Design And Application Of Nanomedicine With Tumor Hypoxic Microenvironment

The tumor microenvironment(TME)has profound impacts on cancer progression and remodeling of the TME has emerged as a strategy to facilitate cancer therapy.Recently,great progress in TME modulation has been made,especially with the rapid developments in nanomedicine.We studied the controllable synthesis,systemic safety evaluation,tumor treatment and inhibition of tumor metastasis of nano drug delivery systems based on tumor acidity and hypoxia microenvironment with developing a new therapeutic strategy for tumor microenvironment regulation and targeting.The main content of this dissertation is divided as below:1.Intratumoral glucose depletion-induced cancer starvation represents an important strategy for anticancer therapy but it is often limited by the systemic toxicity,non-specificity,and adaptive development of parallel energy supplies.Herein,we introduce a concept of cascaded catalytic nanomedicine by combining targeted tumor starvation and deoxygenation-activated chemotherapy for an efficient cancer treatment with reduced systemic toxicity.Briefly,nano-clustered cascaded enzymes were synthesized by covalently crosslinking glucose oxidase(GOx)and catalase(CAT)via a pH-responsive polymer.The release of the enzymes can be first triggered by the mildly acidic tumor microenvironment and then be self-accelerated by the subsequent generation of gluconic acid.Once released,GOx can rapidly deplete glucose and molecular oxygen in tumor cells while the toxic side-product,i.e.,H2O2,can be readily decomposed by CAT for site-specific and low-toxicity tumor starvation.Furthermore,the enzymatic cascades also created a local hypoxia with the oxygen consumption and reductase-activated prodrugs for an additional chemotherapy.The current report represents a new combinatorial approach using cascaded catalytic nanomedicine to reach concurrent selectivity and efficiency of cancer therapeutics.2.We presented a general strategy to encapsulated enzyme,protein,gene,fluorescent probe,and molecule drugs into compartmentalized nMOFs.Subsequently,a compartmentalized structure of multi-layers of nMOFs acted as a nanocarrier to loading functional molecule in different layer.(GOx+CAT)/nMOFs@BSATPZ/nMOFs with compartmentalized structure were employed as catalyst nanomedicine to delivery cascaded enzymes.Cascaded enzymes of GOx and CAT oxidized glucose in a H2O2-free fashion throughout the whole process,resulting in accumulation of hypoxia.The pH-sensitive of nMOFs could prevent the enzymes from premature exposure to off-target blood glucose,which ensured the selective release of nMOFs under the tumoral acidic conditions only.Benefiting from such structure with BSATPZ,(GOx+CAT)/nMOFs@BSA-TPZ/nMOFs would preferentially accumulate in the tumor.We verified the cascade reactions of(GOx+Cat)/nMOFs@BSATPz/nMOFs could promote conversion of glucose to gluconic acid,which would reduce the value of pH to accelerate the decomposition of nMOFs.Along with the depletion of glucose,cascade reactions of(GOx+CAT)/nMOFs@BSATPZ/nMOFs would contribute to enhance tumor hypoxia,which would induce the cancer cell damages with deoxygenation activated BSATPZ.Without significant toxic side effects,such synergistic therapy delivered by nMOFs based on carriers with biocompatible components may be a promising strategy for cancer therapy.This strategy provides an innovative approach to achieving synergistic treatment through tumor starvation and deoxygenation-activated chemotherapy,thereby enhancing tumor treatment and inhibiting metastatic tumors.