Tumor Acidity(pHe)-Responsive Polymeric Nanocarrier For Enhancing Intracellular/Extracellular Drugs Delivery Efficiency

Due to the complex physiological environment of tumors and multiple physiological barriers in vivo,the overall delivery efficiency of nanomedicines is unsatisfactory after in vivo circulation,tumor enrichment,and infiltration,cell uptake,and drug release.Therefore,how to effectively improve the drug delivery efficiency is one of the keys to improving the anti-tumor efficacy of nanomedicines.Here,we developed tumor acidity(pHe)-responsive polymeric nanocarriers for enhancing extracellular/intracellular target drug delivery efficiency:1.The cell nucleus-targeted delivery of therapeutic agents plays a critical role in cancer therapy since the biological target of many anticancer therapeutics is the cell nucleus.However,multiple physiological barriers limit the delivery efficiency of free drugs,resulting in unsatisfactory therapeutic effects.Herein,thioketal crosslinked polyphosphoester-based nanoparticles with a tumor acidity(pHe)-sensitive transactivator of transcription(TAT)peptide(DA-masked TAT-decorating reactive oxygen species(ROS)-sensitive Ce6/DOX-loaded hyperbranched nanoparticles(^DTRCD)are explored for cascade nucleus-targeted drug delivery.Following administration,^DTRCD experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue.Subsequently,ROS generated by ^DTRCD under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers the intracellular release of the payload in the nuclei.As evidenced by in vivo experiments,such pHe/photo dual-sensitive polymeric nanocarriers offer remarkable therapeutic effects,efficiently suppressing tumor growth.This multistage cascade nucleus targeted drug delivery concept provides new avenues to develop nucleus targeted drug delivery systems.2.Differ from intracellular target drugs,extracellular target drugs need delivery and release outside the cell for anticancer function.Therefore,we constructed a tumor acid-responsive nanocarrier achieved in-situ tumor assembly for delivering extracellular target drugs and enhance anti-tumor efficacy based on biological orthogonal reaction.The hydrophilic segment of PEG-b-PLA was modified with cysteine residues(Cys)or 2-cyano-6-aminobenzothiazole(CBT)and obtained Cys-PEG-b-PLA and CBT-PEG-b-PLA,respectively.Then,the terminal Cys of Cys-PEG-b-PLA has shielded with 2,3-dimethylmaleic anhydride and obtained DA-Cys-PEG-b-PLA.After systematic administration of ^DA-CysNP plus ^CBTNP nanoparticles prepared by the two polymers at the same time,^DA-CysNP can regenerate Cys in the tumor acidity microenvironment,and occur biological orthogonal reaction with ^CBTNP,which surface modified with CBT,realize in-situ assembly in the tumor site.It can effectively prolong the retention time of nanoparticles in the tumor site.This nano-drug delivery system can deliver batimastat(BB-94,an extracellular target drug)or small molecule drugs,such as DOX,NLG919,and BLZ945,which could effectively inhibit the metastasis and growth of tumors.This strategy provides a new design method of nanocarrier to deliver extracellular target or membrane target anticancer drugs.