Immunogenic Treatment of Metastatic Breast Cancer Using Targeted Carbon Nanotube Mediated Photothermal Therapy in Combination with Anti-Programmed Cell Death Protein-1.
Gabriela N F FariaClement G KarchSampurna ChakrabortyTingting GuAlexis WoodwardAdam AissanouSathish LageshettyRicardo Prada SilvyDaniel ResascoJorge Andres BallonRoger G HarrisonPublished in: The Journal of pharmacology and experimental therapeutics (2024)
The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single-walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anticancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45°C). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-programmed cell death protein-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. SIGNIFICANCE STATEMENT: This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-programmed cell death protein-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45°C and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.
Keyphrases
- induced apoptosis
- cancer therapy
- cell cycle arrest
- cell death
- dna damage
- immune response
- flow cytometry
- global health
- cell cycle
- protein protein
- high fat diet induced
- metastatic breast cancer
- public health
- endothelial cells
- amino acid
- photodynamic therapy
- drug delivery
- oxidative stress
- metabolic syndrome
- free survival
- signaling pathway
- inflammatory response
- aortic valve
- pi k akt
- type diabetes
- young adults
- dendritic cells
- combination therapy
- left ventricular
- insulin resistance
- wild type
- atrial fibrillation
- newly diagnosed
- structural basis