Abstract
Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeu-tics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic envi-ronment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond pro-motes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.
基金项目
国家重点研发计划(2022YFA1205703)
国家重点研发计划(2022YFA1205702)
国家自然科学基金(51773099)
国家自然科学基金(51933006)
国家自然科学基金(52103183)
Haihe Laboratory of Sustainable Chemical Transformations(YYJC202102)
维普
万方数据