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Antibody conjugated PLGA nanoparticles for targeted delivery of paclitaxel palmitate: efficacy and biofate in a lung cancer mouse model.
- Source :
-
Small (Weinheim an der Bergstrasse, Germany) [Small] 2013 Dec 20; Vol. 9 (24), pp. 4221-36. Date of Electronic Publication: 2013 Jul 21. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Amides chemistry
Animals
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized chemistry
Area Under Curve
Cell Line, Tumor
Cetuximab
Cysteine chemistry
Drug Delivery Systems
ErbB Receptors chemistry
Humans
Immunotherapy
Mice
Mice, SCID
Nanoparticles chemistry
Nanotechnology
Neoplasm Transplantation
Polylactic Acid-Polyglycolic Acid Copolymer
Sulfhydryl Compounds chemistry
Surface Plasmon Resonance
Surface Properties
Antibodies chemistry
Lactic Acid chemistry
Lung Neoplasms drug therapy
Nanoparticles administration & dosage
Paclitaxel chemistry
Palmitates administration & dosage
Polyglycolic Acid chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1613-6829
- Volume :
- 9
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Small (Weinheim an der Bergstrasse, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 23873835
- Full Text :
- https://doi.org/10.1002/smll.201301417