Redox-responsive Paclitaxel Dimer Nano-prodrugs For Tumor Treatment

Poor solubility in water and serious side effects severely restrict the clinical application of the chemotherapy drug paclitaxel(PTX).The emergence of nanotechnology has promoted the further development of chemotherapeutic drugs.After PTX is made into nano-formulations,the solubility of PTX has been greatly improved.In particular,the PTX dimer nano-prodrugs utilize the self-assembly properties of the dimer itself to improve the solubility of PTX,at the same time,they also have a satisfactory drug loading capacity.What is more,due to the higher levels of ROS and GSH in tumor cells,dimeric nano-prodrugs formed by a series of redox-responsive linkers have also been extensively developed.Insufficient drug release in tumors has become the biggest problem that plagues PTX dimer nano-formulations.Although the use of exogenous stimuli to regulate drug release can improve the efficacy,the system is too complicated,which not only violates the original intention of simple preparation of dimer prodrugs,but also increases the difficulty of clinical transformation.The development of sensitive and responsive PTX nano-formulations has important research significance.Because of its simplicity and high efficiency,this nano-preparation is more likely to be used in clinical treatment.Herein,we designed and synthesized four PTX dimer nano-prodrugs(PTX2-R),which have different linkers,including a mono-thioether bond(S),disulfide with one methylene on each side(SS1),disulfide with two methylene on each side(SS2)and the carbon chain composed of six methylene groups(C6).We studied the differences in their redox responsiveness and specific response mechanisms,and finally compare their anti-tumor capabilities.We found that the S linker is the most sensitive to the oxidizing environment,while SS1 linker is the most sensitive to the reducing environment.The sensitivity of redox response has an important influence on drug release,cytotoxicity and anti-tumor ability.The PTX dimer based on SS1 has the fastest drug release and the best anti-tumor effect.This study supplies a reference for the design of follow-up redox-responsive nano-prodrugs,which is meaningful for tumor treatment.