Actively Targeted Cetuximab Conjugated γ-Poly(glutamic acid)-Docetaxel Nanomedicines for Epidermal Growth Factor Receptor Over Expressing Colon Cancer Cells
Receptor targeted therapy is advantageous in overcoming the toxicity burden of conventional cancer chemotherapeutics. Over expression of epidermal growth factor receptor (EGFR) on cancer cells and its role in metastasis, malignancy and drug resistance in many human cancers lead to its selection as a promising target for cancer treatment. The present work investigated the preparation and characterization of docetaxel (DTXL) loaded γ-poly (glutamic acid) (γ-PGA) nanoparticles (Nps) conjugated with EGFR antibody (Cetuximab, CET) targeted to colon cancer cells (HT-29), highly over expressing EGFR. The flow cytometric analysis revealed two fold increased cellular uptake of CET-DTXL-γ-PGA Nps by HT-29 (EGFR+ ve) cells compared to that of IEC-6 (EGFR-ve) cells confirming the active targeting. Cytotoxicity assays (MTT and LDH) showed superior anti-proliferative activity of CET-DTXL-γ-PGA NPs over DTXL-γ-PGA Nps against HT-29 cells. The cell cycle analysis indicated that CET-DTXL-γ-PGA NPs induced cell death in enhanced percentage of HT-29 cells by undergoing cell cycle arrest in G2/M phase compared to that of DTXL-γ-PGA Nps. The mechanism of cancer cell death was analyzed via apoptotic and mitochondrial membrane potential assays and showed that targeted Nps treatment reduced the mitochondrial membrane potential thereby inducing enhanced HT-29 cell death (apoptosis and necrosis). The biodistribution of targeted and non-targeted Nps were analyzed in vivo in Swiss albino mice using NIR imaging. ICG-CET-DTXL-γ-PGA Nps (targeted) and ICG-DTXL-γ-PGA Nps (non-targeted) followed the similar biodistribution pattern in vivo, but with different elimination time. In short, CET-DTXL-γ-PGA nanoparticles enhance the tumor selective therapeutic efficacy for colon cancer.
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Document Type: Research Article
Publication date: August 1, 2014
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