Triple negative breast cancer (TNBC) does not respond to some of the most effective therapies available for breast cancer treatment. Even aggressive surgery, i.e. mastectomy, does not improve outcome. In fact, patients receiving breast conserving surgery (BCS) and radiation therapy exhibit better breast cancer specific and overall survival than patients that undergo a mastectomy, for both metastatic and non-metastatic disease. This is thought to be due to the radiation-induced abscopal effect. Therefore, we hypothesize that and adjuvant treatment that can both improve local regional control during BCS and enhance the abscopal effect could improve the current standard of care. One such option is photodynamic therapy (PDT). We will utilize mesothelin-targeted photosensitizers (PS). We have previously found that mesothelin is strongly expressed in the majority of TNBCs and expression is highly associated with both overall and disease-specific survival. Since most PS are lipophilic, they are often encapsulated within nanoparticles to improve their solubility and to facilitate systemic delivery. Nanoparticles can be designed to carry high PS payloads, extend the PS circulation time, improve tumor accumulation, and reduce off-target phototoxicity by minimizing PS uptake in healthy tissue. However, in order to maximize the benefit of nanoparticles, new nanoformulations must be developed that minimize the self-quenching of reactive oxygen species generation. Moreover, new strategies must be established to help facilitate the penetration of PS-loaded nanoparticles into tumors. Recently, we found that the amphiphilic photosensitizer Chlorin e6 (Ce6) was able to form a stable, water-soluble coating on nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs). Due to the unique orientation of Ce6 on the SPION surface, little to no quenching of singlet oxygen production was observed. This led to the effective use of the Ce6-coated SPION nanoclusters (CSNs) as a PDT agent in a murine model of TNBC, leading to a significant slowing of tumor growth. The overall goal of this proposal is to improve upon this work by combining CSNs with mesothelin-targeting and magnetophoresis to improve the specificity, accumulation, penetration, and efficacy of CSNs in treating TNBC. Magnetophoresis will be applied using a custom magnetic device that can radially profoundly disperse CSNs from any location in a living subject. This innovative technology will improve the ability of CSNs to reach their intended targets.The specific aims for this proposal are as follows: Aim 1. Synthesize and characterize the physical-chemical properties of mesothelin-targeted, Ce6-coated SPION nanoclusters (CSNs) and characterize a 2nd generation magnetic device; Aim 2. Evaluate the tumor accumulation and penetration of CSNs in a murine model of TNBC; Aim 3. Evaluate the efficacy and toxicity of PDT with CSNs in a murine model of TNBC.