of Science and Technology Commission(LGKCYLWS2020089)the National Key R&D Program of China(2017YFE0102400)Shenzhen Science and Technology Program(JCYJ20190807160401657).
文摘Despite extensive use of radiotherapy in nasopharyngeal carcinoma(NPC)treatment because of its high radiosensitivity,there have been huge challenges in further improving therapeutic effect,meanwhile obviously reducing radiation damage.To this end,synergistic chemoradiotherapy has emerged as a potential strategy for highly effective NPC therapy.Here,we developed RGD-targeted platinum-based nanoparticles(RGD-PtNPs,denoted as RPNs)to achieve targeted chemoradiotherapy for NPC.Such nanoparticles consist of an RGD-conjugated shell and a cis-platinum(CDDP)crosslinking core.Taking advantage of RGD,the RPNs may effectively accumulate in tumor,penetrate into tumor tissues and be taken by cancer cells,giving rise to a high delivery efficiency of CDDP.When they are fully enriched in tumor sites,the CDDP loaded RPNs can act as radiotherapy sensitizer and chemotherapy agents.By means of X-ray-promoted tumor cell uptake of nanoparticle and CDDP-induced cell cycle arrest in radiation-sensitive G2/M phases,RPNs may offer remarkable therapeutic outcome in the synergistic chemoradiotherapy for NPC.
