Targeted Dual-responsive Nanocarriers For Cancer Chemotherapy Combined With Photodynamic/Photothermal Therapy

Nowadays,anti-tumor therapy is still grim and chemotherapy remains the primary method of cancer treatment.The therapeutic potential of chemotherapeutic drugs is limited by their low bioavailability and toxicity to normal cells.To overcome the drawbacks of chemotherapy,nanocarriers have attracted extensive attention in anti-tumor research.Nanocarriers can be designed to respond to the tumor microenvironment（TME）intelligently,and therefore drugs will be released in the tumor tissue to improve drug availability and biosecurity.Hollow mesoporous silica nanoparticles（HMSNs）not only have ordered mesoporous structure,controllable particle size,easy modification and functionalization and good biocompatibility,but also their cavity structure can load a mass of drugs,which is suitable as a drug carrier and has attracted wide attention.Therefore,in this study,based on HMSNs,we have constructed a TME dual-responsive targeted nanoparticle for multi-modal combination therapy.The research contents are as follows:（1）In this study,we constructed a targeted nanoparticle（ICG/DOX@HMSNs-SS-N=C-HA or ID@HMSNs-SNH for short）with dual-response and multi-modal combination therapy).The chemotherapeutic agent doxorubicin（DOX）and the photosensitizer ICG were loaded into HMSNs by physical embedment,and the HMSNs were coated with oxidized hyaluronic acid（OHA）through a p H-sensitive Schiff base bond and redox-sensitive disulfide bond to prevent drug leakage.（2）In vitro experiments verified that the nanoparticles can intelligently control the release of drugs and had the potential of effective photodynamic/photothermal therapy（PDT/PTT）for anti-tumor.The Nano system exhibited high drug loading and encapsulation efficiency.Experiments showed that the drug release process had acid sensitivity and redox responsiveness,and the drug release increases in weakly acidic and high GSH environments.Under the condition of p H 5.0+10 m M GSH,the cumulative release at 72 h reached 74.61±2.76%（DOX）and 55.61±1.82%（ICG）.Nanoparticles respond to the tumor microenvironment to release drug,increasing drug concentration in tumor tissue cells and enhancing drug efficacy.（3）Cell uptake experiments proved that they could selectively target tumor cells overexpressing CD44 receptors,thus reducing their uptake by normal cells.Moreover,cytotoxicity experiments displayed their satisfactory inhibiting cancer cells（Hep G2）effect with an IC₅₀ value of 0.09μg/m L under 808nm laser irradiation,it can inhibit tumor activity by chemotherapy combined with photodynamic photothermal therapy.In summary,the obtained ID@HMSNs-SNH can respond to the slightly acidic and reducing tumor microenvironment to release drugs,showing a good ability for chemotherapy combined with PTT/PDT in vitro.