Responsive boronate ester lipid nanoparticles for enhanced delivery of veliparib and platinum (IV) prodrug in chemotherapy.

The chemotherapeutic effectiveness of breast cancer treatment is currently unsatisfactory due to inadequate drug delivery, suboptimal drug release, and drug inactivation. Herein, we present an innovative boronate ester lipid nanoformulation to improve the delivery of a platinum (IV) prodrug (Pt-C12) and veliparib (Veli), aiming to increase their therapeutic efficacy through a synergistic effect. We identify the optimal ratio of Pt-C12 to Veli for achieving synergy in vitro, followed by the encapsulation of Pt-C12 and Veli in lipid nanoparticles (NPs) incorporating responsive boronate ester lipids (LPC-PPE) to produce responsive lipid NPs (LPV NPs). These LPV NPs demonstrate high sensitivity to low levels of hydrogen peroxide (HO), enabling efficient drug release. In contrast, the nonresponsive lipid NP (DPV NP) control shows minimal responsiveness to HO. Furthermore, acidic tumor microenvironments trigger phenylboronic acid (PBA) generation from LPC-PPE in the LPV NPs. Compared with DPV NPs, the interaction between PBA on the LPV NPs and sugar components on tumor cells significantly improves LPV NP cellular uptake and lysosomal escape in vitro. Due to the enhanced cellular delivery and the synergistic drug combination, the LPV NPs induce an increase in apoptosis in 4 T1 cells compared with control groups. Moreover, the LPV NPs exhibit greater efficiency of drug delivery to tumors than the DPV NPs, and have a greater inhibitory effect on tumors than the controls. Overall, our findings highlight the potential of functional lipids and synergistic drug combinations in overcoming obstacles in breast cancer treatment and advancing the development of responsive delivery systems.