| Chemotherapy as the main therapeutic method for advanced cancer therapy,its effectiveness and safety is still a scientific issue which attracted considerable attention to scholars.In recent years,nanoparticle delivery systems such as polymer nanoparticles,dendrimers,micelles,liposomes,and intelligent drug delivery systems such as enzyme-sensitive,pH-sensitive,and photothermal-sensitive have attracted widespread attention.But due to the complexity of human tissue,it is difficult for a single intelligent drug delivery system to break through multiple biological barriers.So the multifunctional viral-mimicking drug delivery vehicle is favored for its good targeting and smart drug delivery gradually.Therefore,based on the core idea from structural mimics to functional simulations,this study makes full use of the special microenvironment of tumor tissue to design a multifunctional responsive virus-like targeted drug delivery system,which including active targeting,enzyme sensitivity,and acid sensitivity.In order to overcome the heavy barriers encountered in the systemic long circulation of drugs and to improve the anti-tumor efficacy,herein,viral mimics multifunctional infections self-assembled form tailor-made polymeric micelles for programmed targeted drug delivery is reported.We designed multiple stimuli-activated prodrug（HA-pep-Lys-s-s-DTX,HA-DTX）from structural mimics to functional simulations.HA links with oligopeptide Boc-PLGLAG to synthesis the MMP-2 enzyme sensitive parts.Then hydrazone bond was selected as the acid sensitive segment.At the last,DTX was conjugated to the front block by disulfide bond as reduction section.Thus,the modified multisensitive prodrug self-assemble into micelles（HPLD）by dialysis method.HA as a hydrophilic capsid of the virus-like vehicle increased the systemic circulation time.Furthermore,accumulate HPLD in tumor tissue by actively target,and then HA shells were peeling off with the action of MMP-2enzyme.Simultaneously,the residues were endocytosis into cells in PLD nanomicelles form and followed by the cleavage of hydrazone bond in acidic environment（pH=5.0）to promote lysosomal escape with“proton sponge”effects.Furthermore,killing tumor cells with antitumor drugs DTX were achieved with GSH redox sensitive in cytoplasm.Break through variety of physiological barriers and cell barriers to improve the targeted anti-tumor effect of the broad-spectrum anti-tumor drug docetaxel.The smart drug delivery structures were chartered by 1H-NMR and MS.Dynamic light scattering（DLS）and transmission electron microscope（TEM）studies the size distribution,zeta potential and morphological structure.DTX content of the system was detected by UV-vis absorption.The in vitro drug release behavior,celluar uptake and penetration ability in A549 lung cancer cell line,and the anti-tumor activity in vitro and in vivo of HPLD prodrug were systematically studied.The study results showed that the average size,zeta potential and drug loading was 253.2?8.1 nm,-15.5 mV and 8.9 wt%,respectively.The trigger drug release characteristics were observed when cultured with simulated tumor cells microenvironment in vial bottle.The accumulated drug release ratio was about 5.8-fold higher in tumor cells microenvironment than normal tissues.At the same time,the multiple bio-responsive delivery system has better antitumor activity in vitro compared to the free chemotherapy drug docetaxel（DTX）.The HPLD IC50 value（0.24μg/mL）is 45.3%lower than the free docetaxel IC50 value（0.53μg/mL）in A549 lung cancer cells.Cell uptake and tumor spere penetration studies showed that HPLD micelles had better celluar uptake and penetration ability than free DTX.The in vivo antitumor efficient in A549 xenograft tumor model demonstrated that smart HPLD system could overcome a series of physiological barriers to exert better anti-tumor effect（tumor inhibition:80.1%）than free DTX（tumor inhibition:61.2%）.In conclusion,virus-inspired multiple stimuli-activated polymeric micelles provide a novel and versatile approach for anti-tumor drug delivery. |
