| The appearance of tumor-microenvironment-sensitive nanomedicines greatly improved the short half-life,poor targeting efficiency,low drug efficiency and severe toxicity of most chemotherapeutic drugs,and significantly increased the specific release of the tumor site of the drugs,which brought better therapeutic effect.However,even if the nanomedicines could achieve 100%delivery and release at tumor sites accurately,the drugs’ lower cellular uptake ability and poor tumor tissue penetration still restrict the effectiveness of the drugs.Based on the "short-range attack" mechanism of cytotoxic drugs entering tumor cells,and the "long-range attack" mechanism of vascular disrupting agents(VDAs)by destroying the tumor vein system,blocking the tumor’s internal nutrition and oxygen supply and leading to the necrosis of tumor,we designed three strategies:"short-range strengthening","long-range attack" and "space-time coordination" to improve the antitumor effect of tumor-microenvironment-responsive nanomedicines respectively:1)A reactive oxygen species(ROS)responsive nanocarrier was prepared,and after the modification of a model drug(Rodamine B,RhoB)and a cytotoxic drug(Hydroxycamptothecin,HCPT),the modified prodrugs were loaded into the nanocarrier to obtain new nanomedicines.As the cellular uptake ability of these drugs were improved due to the modification,the nanomedicines would realize more powerful short-range attack to the tumor selectively.The HCPT was modified by guanidine to improve the cell penetration ability and cytotoxicity.And the ROS responsive micelle was obtained by binding hydroxymethyl phenyl borate pinacol ester(HAPE)with poly(glutamic acid)-graft-poly(ethylene glycol)(PLG-g-mPEG),achieved the super high encapsulation of HCPT-Gu by hydrophobic interaction,hydrogen bond interaction and π-π stacking interaction in physiological condition.The diameter of the compact micelles was 58.0±13.1 nm,which could achieve rapid release of HCPT-Gu with the action of H2O2 and realize 80.6%tumor growth inhibition rate.2)A novel glutathione(GSH)responsive nanocarrier was prepared and bonded one kind of VDAs to achieve targeted-tumor drug delivery.Poly(lipoic acid)-graft-poly(ethylene glycol)(PALA-g-mPEG)was prepared by simple self-polymerization of alpha-lipoic acid and graft with mPEG.Then Combretastatin A4(CA4)was bonded to obtain PALA-g-mPEG/CA4 micelle,the diameter was 122.6±23.8 nm,which prolong the circulation time in vivo and realize GSH responsive disintegration on the main chain of disulfide bond.The strategy of this "long-range attack" effectively caused tumor necrosis and achieved 83.1%tumor growth inhibition rate.3)The conjugate of DMXAA(one kind of VDAs)and honokiol(one cytotoxic drug,HNK)was prepared.After binding to the GSH responsive nanocarrier PALA-g-mPEG,cooperative therapeutic delivery system was achieved by "long-range and short-range attack" combined with "old and new inhibition".The hydration radius of the micelles was 57.1±10.1 nm.After degradation by GSH,DMXAA would lead to the necrosis of internal tumor,and honokiol would kill the external cancer cells,which can realize "elong-range and short-range attack".At the same time,DMXAA would destroy the existing vascular system,and honokiol would inhibit neovascularization,which can achieve "new and old blood vessels inhibition".This strategy of using different action mechanisms of the drugs to realize double cooperation of "space" and "time" achieved 93.0%tumor growth inhibition rate. |
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