Acid Active Receptor-Specific Peptide Ligand for In Vivo Tumor-Targeted Delivery

Targeting therapy of tumors in their early stages is crucial to increase the survival rate of cancer patients. Currently most drug‐delivery systems target the neoplasia through the tumor‐associated receptors overexpressed on the cancer cell membrane. However, the expression of these receptors on normal cells and tissues is inevitable, which leads to unwanted accumulation and side effects. Characteristics of the tumor microenvironment, such as acidosis, are pervasive in almost all solid tumors and can be easily accessed. It is shown that the different extracellular pH value can be used to activate/inactivate the receptor‐mediated endocytosis on tumor/normal cells. This idea is implemented by conjugating a shielding molecule at the terminus of a receptor‐specific ligand via a pH‐sensitive hydrazone bond. The acid‐activated detachment of the shielding molecule and enhanced tumor/background accumulation ratio are demonstrated. These results suggest that acid active receptor‐specific peptide ligand‐modified tumor‐targeting delivery systems have potential use in the treatment of tumors. To reduce or even avoid the uptake of receptor‐mediated transport systems by healthy cells due to expression of receptors on normal cells, and to keep the tumor‐targeting delivery efficiency, emphasis is placed on combining other tumor properties with overexpressed receptors. The design of nanoparticles (NPs) that bind with receptors only after entering the tumor acidic environment is considered. In neutral conditions, targeting ligands are shielded and internalization is not induced.