title: Molecularly targeted gemcitabine-loaded nanoparticulate system towards the treatment of EGFR overexpressing lung cancer.
abstract: Molecularly targeted therapy emerged as a novel therapeutic strategy in the treatment of multiple cancers. In the present study, we have developed gemcitabine (GEM)-loaded cetuximab (CET) surface modified poly(lactic) acid (PLA) nanoparticles (NP) (CET-GEM/PLA NP) to target to epidermal growth factor receptor (EGFR) overexpressing non-small cell lung cancer (A549) cells. The resultant CET-GEM/PLA NP showed a very uniform particle size of∼120 nm and spherical morphology. It exhibited a pH-dependent controlled release pattern. A sustained release of drug in the physiological conditions and faster release in tumor pH will greatly improve the chemotherapeutic efficiency of therapeutic system. Higher or enhanced cellular uptake of CET-GEM/PLA NP in A549 cancer cells clearly indicates the EGFR-mediated receptor based active targeting. Nearly, a two-fold increase in fluorescent intensity was observed for CET-GEM/PLA NP comparing to that of non-targeted NP in the cancer cells. EGFR-mediated internalization of the targeted NP was further confirmed by the confocal microscopy. MTT assay clearly showed the enhanced cell killing effect of CET-conjugated NP due to the selective delivery of GEM to the EGFR over expressing cancer cells. Finally, comparing to the non-targeted NP, CET-GEM/PLA NP showed greater level of cell apoptosis (early and late apoptosis∼40%). Our results showed that antibody conjugation on the surface of NP could be a potential treatment strategy for EGFR over expressing cancer cells. This suggests that CET-GEM/PLA NP could be potentially used for the treatment of NSCLC (lung cancers).
authors.affiliation: Department of Thoracic Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China.
authors.forename: Xian-Bao
authors.initials: XB
authors.lastname: Wang
authors.affiliation: Department of Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, China. Electronic address: zhouhaiyan180@gmail.com.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhou
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage*; D010316:Particle Size; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000093542:Gemcitabine
keywords: Apoptosis; Cetuximab; EGFR; Gemcitabine; Lung cancer; Nanoparticles