Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer.

Abstract

We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications.

• Authors: Fanfan Fu, Yilun Wu, Jingyi Zhu, Shihui Wen, Mingwu Shen, Xiangyang Shi
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 6 Issue 18 Pg. 16416-25 (Sep 24 2014) ISSN: 1944-8252 [Electronic] United States
• PMID: 25185074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dendrimers
• Disaccharides
• Drug Carriers
• PAMAM Starburst
• Polyethylene Glycols
• lactobionic acid
• Doxorubicin

Topics

• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Cell Survival (drug effects)
• Dendrimers (chemistry)
• Disaccharides (chemistry)
• Doxorubicin (chemistry, pharmacokinetics, pharmacology)
• Drug Carriers (chemistry)
• Hep G2 Cells
• Humans
• Liver Neoplasms
• Polyethylene Glycols (chemistry)