GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy

Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.

GSH-triggered sequential catalysis for tumor imaging and eradication based on star-like Au/Pt enzyme carrier system

Distinctively different metabolism between tumor cells and normal cells endows tumor tissues unique microenvironment.In this regard,we have successfully prepared a sequential catalytic platform based on Au/Pt star for tumor theragnostic.The multifunctional probes consisted of a gold/platinum star-shaped core(Au/Pt star)conjugated with a GSH-sensitive disulfide bond(S–S),a targeting ligand(rHSA-FA),a near-infrared fluorophore(IR780)and glucose oxidase(GOx).When systemically administered in a xenografted murine model,the probes specifically targeted the tumor sites.As the disulfide linker was cleaved by intracellular GSH,the IR780 molecules could be released for photo-thermal therapy&photodynamic therapy(PTT&PDT)and imaging.Subsequently,the Pt nanolayer of the Au/Pt star and the GOx formed a sequential catalytic system:GOx effectively catalyzed intracellular glucose by consuming oxygen to generate H2O2 and enhance the local acidity,and the Pt layer exhibited peroxidase-like property to catalyze H2O2 producing toxic·OH for tumor oxidative damage.Here we demonstrated that our probes simultaneously possessed a GSH-sensitive release,real-time imaging ability,and synergetic cancer starving-like therapy/enzyme oxidative therapy/PTT/PDT features,which provides a potential strategy for effective tumor theragnostic.

Microenvironment-responsive chemotherapeutic nanogels for enhancing tumor therapy via DNA damage and glutathione consumption

Although targeted therapy and immunotherapy are now shining in the treatment of some cancers,chemotherapy is still the cornerstone of drug treatment for many cancer patients.The emergence of chemotherapy prodrugs can improve the drug activity and reduce the side effects of chemotherapy.When used,the tumor microenvironment has characteristics different from normal tissues,and the existence of the microenvironment provided a more convenient way to design responsive nanodrugs.Herein,we designed a glutathione(GSH)-responsive prodrug nanogels for enhancing tumor chemotherapy.In the nanogels of HHNP,10-hydroxycamptothecin(HCPT)played an essential role in killing cancer cells.HCPT was jointed with a cross-linker agent with disulfide bond and was further coated with polyethylene glycol,which not only prolonged the half-life of the drug,but also made HCPT accurate transport to the tumor fractions and achieved precise and controllable release.The proposal of HHNP effectively retained the biological activity of the drug,and introduced functions such as targeting,selective release and biodegradation,which greatly improved the medical efficiency of the drug and effectively reduced the toxic and side effects.This chemotherapeutic prodrug nanogel offers a new window for constructing efficient drug delivery platform.