Preparation Of Photothermal-chemotherap And Synergistic Penetrating Enhanced Nanocarriers For Cancer Therapy

At present,malignant tumors have become one of the most important diseases leading to human abnormal death.Research on tumor treatment has become the most important research direction in the field of biomedicine.In tumor tissues,there are some special stem cell-like tumor cell population.These cells not only have high drug resistance,but overexpress CD44 protein specifically.They can also differentiate to tumor cells that re-maintain tumor growth and metastasis under specific stimuli.During the treatment of tumors,if the drug can't effectively remove the cancer stem cells,the tumor is likely to recur and metastasize.Therefore,the key to tumor treatment is to absolutely eliminate tumor stem cells while reducing tumor volume.As an emerging treatment program,photothermal therapy can not only effectively kill tumor cells,but also enhance the ability of nanodrug penetration in tumor tissues,so it has become a promising therapeutic method in application.However,due to the ability of light in penetrating tumor tissue,photothermal therapy has limited effects on bulk solid tumors.Compared with photothermal therapy,chemotherapy has obvious advantages in suppressing large solid tumors.However,due to the dense tumor extracellular matrix,most nanodrugs are still difficult to effectively penetrate tumor tissues and remove tumor stem cells.Based on the respective advantages of photothermal therapy and chemotherapy,we hope to achieve highly-efficient inhibition of tumor proliferation and metastasis through the synergistic combination of both therapeutic strategies.Considering the background mentioned above,we designed a reduction responsive chitosan nanocarrier capable of targeting tumor stem cell CD44 protein and co-encapsulating hydrophobic chemotherapeutic drugs and photothermal dyes by hydrophobic interaction.Since chitosan is rich in amino groups,the surface of the drug-loaded nanoparticle is covered by positive charge.In order to prevent the drug-loaded nanoparticle from being removed by the reticuloendothelial system during blood circulation,PEG layer was coated on the nanoparticle shell by the pH responsive Schiff base bond to reduce the surface charge,to increase the stability during circulation,and also to prolong the circulation time of the drug-loaded micelles.In addition,a targeted penetrating peptide iRGD was also introduced to the shell by Schiff base bond,thereby promoting extravasation of drug-loaded nanoparticle from tumor blood vessels and enhancing tumor tissue penetration.The above-mentioned nanomedicine can not only efficiently enrich and penetrate the tumor tissue,but also achieve efficient chemo-photothermal synergy under the action of 0.8 W/cm2 808 nm near-infrared light irradiation and the loaded gambogic acid.