Hydroxyethyl Starch Conjugate-Based Nanomedicine For Enhanced Antitumor Therapy

Chemotherapy has been used as one of the main approaches in tumor treatment.Although chemotherapy has been utilized in the treatment of a wide range of tumors,the chemotherapeutic agents currently used in clinical practice are generally not specifically targeted,which can lead to poor treatment outcomes on the one hand and a variety of side effects to varying degrees on the other.With in-depth research into the occurrence,development and treatment of tumor,nanomedicines based on vast diverse nanocarriers have been developed and have shown important clinical applications.Many nano-drug carriers have been developed for the delivery of antitumor drugs,which suffer several inadequacies resulting in inefficient drug delivery:（1）Nano-drug delivery systems formed by intermolecular interactions such as hydrophobic and electrostatic interactions,often lead to uncontrollable drug release and premature drug leakage;（2）The instability of photosensitizers as well as low concentration of singlet oxygen production oftentimes cause inefficient photodynamic therapy.The utilization of biodegradable and biocompatible polymers as a backbone,the covalent binding of anti-tumor small molecule drugs to such polymer molecular chains and the assembly of the obtained nanodrugs are gaining importance in the field of antitumor therapy.Hydroxyethyl starch（HES）is a biodegradable branched chain starch derivative,and it has been used as a plasma expander for years with good safety.HES has superior potential in acting as promising nanocarriers for delivering diagnostic and therapeutic agents towards cancers due to its good water solubility,very low allergenicity,high daily parenteral tolerated dose,and chemically modifiable multifunctionality.Based on the superiority of HES,three HES-based polymeric NPs have been explored for tumor therapy with the following major studies and results.（1）The HES-derived nanoparticles（HES-SeSe-COOH NPs）with therapeutic effects were obtained and their in vitro anti-tumor efficiency were evaluated.Firstly,a novel type of diselenide bond-bridged HES-based derivatives（HES-SeSe-COOH）has been synthesized via a specially designed three-step synthetic route with multi-response properties,and the HES-SeSe-COOH NPs were prepared by a self-assembly method.Due to the large number of diselenide bonds in HES-SeSe-COOH NPs,they can respond to the high expression of glutathione（GSH）and H₂O₂ in tumor cells,and can be found to significantly consume intracellular GSH and impel a large rise in intracellular reactive oxygen species（ROS）levels,resulting in the cytotoxicity against HepG2 and 4T1 cells.Therefore,active nanocarriers can act as therapeutic agents themselves,while providing guidance for the construction of intelligent and efficient drug delivery systems.（2）Selenium-containing nanoparticles with cascade drug release properties can enhance chemotherapy-photodynamic therapy.By coupling HES-SeSe-COOH with doxorubicin（DOX）to construct novel HES-SeSe-DOX conjugates,the Chlorin E6（Ce6）was further self-assembled with HES-SeSe-DOX to form size-controlled and stable HES-SeSe-DOX/Ce6 NPs.The Ce6 molecules in HES-SeSe-DOX/Ce6 NPs can serve as an imaging agent and crucially function as a photosensitizer for implementing PDT and assisting in the cleavage of diselenide bonds via the induced ¹O₂.HES-SeSe-DOX/Ce6 NPs can be triggered in two steps by intracellular GSH,H₂O₂ and Ce6-induced ¹O₂,which leads to the cascade release of DOX and Ce6 to inhibit the growth of tumor cells.In addition,the process of diselenium bond cleavage can not only consume intracellular GSH but also induce the increase of ROS level,actuating the disruption of the original intracellular redox balance and the enhanced chemo-photodynamic antitumor therapy.（3）A novel dual-responsive prodrug nanoparticles（HES-SS-hyd-DOX NPs）were developed to achieve enhanced antitumor therapy.It used HES as a carrier and coupled DOX to HES by tandem redox-responsive disulfide bonds and pH-responsive hydrazone bonds to achieve desired HES-SS-hyd-DOX NPs.Three additional DOX-bound HES conjugate NPs with only a single responsive or non-responsive bond were constructed as control to investigate the effect of different stimulus-responsive linkage chains on DOX release from HES-based conjugate nanoparticles.All four self-assembled prodrug NPs have well-defined stability in aqueous media.The results of in vitro and in vivo experiments showed that the dual pH/redox-responsive HES-SS-hyd-DOX NPs exhibited significant antitumor effects.Compared with the other three DOX-conjugated HES NPs,the multifunctional linker in the HES-SS-hyd-DOX NPs played a key role in the rapid and sufficient release of the conjugated DOX.