Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro

Abstract

The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are “photodynamically primed”, or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.

Exploiting Unique Features of Microneedles to Modulate Immunity

“…As a result, effector cells can return to the periphery to eliminate the primary tumor and prevent metastasis. [104,105] This class of therapies is approved by the FDA for cancers such as basal cell skin cancer and non-small cell lung cancer. [106,107] MNAs could provide an alternative to this traditional form of delivery because they target the release of TAAs and adjuvants to APCs in the skin.…”

“…As a result, effector cells can return to the periphery to eliminate the primary tumor and prevent metastasis. [ 104,105 ] This class of therapies is approved by the FDA for cancers such as basal cell skin cancer and non‐small cell lung cancer. [ 106,107 ]…”

Critical PDT Theory III: Events at the Molecular and Cellular Level

“…Successful application of PDT can lead to the eradication of localized neoplasia without many of the adverse effects associated with chemotherapy and ionizing radiation. Protocols involving combinations of PDT and chemotherapy are also being investigated [ 41 , 42 , 43 ]. The news that yet one more product can catalyze formation of reactive species upon irradiation is of limited interest unless that agent has some unusual properties that are superior to agents already available.…”

Transient fluid flow improves photoimmunoconjugate delivery and photoimmunotherapy efficacy

“…Consistent with these dual functions, we and others have shown that PICs targeting the EGFR can attenuate EGFR and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. 17 , 18 Nonetheless, one of the major challenges associated with PIT is limited photosensitizer delivery to cancer cells. 18 , 19 , 20 This can be attributed to several factors including finite antigen numbers per cancer cell, limited number of photosensitizer-to-antibody payload, and poor tumor accessibility of antibodies.…”

“… 17 , 18 Nonetheless, one of the major challenges associated with PIT is limited photosensitizer delivery to cancer cells. 18 , 19 , 20 This can be attributed to several factors including finite antigen numbers per cancer cell, limited number of photosensitizer-to-antibody payload, and poor tumor accessibility of antibodies. 20 This study overcomes this limitation through the rigorous examination of transient flow as a drug delivery platform to enhance total cellular PIC delivery and thereby bolster cytotoxic effects.…”