Tumor Microenvironment-Targeted Bacteriochlorophylls as Theranostic Agents for Triple Negative Breast Cancer

New compounds comprising light activated bacteriochlorophyll (Bchl) conjugates with the tri-peptide Arg-Gly-Asp (Bchl-RGD, e.g. STL-6014) are shown to target several cell populations in the tumor microenvironment of triple negative breast cancer. The compounds uptake enables imaging, prognosis, primary tumor eradication and provocation of anti-tumor immunity.

STL-6014, selectively accumulates in the primary tumor and lung metastases of murine 4T1 mammary and human MDA-MB-231 breast cancer tumors in mouse models and resides in the tumor necrotic domains for >9 days. FACS analysis, NIR fluorescence microscopy and co-administration of Bchl free RGD analogues, showed integrin dependent uptake by cancer and endothelial cells, cancer associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAMs). Within each cell population, high, low and null STL-6014 uptakes were observed. The tumor cell composition was modified following STL-6014 administration. TAMs and neutrophils numbers were elevated, while the population of cancer cells was reduced at 24 h post administration and then proliferated at a slower rate. Continuous i.v loading of STL-6014 retarded tumor growth. β3 integrin’s expression correlated well with the percentage of high uptake cell population in each subset, supporting active transport mechanism. Drug uptake and accumulation is mediated by recruited neutrophils that aggregate with tumor associated platelets. Illumination of 4T1 tumors by NIR diode laser (15min, 755nm) at 6h post STL-6014 administration resulted in a complete ablation of the treated tumors in 63% of the animals 21 days later through necrotic and apoptotic pathways. Preliminary results using combinations of immune modulators and PDT provide indications for increased animal survival through systemic, anti-metastatic effect.

In conclusion, STL-6014 provides new means for imaging and treatment of TNB cancers in both the local and metastatic settings.