In situ apolipoprotein E-enriched corona guides dihydroartemisinin-decorating nanoparticles towards LDLr-mediated tumor-homing chemotherapy

The therapeutic efficiency of active targeting nanoparticulate drug delivery systems(nano-DDS)is highly compromised by the plasma proteins adsorption on nanoparticles(NPs)surface,which significantly hinders cell membrane receptors to recognize the designed ligands,and provokes the off-target toxicity and rapid clearance of NPs in vivo.Herein,we report a novel dihydroartemisinin(DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E(apoE)on the NPs surface.The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA(PPD)NPs circulation capability in blood,facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention(EPR)effect and low-density lipoprotein receptor(LDLr)-mediated target transport,and ultimately improve the in vivo antitumor activity.Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.

Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.