Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-deli...Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.展开更多
pH-responsive micelles with a biodegradable PLA core and a mixed PEG/PDPA shell were prepared by self-assembly of poly（ethylene glycol）-b-poly（lactic acid） （PEG-b-PLA） and poly（2-（diisopropylamino）ethyl metha...pH-responsive micelles with a biodegradable PLA core and a mixed PEG/PDPA shell were prepared by self-assembly of poly（ethylene glycol）-b-poly（lactic acid） （PEG-b-PLA） and poly（2-（diisopropylamino）ethyl methacrylate）-b-poly（lactic acid） （PDPA-b- PLA）. The micellization status with different pH and the enzyme degradation behavior were characterized by IH-NMR spectroscopy, dynamic light scattering measurement and zeta potential test. The pH turning point of PDPA block was determined to be in the range of 5.5-7.0. While the pH was above 7.0, the PDPA block collapsed onto the PLA core and could protect the PLA core from invasion of enzyme, as a result, the micelle exhibited a resistance to the enzymatic degradation.展开更多
After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggre...After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.展开更多
基金This work was financially supported by the National Key R&D Program of China(Nos.2022YFA1205703 and 2022YFA1205702)the National Natural Science Foundation of China(Nos.51773099,51933006 and 52103183)Haihe Laboratory of Sustainable Chemical Transformations(No.YYJC202102).
文摘Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.
基金supports by the National Natural Science Foundation of China (Nos. 21404082 and 51503104)the State Key Laboratory of Medicinal Chemical Biology of China (No. 201603001)Natural Science Foundation of Tianjin (Nos. 15JCQNJC05900, 15JCQNJC13400 and 16JCQNJC03000)
文摘pH-responsive micelles with a biodegradable PLA core and a mixed PEG/PDPA shell were prepared by self-assembly of poly（ethylene glycol）-b-poly（lactic acid） （PEG-b-PLA） and poly（2-（diisopropylamino）ethyl methacrylate）-b-poly（lactic acid） （PDPA-b- PLA）. The micellization status with different pH and the enzyme degradation behavior were characterized by IH-NMR spectroscopy, dynamic light scattering measurement and zeta potential test. The pH turning point of PDPA block was determined to be in the range of 5.5-7.0. While the pH was above 7.0, the PDPA block collapsed onto the PLA core and could protect the PLA core from invasion of enzyme, as a result, the micelle exhibited a resistance to the enzymatic degradation.
基金financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306)Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18)+1 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014)Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004)
文摘After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.
