Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the a...Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.展开更多
Although drug delivery systems(DDS)are efficient in brain delivery,they face failure in clinical settings due to their potential toxicity to the central nervous system.Little is known about where the DDS will go after...Although drug delivery systems(DDS)are efficient in brain delivery,they face failure in clinical settings due to their potential toxicity to the central nervous system.Little is known about where the DDS will go after brain delivery,and no specific elimination route that shares a passage with DDS has been verified.Hence,identifying harmless DDS for brain delivery and determining their fate there would strongly contribute to their clinical translation.In this study,we investigated nonreactive gold nanoclusters,which can deliver into the brain,to determine the elimination route of DDS.Subsequently,nanoclusters in the brain were systemically tracked and were found to be critically drained by the glymphatic system from the blood vessel basement membrane to periphery circulations(77.8±23.2%and 43.7±23.4%contribution).Furthermore,the nanoclusters could be actively transported across the blood-brain barrier(BBB)by exosomes(30.5±27.3%and 29.2±7.1%contribution).In addition,microglia promoted glymphatic drainage and passage across the BBB.The simultaneous work of the glymphatic system,BBB,and microglia revealed the fate of gold nanoclusters for brain delivery and provided a basis for further braindelivery DDS.展开更多
基金supported by National Natural Science Foundation of China (82173762)111 Project (B18035,China)+1 种基金the Key Research and Development Program of Science and Technology Department of Sichuan Province (2022JDJQ0050,2022YFS0334)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China。
文摘Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.
基金National Natural Science Foundation of China(81961138009)111 Project(B18035)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2020YFS0570).
文摘Although drug delivery systems(DDS)are efficient in brain delivery,they face failure in clinical settings due to their potential toxicity to the central nervous system.Little is known about where the DDS will go after brain delivery,and no specific elimination route that shares a passage with DDS has been verified.Hence,identifying harmless DDS for brain delivery and determining their fate there would strongly contribute to their clinical translation.In this study,we investigated nonreactive gold nanoclusters,which can deliver into the brain,to determine the elimination route of DDS.Subsequently,nanoclusters in the brain were systemically tracked and were found to be critically drained by the glymphatic system from the blood vessel basement membrane to periphery circulations(77.8±23.2%and 43.7±23.4%contribution).Furthermore,the nanoclusters could be actively transported across the blood-brain barrier(BBB)by exosomes(30.5±27.3%and 29.2±7.1%contribution).In addition,microglia promoted glymphatic drainage and passage across the BBB.The simultaneous work of the glymphatic system,BBB,and microglia revealed the fate of gold nanoclusters for brain delivery and provided a basis for further braindelivery DDS.
