Carrier-Free Cisplatin–Dactolisib Nanoparticles for Enhanced Synergistic Antitumor Efficacy

Cisplatin (CDDP) is one of the most commonly used chemotherapeutic agents for solid tumors and hematologic malignancy. However, its therapeutic outcomes have remained unsatisfactory due to severe side effects, a short elimination half-life, the emergence of drug resistance, and the induction of metastasis. Combination with other chemotherapeutic agents has been proposed as one strategy to address the drawbacks of CDDP-based therapy. Therefore, this study aimed to boost the antitumor efficacy of cisplatin (CDDP) with a PI3K/mTOR dual inhibitor, dactolisib (BEZ), via a carrier-free codelivery system based on the self-assembly of the coordinated CDDP-BEZ. The synthesized CDDP-BEZ nanoparticles (NPs) possess sensitive pH-responsiveness, facilitating the delivery of both drugs to cancer cells. CDDP-BEZ NPs specifically enhanced cytotoxicity in cancer cells due to the synergy between cisplatin and dactolisib, resulting in augmented DNA damage, activation of mitochondria-dependent apoptosis, and increased inhibition on the PI3K/mTOR signaling axis. The inhibition of tumor migration and metastasis by CDDP-BEZ NPs was observed both in vitro and in vivo. Our data suggest that CDDP-BEZ NPs could serve as a safe and effective platform to maximize the synergy between both drugs in combating cancer, presenting a strategy to promote the therapeutic efficacy of platinum-based chemotherapeutic agents by combining them with PI3K inhibitors.