Wireless Implantable Light-Emitting Device (WILD) for Immunogenic Photodynamic Therapy of Breast Cancer

Introduction: : Photodynamic therapy (PDT) has gained traction as a method for inducing immunogenic cancer cell death, a strategy that can prime the immune system to fight both primary and metastatic tumors. However, the utility of PDT in breast cancer is limited by poor tissue light penetration. To address this, we are developing a revolutionary approach to neoadjuvant PDT using a wireless, implantable light-emitting device (WILD), which is inserted via a standard core needle biopsy. Powered externally by an RF antenna, the on average 23 mm3 WILD delivers red light to activate 5-aminolevulinic acid (5-ALA)-derived protoporphyrin IX (PpIX) within tumors. This enables continuous, localized PDT throughout the preoperative treatment window. Our studies aim to demonstrate that this engineered system not only limits growth of primary breast tumors but also triggers systemic immune responses capable of targeting distant lesions. This multidisciplinary work integrates photochemistry, electrical engineering, and tumor immunology to establish a platform for minimally invasive, immunogenic cancer therapy.

Materials and

Methods: : We designed and fabricated miniature (23 mm3) red-emitting WILD implants optimized for 630 nm emission, sufficient to penetrate >10 mm of tumor tissue. Uniformity and thermal safety were validated via optical power measurements and infrared imaging. To evaluate biological efficacy, we used in vitro 4T1 cell photoinactivation assays with 5-ALA and WILD light exposure. In vivo, orthotopic 4T1 tumors were generated in BALB/c mice. WILD devices were implanted intratumorally using a 12G biopsy needle after tumors reached an acceptable size. Mice received 250 mg/kg 5-ALA via oral gavage 3 hours before four 30-minute irradiation sessions, spaced on alternating days. Tumor volumes were tracked, and ex vivo samples underwent histology, western blot analysis, and an immune array to assess apoptosis, proliferation, myeloid infiltration, and pyroptosis. All animal studies adhered to IACUC-approved protocols and were conducted in collaboration with electrical and biomedical engineering teams.

Results, Conclusions, and Discussions:: In vitro studies confirmed that WILD-enabled photodynamic therapy (PDT) using 5-ALA significantly reduced 4T1 cell viability, while treatment with light or 5-ALA alone had minimal effect, supporting a synergistic PDT effect. In vivo fluorescence imaging verified selective accumulation of protoporphyrin IX (PpIX) in tumors within three hours post oral 5-ALA administration. The WILD implant was successfully delivered into 4T1 tumors in BALB/c mice using a 12G biopsy needle and activated via wireless radiofrequency to emit red light. CT imaging post-sacrifice confirmed intratumoral placement. Histological analysis revealed cell death and tissue disruption in treated tumors. Tumor volumes consistently decreased over four treatment sessions in WILD+5-ALA cohorts compared to the 5-ALA only control, maintaining a similar size to the saline control.
Importantly, a 32-target cytokine and chemokine array of the mouse serum (Eve Technologies, MD32, Calgary, AB, Canada) revealed elevated levels of multiple pro-inflammatory and immune-activating cytokines/chemokines in WILD+5-ALA-treated tumors compared to those treated with 5-ALA alone or saline. These results indicate that the combined treatment not only induces local tumor cytotoxicity but also enhances immune system engagement.
These findings demonstrate that WILD-mediated PDT can trigger immunogenic cell death and stimulate systemic anti-tumor responses in a murine breast cancer model. The miniature, wirelessly powered implant offers a promising, minimally invasive tool for neoadjuvant therapy, especially in tumors located too deep for conventional light delivery. Ongoing work will optimize dosing regimens, investigate checkpoint inhibitor co-therapies, and expand immune profiling. This platform offers new potential for precision-targeted PDT and immune activation in breast and other solid tumors.

Acknowledgements and/or References (Optional)::