Enhancing Redox-responsive Drug Delivery Via Hybrid Nanocarriers

Stimuli-responsive nanocarriers have received increasing attention in the treatment of tumors.Due to the reducing microenvironment in the tumor cells,redox-sensitive nanocarriers can be used for drug targeting and controlled release.Drug molecules can be chemically or physically attached or encapsulated in nanocarriers.Because the concentration of glutathione(GSH)in the cytoplasm is about 1000 times higher than that outside the cell,the drug covalently linked to the carrier can effectively avoid premature drug release during the systemic circulation.However,efficacy of the redox-responsive anticancer nanomedicine is limited by the slow kinetics of thiol-disulfide exchange reaction that hinders the rapid drug release.Tris(3-hydroxypropyl)phosphine(THPP)has been widely used in the field of biomedicine as an efficient disulfide bond reducing agent.Therefore,we presumed to integrate THPP and disulfide bonds in the same nanocarrier to enhance redox-responsive drug delivery.Zeolitic imidazolate framework-8(ZIF-8)was selected for THPP encapsulation.The preparation method includes solvothermal synthesis,hydrothermal synthesis,ultrasound/sonochemical synthesis,mechanochemical synthesis,and accelerated aging methods.In addition,the diameter and pore size of ZIF-8 can be controlled by adjusting the formulation and operating parameters.ZIF-8 has good dispersibility,high load capacity,good thermal and chemical stability,and p H sensitivity.All these characteristics make ZIF-8 ideal for drug delivery.Post THPP encapsulation in ZIF-8,the phase change material(PCM)was coated onto the surface of ZIF-8 to prevent THPP leaking.Finally,the anticancer drug curcumin-conjugated polymer m PEG-PLys(SS-Cur)was adsorbed on the nanocarrier surface.It is expected that the disulfide bond can be broken in tumor cells for enhancement of redox-responsive cancer therapy.The nanocarrier of THPP@ZIF-8@PCM@m PEG-PLys(SS-Cur)was prepared.The curcumin loading was determined to be 5.38 ± 0.4 %(w/w)with the aid of high-performance liquid chromatography(HPLC).Dynamic light scattering(DLS)characterization demonstrated that the nanocarrier possessed an appropriate size distribution.THPP was shown superior to break disulfide bond in contrast to glutathione(GSH),which resulted in enhanced curcumin toxicity in model cells(4T1).Likewise,the enhanced in vivo antitumor efficacy of this hybrid nanocarrier was demonstrated in 4T1 tumor-bearing mice.The current work would effectively avoid the disadvantages of traditional redox-responsive nanocarriers for antitumor therapy and provide a proof-of-concept of enhancing redox-responsive nanocarrier for antitumor therapy.