Conjugation of arginine-glycine-aspartic acid peptides to poly(ethylene oxide)-b-poly(epsilon-caprolactone) micelles for enhanced intracellular drug delivery to metastatic tumor cells.

Abstract

An arginine-glycine-aspartic acid (RGD) containing model peptide was conjugated to the surface of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as a ligand that can recognize adhesion molecules overexpressed on the surface of metastatic cancer cells, that is, integrins, and that can enhance the micellar delivery of encapsulated hydrophobic drug into a tumor cell. Toward this goal, PEO-b-PCL copolymers bearing acetal groups on the PEO end were synthesized, characterized, and assembled to polymeric micelles. The acetal group on the surface of the PEO-b-PCL micelles was converted to reactive aldehyde under acidic condition at room temperature. An RGD-containing linear peptide, GRGDS, was conjugated on the surface of the aldehyde-decorated PEO-b-PCL micelles by incubation at room temperature. A hydrophobic fluorescent probe, that is, DiI, was physically loaded in prepared polymeric micelles to imitate hydrophobic drugs loaded in micellar carrier. The cellular uptake of DiI loaded GRGDS-modified micelles by melanoma B16-F10 cells was investigated at 4 and 37 degrees C by fluorescent spectroscopy and confocal microscopy techniques and was compared to the uptake of DiI loaded valine-PEO-b-PCL micelles (as the irrelevant ligand decorated micelles) and free DiI. GRGDS conjugation to polymeric micelles significantly facilitated the cellular uptake of encapsulated hydrophobic DiI most probably by intergrin-mediated cell attachment and endocytosis. The results indicate that acetal-terminated PEO-b-PCL micelles are amenable for introducing targeting moieties on the surface of polymeric micelles and that RGD-peptide conjugated PEO-b-PCL micelles are promising ligand-targeted carriers for enhanced drug delivery to metastatic tumor cells.

• Authors: Xiao-Bing Xiong, Abdullah Mahmud, Hasan Uludağ, Afsaneh Lavasanifar
• Journal: Biomacromolecules (Biomacromolecules) Vol. 8 Issue 3 Pg. 874-84 (Mar 2007) ISSN: 1525-7797 [Print] United States
• PMID: 17315946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Lactones
• Micelles
• Peptides
• poly(ethylene oxide)-b-poly(caprolactone)
• Aspartic Acid
• Polyethylene Glycols
• Arginine
• Glycine

Topics

• Aldehydes (chemistry)
• Arginine (chemistry)
• Aspartic Acid (chemistry)
• Cell Line, Tumor
• Drug Delivery Systems
• Glycine (chemistry)
• Humans
• Lactones (chemistry)
• Micelles
• Microscopy, Confocal
• Microscopy, Fluorescence
• Models, Chemical
• Neoplasm Metastasis
• Neoplasms (metabolism)
• Peptides (chemistry)
• Polyethylene Glycols (chemistry)