Sequential self-assembly and release of a camptothecin prodrug for tumor-targeting therapy

Chemotherapy is the most commonly used method to treat malignant tumors with a wide range of drugs. However, chemotherapeutic drugs are characterized by poor solubility, low stability and specificity, as well as drug resistance, which led to their limited bioavailability and severe adverse effects. Therefore, most researches focus on one or two strategies while a few researches focus on three strategies to improve the efficacy of drugs. Herein, we combined three strategies (targeted therapy, prodrug design and drug delivery) to exploit a self-assembled camptothecin (CPT) prodrug (CPT-SS-FFEYp-Biotin) for enhancing therapeutic efficacy and reducing side effects of CPT. CPT-SS-FFEYp-Biotin enters into tumor cells following the recognition between biotin and biotin receptors. Moreover, the over-expressed alkaline phosphatase (ALP) on cell membranes specifically dephosphorylates CPT-SS-FFEYp-Biotin to CPT-SS-FFEY-Biotin, which self-assembles into a CPT hydrogel with the local enrichment of CPT. Subsequently, excess glutathione (GSH) in tumor cells can reduce the disulfide bond of CPT-SS-FFEY-Biotin to slowly release CPT for sustained tumor therapy. Cell experiments demonstrated that CPT-SS-FFEYp-Biotin enhances therapeutic efficacy of CPT on tumor cells while being safer to normal cells than CPT. Moreover, CPT-SS-FFEYp-Biotin effectively improved anti-tumor treatment of CPT <i>in vivo</i>. We envision that the integration of these three strategies is helpful to exploit a variety of prodrugs for effective anti-tumor treatment in the future.