PET-MR Guided, Pre-targeted delivery to HER2(+) Breast Cancer Model

Purpose: HER2(+) metastatic breast cancer (mBC) is one of the most aggressive and lethal cancer types among females. While initially effective, targeted therapeutic approaches with trastuzumab and pertuzumab antibodies and antibody-drug conjugates (ADC) lack long-term efficacy against HER2(+) mBC and can cause severe systemic toxicity due to off-target effects. Therefore, the development of novel targeted delivery platforms that minimize toxicity and increase therapeutic efficacy is critical to the treatment of HER2(+) breast cancer (BC). A pretargeting delivery platform can minimize the non-specific accumulation and off-target toxicity caused by traditional one-step delivery method by separating the single delivery step into a pre-targeting step with high-affinity biomarker binding ligand followed by the subsequent delivery step of therapeutic component with fast clearance. Each delivery component is functionalized with bioorthogonal reactive groups that quickly react in situ , forming cross-linked clusters on the cell surface, which facilitates rapid internalization and intracellular delivery of therapeutics. Procedures: We have successfully developed a click chemistry-based pretargeting platform for HER2(+) BC enabling PET-MR image guidance for reduced radiation dose, high sensitivity, and good soft tissue contrast. Radiolabeled trastuzumab and superparamagnetic iron-oxide carriers (uSPIO) were selected as pretargeting and delivery components, respectively. HER2(+) BT-474 cell line and corresponding xenografts were used for in vitro and in vivo studies. Results: An enhanced tumor accumulation as well as tumor- to-organ accumulation ratio was observed in pretargeted mice up to 24 h post uSPIO injection. A 40% local T 1 decrease in the pretargeted mice tumor was observed within 4 h, and an overall 15% T 1 drop was retained for 24 h post uSPIO injection. Conclusions: Prolonged tumor retention and increased tumor-to-organ accumulation ratio provided a solid foundation for pretargeted image-guided delivery approach for in vivo applications.