Nanomedicines For Tumor Microenvironment Modulation And Applications Thereof

Tumor possesses intricate and distinctive tumor microenvironment(TME)distinctive from normal organs and tissues,which promotes tumor progression and metastases,and also result in resistance of tumors to various therapies.Therefore,modulation of TME,including tumor hypoxia,tumor low pH,the extracellular matrix,as well as the immune microenvironment within the tumor,in combination with many existing tumor therapies have been proposed as an alternative approach to improve the therapeutic outcomes of current cancer therapies.In this dissertation,we focus on the development of hierarchical nanomedicines for tumor microenvironment modulation and applications thereof.The main content of this dissertation is described in three parts as below:1.We developed a DNA-dual-targeting approach for enhanced cancer radiotherapy using a hierarchical multiplexing nanodroplet,which can simultaneously promote DNA lesion formation and prevent subsequent DNA damage repair.Specifically,the ultra-small gold nanoparticles encapsulated in the liquid nanodroplets can concentrate the radiation energy and induce dramatic DNA damage.Additionally,the ultrasound-triggered burst release of oxygen(O2)may relieve tumor hypoxia and fix the DNA radical intermediates produced by ionizing radiation,prevent DNA repair and eventually result in tumor cell death.Our DNA-dual-targeting design of simultaneously enhancing DNA damage and preventing DNA repair presents an innovative strategy to effective cancer radiotherapy.2.We developed a strategy toward tumor reoxygenation based on biomimetic ultrathin 2D graphdiyne oxide(GDYO)nanosheets,which camouflaged with red cell membrane with tumor-penetrating peptides iRGD anchoring(GDYO@i-RBM),were described.GDYO@i-RBM can efficiently accumulate in hypoxia region though iRGD anchored RBM camouflage;its photochemical effect not only promotes oxygen(O2)evolving via photocatalysis water splitting,but also improves blood perfusion via photothermal conversion.Thus,accompanied with the simultaneous generation of large amounts of o2 and 1O2 in cells,tumor hypoxia induced restriction effect in PDT was successfully reversed by signal laser irradiation.GDYO@i-RBM offers significantly synergistic anticancer effects and superior therapeutic safety both in vitro and in vivo.3.We developed a tumor acidity(pHe)-activated TAT peptide decorated and Pt(IV)prodrug encapsulated polymeric nanoparticles(DATAT-NP/Pt)to overcome the in vivo cisplatin resistance.After systemic administration,the resulting nanoparticles DATAT-NP/Pt avoids rapid clearance in blood circulation by masking TAT peptide and efficiently circulates into tumor tissue.Then,the tumor low pH microenvironment which is capable of activating the masked TAT peptide of DATAT-NP/Pt,and the regenerated TAT peptide facilitates tumor cell internalization to significantly increase the intracellular platinum drugs.More importantly,the TAT peptide can be recognized by the nuclear pore complexes and quickly translocate DATAT-NP/Pt into the perinuclear region,which allows for higher nuclear drug concentrations,resulting in increased interaction of released platinum drug and DNA,finally overcoming drug resistance.