Dual targeting of FR+CD44 overexpressing tumors by self-assembled nanoparticles quantitatively conjugating folic acid-hyaluronic acid to the GSH-sensitively modified podophyllotoxin

Ligand-receptor recognition-based nanodrug delivery systems incorporate stimulus-responsive functionality to proactively transport chemotherapeutics to lesional tissues and intelligently release drugs in response to stimulation, thereby augmenting drug accumulation at target sites, boosting drug bioavailability, and avoiding systemic toxicity, which reveals a promising potential in malignant tumor therapy. Herein, we designed and prepared a dual-targeted nanomedicine, FA-HA-SS-PPT, utilizing microwave-assisted quantitative conjugating of podophyllotoxin (PPT) to folic acid (FA) and hyaluronic acid (HA) carriers via short-chain PEG bearing the tumor microenvironment-sensitive disulfide bond. The FA-HA-SS-PPT nanoparticles developed by self-assembly exploited the peculiarity of specifically binding to the folate receptor (FR) and CD44 receptor, initiated targeting to translocate the drug into the tumor cells and released the PPT by self-cyclization in high intracellular GSH concentration. Furthermore, this nanomedicine demonstrated superior tumor cytotoxicity and proliferation inhibition in vitro by triggering the mitochondrial apoptotic pathway and suppressing the microtubule protein formation. Notably, quantitative disulfide bond conjugation and nanomedicine formation endowed FA-HA-SS-PPT nanoparticles with astonishing in vivo circulatory stability and tumor microenvironmental responsiveness, further reinforcing drug security and anti-tumor capability. Therefore, quantitatively conjugating drugs provide a promising safe and efficient means to treat multi-receptor overexpressing tumors with multi-targeted nanomedicines.