Polyglycerol-coated nanodiamond as a macrophage-evading platform for selective drug delivery in cancer cells.
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.
Department of Chemistry, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan.
Li
L
Zhao
Institute of Ophthalmological Research, Department of Ophthalmology, Renmin Hospital of Wuhan University, 430060 Wuhan, China.
Yong-Hong
YH
Xu
Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan.
Tsukasa
T
Akasaka
Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan.
Shigeaki
S
Abe
Department of Chemistry, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan.
Naoki
N
Komatsu
Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan.
Fumio
F
Watari
Department of Biomedical, Dental Materials and Engineering, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan. Electronic address: mornsmile@yahoo.com.
Xiao
X
Chen
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005990:Glycerol / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D008264:Macrophages / Q000378:metabolism*; D058612:Nanodiamonds / Q000737:chemistry*; D009369:Neoplasms / Q000628:therapy; D009842:Oligopeptides / Q000494:pharmacology; D010587:Phagocytosis; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D058612:Nanodiamonds; D009842:Oligopeptides; D011108:Polymers; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C043941:polyglycerol; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; D005990:Glycerol
Cancer cells; Coating; Detonation nanodiamond; Polyglycerol; RGD peptide; Selective delivery