Construction Of Nano-Drug Delivery System For Tumor Hypoxia And Exploration In PDT/CT Combined Therapy

Effective treatment of malignant tumors is a major challenge in the current medical field.Radiation therapy(RT),chemotherapy(CT),and photodynamic therapy(PDT)as the basic treatment of cancer have drawbacks:RT treatment scope is limited,CT efficacy is limited by chemotherapy resistance,tumor anoxic environment makes PDT treatment effect reduced,and so on.With the rapid development of nanotechnology,researchers are looking for the new and high efficiency anti-tumor therapies.Based on the tumor microenvironment,the construction of intelligent responsive nano-drug delivery system and multi-mode combination therapy can improve the tumor therapeutic effect.For example,combination therapy of PDT and CT is more efficient than monotherapy.However,early drug release and tumor hypoxia on drug carrier loading are still the main reasons for the low efficiency of systemic toxicity and PDT/CT combined therapy.Based on this background,we designed a nano drug delivery system Hb-(MB/RSR13)-BTIB-(DOX-BTMSPE)NPs(represented by HRMBDB NPs)for tumor hypoxia and explored the application of this system in PDT/CT combined therapy.Firstly,the singlet oxygen(1O2)-specific response of silicone material BTMSPE was used as the nuclear layer material.The nuclear layer.was loaded with the anticancer drug DOX,and acid-sensitive material BTIB as the carrier shell.the shell layer was loaded with the photosensitizer methylene blue(MB)and the hemoglobin allosteric modifier efaproxiral(RSR13),and the oxygen-carrying hemoglobin(Hb)was modified on the surface of the drug carrier.HRMBDB NPs were successfully prepared.The HRMBDB NPs had complete morphology and good dispersion.Since ambient oxygen partial pressure affects the oxygen-carrying and oxygen-releasing process of Hb,if Hb is already in a low-oxygen environment(such as tissue cells,etc.)before entering the tumor hypoxic environment,the oxygen-releasing capacity of Hb would be limited and the actual oxygen supply capacity of Hb in the treatment process would be greatly weakened.Studies have shown that typically one hemoglobin molecule binds to four molecules of oxygen,but only one is released.Based on this,we can use RSR13 to promote the dissociation of Hb and oxygen molecules,and reduce the dependence of Hb oxygen release process on the environment.Under normal or low oxygen,HRMBDB NPs can maintain a good oxygen carrying and oxygen release capacity.Moreover,when HRMBDB NPs entered the tumor microacidic and hypoxic environment,the shell-loaded photosensitizers MB and RSR13 were rapidly released after the acid trigger.Even in low oxygen environment,RSR13 can effectively combine with the surface modified Hb of nanomaterial,change the three-dimensional structure of Hb,increase the oxygen release of oxy-Hb,and improve the oxygen level in the hypoxic environment of tumor.The increase in oxygen content can also improve the effect of PDT.The photosensitizer MB,under the irradiation of 660 nm,can effectively produce highly active singlet oxygen(1O2)which is released by 1O2-mediated nuclear anticancer DOX after activation.The results showed that,compared with HMBDB NPs without RSR13,the increased oxygen release of HRMBDB NPs in the hypoxic environment could significantly improve the hypoxic environment of the tumor,promote the production of 1O2,improve the cytotoxicity of the 1O2-mediated anticancer drug DOX,and enhance the effect of PDT/CT.The novel nanomaterials prepared for the hypoxia of the tumor and having dual responsiveness can make full use of the tumor micro-acid environment,the high photodynamic product ROS content,and RSR13 enhance the oxygen release function of Hb.The novel nanomaterials can reduce the dependence of the oxygen release process of Hb on the environment,and significantly improve the tumor hypoxia environment,as well as the photodynamic efficiency and chemical resistance of the tumor caused by hypoxia,so as to achieve the goal of effective anti-tumor.