In Situ Injectable Sequentially Responsive Hydrogel Based on Triblock Copolymers for Breast Cancer Theranostic Amplification

Celastrol (Cel), a natural small molecule, effectively inhibits breast cancer but has poor solubility and systemic toxicity. Herein, an in situ injectable sequentially responsive celastrol hydrogel (FCPC) based on the temperature-sensitive poloxamer F127 and tumor-acidity-cleavable maleic acid amide is rationally designed. Once injected into tumor tissue, FCPC forms a stable gel state rapidly, followed by continuously releasing activity molecules for five days. This injectable thermosensitive drug delivery system extends the drug residence time and targeted release. The platform greatly strengthens the Cel's antitumor ability both in vitro and in vivo and meanwhile reduces cancer metastasis and toxic side effects. Studies suggest FCPC may act by suppressing PI3K-Akt and MAPK pathways. Such an injectable sequentially responsive hydrogel intelligently solves the administration problem caused by poor solubility of natural small molecule and has the potential for clinical applicability.