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. 2014 Mar 21:4:4430.
doi: 10.1038/srep04430.

Inorganic nanovehicle targets tumor in an orthotopic breast cancer model

Goeun Choi  1 , Oh-Joon Kwon  2 , Yeonji Oh  1 , Chae-Ok Yun  2 , Jin-Ho Choy  1
Affiliations

Inorganic nanovehicle targets tumor in an orthotopic breast cancer model

Goeun Choi et al. Sci Rep. .

Abstract

The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

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Figures

Figure 1
Figure 1. (A) X-ray diffraction (XRD) patterns of (a) pure LDH and (b) MTX-LDH, (B) and (C) high-resolution transmission electron microscopy (HR-TEM) images of MTX-LDH nanohybrid: (B) high-resolution micrograph, (C) intensity histogram of the area shown in the inset of (B), (D) particle size distribution of MTX-LDH nanohybrid, (E) high-resolution transmission electron microscopy (HR-TEM) image of MTX-LDH nanohybrid, and (F) represents the selected area electron diffraction (SAED) patterns for MTX-LDH nanohybrid.
Figure 2
Figure 2. (A) Quantification of cell death by flow cytometric analysis of PI and Annexin V staining after 72-hr treatment with MTX or MTX-LDH (Data show mean ± S.D.), and (B) biodistribution studies for tumor-to-liver ratio of MTX in MTX()- treated group and MTX-LDH ()-one.
(*p < 0.05, **p < 0.01).
Figure 3
Figure 3. (A) and (B) accumulation of LDH in organs of tumor-bearing mice treated with PBS (control, blue), LDH ( red), MTX ( green), or MTX-LDH ( violet) for 5 weeks (n = 3 for each group).
On the first day after the final treatment, the mice were sacrificed and organs, blood, and tumors were collected for measurement of Mg and Al, the major components of LDH.
Figure 4
Figure 4
(A) Anti-tumor activity of MTX and MTX-LDH in the MCF7/mot orthotopic breast cancer model. PBS (formula image), LDH (formula image), MTX (formula image), and MTX-LDH (X) were administered via intraperitoneal injection on days 0, 7, 14, 21, and 28 (indicated by arrows), and tumor volume was measured using calipers every 2 days. (B) Survival rate of tumor-bearing mice treated as in (A). (*p < 0.05, **p < 0.01).
Figure 5
Figure 5
(A) Histological and immunohistological analysis of tumor tissue sections from MCF-7/mot orthotopic tumor-bearing mice. Representative sections were stained with hematoxylin and eosin (H & E), with antibody specific for proliferating cellular nuclear antigen (PCNA), and by TUNEL staining for apoptotic cells. Original magnification: ×12.5, ×400. (B) Quantification of TUNEL-positive spots in tumor sections of PBS, LDH, MTX, and MTX-LDH-treated groups.
Figure 6
Figure 6. Liver toxicity studies to assess liver damage and enzyme function after drug treatment.
(A) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. (B) Hematoxylin and eosin (H & E) staining of liver tissues.
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