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. 2019 Aug 9:14:6425-6437.
doi: 10.2147/IJN.S211981. eCollection 2019.

Dual targeting curcumin loaded alendronate-hyaluronan- octadecanoic acid micelles for improving osteosarcoma therapy

Yanhai Xi #  1 , Tingwang Jiang #  2 , Yinglan Yu  3 , Jiangmin Yu  1 , Mintao Xue  1 , Ning Xu  1 , Jiankun Wen  1 , Weiheng Wang  1 , Hailong He  1 , Yan Shen  3 , Daquan Chen  4 , Xiaojian Ye  1 , Thomas J Webster  5
Affiliations

Dual targeting curcumin loaded alendronate-hyaluronan- octadecanoic acid micelles for improving osteosarcoma therapy

Yanhai Xi et al. Int J Nanomedicine. .

Abstract

Introduction: Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity.

Methods: The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied.

Results: The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR.

Conclusion: The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.

Keywords: alendronate; curcumin; hyaluronic acid; osteosarcoma.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic representation for the synthesis of (A) hyaluronic acid-octadecanoic acid (HA-C18) and (B) alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18).
Figure 2
Figure 2
1H NMR spectrum of (A) hyaluronic acid (HA) and (B) alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18).
Figure 3
Figure 3
Plots of I1/I3 against the logarithim of the ALN-HA-C18 concentration.
Figure 4
Figure 4
The size distribution (A) and transmission electron microscopy (TEM) image (B) of CUR loaded ALN-HA-C18 micelles. (C) In vitro release characteristics of free CUR and CUR loaded ALN-HA-C18 micelles in 1% Tween 80 PBS medium. (D) Binding ratio of CUR, CUR loaded HA-C18 micelles, and CUR loaded ALN-HA-C18 micelles with hydroxyapatite. Data are presented as the mean ± SD (n=3). ***Significant difference between the two groups (***P＜0.001).
Figure 5
Figure 5
In vitro cytotoxicity of blank ALN-HA-C18 micelles, free CUR, and CUR loaded ALN-HA-C18 micelles against HOB cells (A) and MG-63 osteosarcoma cells (B). Fluorescence microscope images (C) and flow cytometry analysis (D) of MG-63 cells incubated with free C6, C6 loaded ALN-HA-C18 micelles with HA and C6 loaded ALN-HA-C18 micelles. Data are presented as the mean ± SD (n=6). *, ** and *** represent P＜0.05, P＜0.01 and P＜0.001, respectively. The bar is 50 μm.
Figure 6
Figure 6
The in vivo antitumor activity of CUR loaded ALN-HA-C18 micelles on osteosarcoma bearing nude mice. (A) Tumor volume changes; and (B) body weight changes. (C) The hematoxylin and eosin (H&E) staining of the heart, liver, spleen, lung and kidney in saline and CUR loaded ALN-HA-C18 micelles group after treatment. Data are presented as the mean ± SD (n=6). *Represents P＜0.05. Bars =100 μm.
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