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

• Published in: Biomaterials 2014-07, Vol.35 (20), p.5393-5406
• Main Authors: Zhao, Li, Xu, Yong-Hong, Akasaka, Tsukasa, Abe, Shigeaki, Komatsu, Naoki, Watari, Fumio, Chen, Xiao
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Antibiotics, Antineoplastic - pharmacology; Cell Line, Tumor; Dentistry; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Delivery Systems - methods; Glycerol - chemistry; Glycerol - pharmacology; Humans; Liposomes; Macrophages - metabolism; Nanodiamonds - chemistry; Neoplasms - therapy; Oligopeptides - pharmacology; Phagocytosis; Polymers - chemistry; Polymers - pharmacology; Reactive Oxygen Species - metabolism; Tumor Necrosis Factor-alpha - metabolism; U937 Cells
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2014.03.041

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.