Polyglycerol-coated nanodiamond as a macrophage-evading platform for selective drug delivery in cancer cells.

Abstract

A successful targeted drug delivery device for cancer chemotherapy should ideally be able to avoid non-specific uptake by nonmalignant cells, particularly the scavenging monocyte-macrophage system as well as targeting efficacy to bring the drug preferentially into tumor cells. To this purpose, we developed a platform based on detonation nanodiamond (dND) with hyperbranched polyglycerol (PG) coating (dND-PG). dND-PG was first demonstrated to evade non-specific cell uptake, particularly by macrophages (U937). RGD targeting peptide was then conjugated to dND-PG through multistep organic transformations to yield dND-PG-RGD that still evaded macrophage uptake but was preferentially taken up by targeted A549 cancer cells (expressing RGD peptide receptors). dND-PG and dND-PG-RGD showed good aqueous solubility and cytocompatibitlity. Subsequently, the anticancer agent doxorubicin (DOX) was loaded through acid-labile hydrazone linkage to yield dND-PG-DOX and dND-PG-RGD-DOX. Their cellular uptake and cytotoxicity were compared against DOX in A549 cells and U937 macrophages. It was found that dND-PG-DOX uptake was substantially reduced, displaying little toxicity in either type of cells by virtue of PG coating, whereas dND-PG-RGD-DOX exerted selective toxicity to A549 cells over U937 macrophages that are otherwise highly sensitive to DOX. Finally, dND-PG was demonstrated to have little influence on U937 macrophage cell functions, except for a slight increase of TNF-α production in resting U937 macrophages. dND-PG is a promising drug carrier for realization of highly selective drug delivery in tumor cells through specific uptake mechanisms, with minimum uptake in and influence on macrophages.

• Authors: Li Zhao, Yong-Hong Xu, Tsukasa Akasaka, Shigeaki Abe, Naoki Komatsu, Fumio Watari, Xiao Chen
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 20 Pg. 5393-5406 (Jul 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 24720879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Drug Carriers
• Liposomes
• Nanodiamonds
• Oligopeptides
• Polymers
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• polyglycerol
• arginyl-glycyl-aspartic acid
• Doxorubicin
• Glycerol

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Drug Carriers (chemistry)
• Drug Delivery Systems (methods)
• Glycerol (chemistry, pharmacology)
• Humans
• Liposomes
• Macrophages (metabolism)
• Nanodiamonds (chemistry)
• Neoplasms (therapy)
• Oligopeptides (pharmacology)
• Phagocytosis
• Polymers (chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• U937 Cells