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

ABSTRACT

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 T1 decrease in the pretargeted mice tumor was observed within 4 h, and an overall 15% T1 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.