title: Antibody conjugated PLGA nanoparticles for targeted delivery of paclitaxel palmitate: efficacy and biofate in a lung cancer mouse model.
abstract: Aberrant signaling of the epidermal growth factor receptor (EGFR) is common to a variety of human cancers and is also found to be over-expressed in most cases of non-small cell lung cancer. For the development of a molecularly targeted therapy, cetuximab-conjugated nanoparticles (immunonanoparticles, INPs) are designed and loaded with the lipophilic paclitaxel palmitate (pcpl) prodrug. Oleyl cysteineamide (OCA) is synthesized whereby its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs, facilitating bioconjugation to cetuximab by thioether bonds. It is demonstrated that the in vitro targeting efficiency and improved cellular internalization and cytotoxicity of this targeted delivery system in lung cancer cells over-expressing EGFR. A quantitative measure of the high binding affinity of INPs to EGFR is demonstrated using surface plasmon resonance. In vivo tolerability and enhanced efficacy of cetuximab pcpl INPs in a metastatic lung cancer model are reported. Its therapeutic efficacy in A549-luc-C8 lung tumors is shown using non-invasive bioluminescent imaging. Intravenous administration of cetuximab pcpl INPs to mice results in significantly higher inhibition of tumor growth and increased survival rates as compared to the non-targeted drug solution, drug-loaded nanoparticles or blank INPs. Pharmacokinetics and organ biodistribution of the prodrug and parent drug are evaluated by LC-MS/MS in lung tumor bearing mice. No enhanced total accumulation of nanoparticles or INPs is found at the tumor tissue. However, persistent pcpl levels with sustained conversion and release of paclitaxel are observed for the encapsulated prodrug possibly suggesting the formation of a drug reservoir. The overall results indicate the potential of this promising targeted platform for the improved treatment of lung cancer and other EGFR positive tumors.
authors.affiliation: The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem, 91120, Israel.
authors.forename: Nour
authors.initials: N
authors.lastname: Karra
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Alina Nemirovski
authors.initials: AN
authors.lastname: Ripin
authors.forename: Ouri
authors.initials: O
authors.lastname: Schwob
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000737:chemistry; D019540:Area Under Curve; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003545:Cysteine / Q000737:chemistry; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000737:chemistry; D006801:Humans; D007167:Immunotherapy; D019344:Lactic Acid / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D036103:Nanotechnology; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000737:chemistry*; D010168:Palmitates / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013438:Sulfhydryl Compounds / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013499:Surface Properties
chemical_list: D000577:Amides; D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D010168:Palmitates; D013438:Sulfhydryl Compounds; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D066246:ErbB Receptors; D003545:Cysteine; D017239:Paclitaxel; D000068818:Cetuximab
keywords: PLGA nanoparticles; biodistribution; conjugation; oleyl cysteineamide; paclitaxel-palmitate