Hyperbaric Oxygen Promotes The Delivery And Anti-tumor Efficiency Of Nanomedicine By Improving Tumor Microenvironment

Hypoxia is a basic feature of solid tumors,which promotes tumor occurrence and development,induces tumor stemness,and causes resistance to chemotherapy,radiotherapy,photodynamic therapy.Therefore,overcoming tumor hypoxia and sensitizing tumor treatment have become a hot-spot in current research.HBO is a clinically effective way to disrupt tissue hypoxia.Compared with other strategies to overcome tumor hypoxia,HBO is more suitable for combining with marketed nanomedicine to address numerous biological barriers in the body,thereby improving the delivery efficiency.By disrupting tumor hypoxia,HBO will improve tumor matrix,mechanical and vascular microenvironment,and enhance the delivery efficiency of nanomedicine into tumor sites,including promoting tumor accumulation,deep penetration and cellular uptake,thereby effectively killing cancer stem cells,inhibiting tumor metastasis and improving the anti-tumor effciency.The main research results of this project are as follows:(1)It is confirmed that HBO can improve tumor hypoxic microenvironment and reduce the expression of HIF-1α,regulate tumor matrix microenvironment and reduce the deposition of collagen fibers and fibronectin,further improve tumor mechanical microenvironment and reduce tumor solid stress.(2)It is confirmed that HBO can regulate tumor vascular microenvironment.On the one hand,it reduces vascular density and promotes the formation of a more orderly structure of tumor blood vessels.On the other hand,it increases blood perfusion and restores vascular function.It is further confirmed that HBO regulates the tumor vascular microenvironment by affecting the expression of VEGFa and VEGFR2.(3)It is confirmed that after the regulation of the matrix,mechanical and vascular microenvironment,the delivery efficiency of nanomedicine will be greatly improved,including the tumor accumulation,deep penetration and cellular internalization.(4)It is confirmed that HBO can directly affect cancer cell stemness and reduce the self-renewal ability of cancer stem cells.HBO can also help nanomedicine eradicate cancer stem cells,which is caused by the improved delivery efficiency of nanomedicine and simultaneously pushing cancer stem cell escape from G0-G1 cycle arrest and to be sensitive to chemotherapy.Further studies have found that after reducing cancer cell stemness and eradicating cancer stem cell,tumor metastasis will be suppressed.(5)It is confirmed that HBO can enhance the cytotoxicity of nanomedicine to 4T1 and Panc02 cell line,and enhance the therapeutic effect of 4T1 and Panc02 orthotopic tumor model.The combination therapy has also been verified with good security.Further studies have shown that compared to another inherent factors which refers to pressure,oxygen is the main factor that improves the antitumor efficacy of nanomedicine.