Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model

Abstract

Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab.

Antibody h-R3-dendrimer mediated siRNA has excellent endosomal escape and tumor targeted delivery ability, and represents efficient siPLK1 silencing and inhibition of cell proliferation, migration and invasion

“…To address the limitations of therapeutic siRNA delivery, a new polymeric gene delivery system based on antibody h-R3 and PAMAM, is described that enhances intracellular delivery of siRNA. Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) against human epidermal growth factor receptor (EGFR) that demonstrated a remarkable antiproliferative, pro-apoptotic and antiangiogenic effect [ 36 – 38 ]. Unlike other anti-EGFR monoclonal antibody, such as mAbs C225 and ABX-EGF, h-R3 did not provoke acneiform rash or folliculitis [ 39 ].…”

Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity

“…Some have found PDT to decrease the expression of EGFR in tumors in vivo or cells in vitro , while others have noted PDT-induced increases in both EGFR levels and its activation [ 14 , 21 , 34 , 35 , 36 ]. Bhuvaneswari et al [ 37 ] reported that hypericin-mediated PDT of xenografts of bladder tumors led to small increases in EGFR expression as measured by Western blotting, and more recently a similar finding was published for EGFR detection by immunohistochemistry after chlorin e6-mediated PDT of xenografts of oral squamous cell carcinoma [ 21 ]. Edmonds et al [ 34 ] reported PDT with benzoporphyrin derivative of multiple cancer cell lines to increase EGFR activation in the absence of changes in total EGFR levels.…”

“…This may in part be attributed to an activation of EGFR signaling in post-treatment proliferating disease when illumination was given at the higher rate of 150 mW/cm. EGFR is well established to contribute to resistance to cancer therapies and molecular targeting of the EGFR pathway can improve therapeutic outcomes to PDT and other types of treatment [ 20 , 21 , 37 , 41 ]. These data suggest that the addition of EGFR-targeting therapy may be particularly beneficial in combination with intrathoracic PDT when higher fluence rates are employed.…”

“…PDT-induced signal transduction involves the well-studied survival pathways of mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), and treatment can alter the expression of growth factors and/or growth factor receptors that activate these pathways [ 14 , 15 , 16 , 17 , 18 ]. Informingly, combinational approaches that inhibit survival signaling in conjunction with PDT will benefit treatment responses, and toward this purpose there has been much interest in the study of drugs that target the epidermal growth factor receptor (EGFR) [ 19 , 20 , 21 , 22 , 23 ]. Given the roles of fluence rate in PDT-induced tissue hypoxia, oxidative stress, vascular damage, cytokine production, and other factors that can contribute to the activation of survival signaling [ 9 , 11 , 13 ], it is of interest to determine whether the induction of signaling is also a function of fluence rate.…”

Targeted photo-chemo therapy of malignancy on the chest wall while cardiopulmonary avoidance based on Fe3O4@ZnO nanocomposites

“…Photodynamic therapy (PDT) is an approved new modality for the treatment of superficial solid tumor recurrent/refractory to conventional treatment based on photosensitizers exposed to light of specific wavelength [4, 5]. Among the photosensitizers, ZnO nanomaterials are regarded as the potential photosensitizing agents for PDT due to their unique phototoxic effect upon the irradiation [6–8].…”