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. 2016 Jun 15;6(9):1378-92.
doi: 10.7150/thno.15156. eCollection 2016.

Phenylboronic Acid-Mediated Tumor Targeting of Chitosan Nanoparticles

Xin Wang  1 , Huang Tang  2 , Chongzhi Wang  2 , Jialiang Zhang  2 , Wei Wu  2 , Xiqun Jiang  2
Affiliations

Phenylboronic Acid-Mediated Tumor Targeting of Chitosan Nanoparticles

Xin Wang et al. Theranostics. .

Abstract

The phenylboronic acid-conjugated chitosan nanoparticles were prepared by particle surface modification. The size, zeta potential and morphology of the nanoparticles were characterized by dynamic light scattering, zeta potential measurement and transmission electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using monolayer cell model, 3-D multicellular spheroid model and H22 tumor-bearing mice. The incorporation of phenylboronic acid group into chitosan nanoparticles impart a surface charge-reversible characteristic to the nanoparticles. In vitro evaluation using 2-D and 3-D cell models showed that phenylboronic acid-decorated nanoparticles were more easily internalized by tumor cells compared to non-decorated chitosan nanoparticles, and could deliver more drug into tumor cells due to the active targeting effect of boronic acid group. Furthermore, the phenylboronic acid-decorated nanoparticles displayed a deeper penetration and persistent accumulation in the multicellular spheroids, resulting in better inhibition growth to multicellular spheroids than non-decorated nanoparticles. Tumor penetration, drug distribution and near infrared fluorescence imaging revealed that phenylboronic acid-decorated nanoparticles could penetrate deeper and accumulate more in tumor area than non-decorated ones. In vivo antitumor examination demonstrated that the phenylboronic acid-decorated nanoparticles have superior efficacy in restricting tumor growth and prolonging the survival time of tumor-bearing mice than free drug and drug-loaded chitosan nanoparticles.

Keywords: 3-D multicellular spheroids; Chitosan nanoparticles; antitumor.; phenylboronic acid.

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Conflict of interest statement

Competing Interests: The authors have no competing interests.

Figures

Figure 1
Figure 1
(a) Schematically showing the preparation of CS NPs, PBA-CS NPs, CS-DOX NPs and PBA-CS-DOX NPs; (b) Size distribution of CS NPs, CS-DOX NPs, PBA-CS NPs and PBA-CS-DOX NPs; (c) Zeta potential of CS NPs and PBA-CS NPs at different pH values; (d) and (e) DOX release profiles from CS-DOX NPs and PBA-CS-DOX NPs in PBS (pH 7.4, 6.5 and 5.5) at 37 oC, respectively.
Figure 2
Figure 2
(a) CLSM images of SH-SY5Y cells incubated with DOX, CS-DOX NPs and PBA-CS-DOX NPs for 4 h; (b) CLSM images of H22 cells incubated with DOX, CS-DOX NPs and PBA-CS-DOX NPs for 4 h; (c) CLSM images of HepG2 cells incubated with DOX, CS-DOX NPs and PBA-CS-DOX NPs for 4 h; (d) Cellular uptake of DOX, CS-DOX NPs and PBA-CS-DOX NPs measured by flow cytometry; Scale bar = 10 μm.
Figure 3
Figure 3
In vitro cytotoxicity of CS-DOX NPs and PBA-CS-DOX NPs against SH-SY5Y cells (a), H22 cells (b) and HepG2 cells (c) for 48 h; IC50 of DOX, CS-DOX NPs and PBA-CS-DOX NPs against SH-SY5Y, H22 and HepG2 cells (d).
Figure 4
Figure 4
CLSM images of SH-SY5Y MCS incubated with free DOX (a and b), FITC-labeled CS-DOX NPs (c and d) and FITC-labeled PBA-CS-DOX NPs (e and f), Scale bars = 100 μm.
Figure 5
Figure 5
Area-normalized distribution of free DOX (a), CS-DOX NPs (b) and PBA-CS-DOX NPs (c) in different regions of MCS at different time in 1st and 2nd ( “*” represents 2nd); (d) Area-normalized distribution of FITC-labeled CS-DOX NPs and PBA-CS-DOX NPs in MCS; Data are represented as mean ± SD (n = 3).
Figure 6
Figure 6
(a) Growth inhibition assay in SH-SY5Y MCS. Representative images of MCS treated with PBA-CS NPs, free DOX, CS-DOX NPs and PBA-CS-DOX NPs. MCS cultured in RPMI 1640 medium as a control; Scale bar = 200 μm; (b) SEM images of MCS at Day 7.
Figure 7
Figure 7
(a) The NIRF images of H22 tumor-bearing mice following intravenous injection of NIR-797 labeled CS NPs and PBA-CS NPs, tumor areas were surrounded with dotted lines; Images of various organs at 120 h post-administration. NIR-797 labeled CS NPs (b); NIR-797 labeled PBA-CS NPs (c); The average photon counts measured by Image J in tumor and liver region at different time points post injection (d).
Figure 8
Figure 8
Penetration of FITC-labeled CS NPs and PBA-CS NPs in tumors at 24 h post-administration, Green nanoparticles and red blood vessels show in the images of H22 tumor sections, Scale bar = 100 μm.
Figure 9
Figure 9
Biodistribution of CS-DOX NPs (a) and PBA-CS-DOX NPs (b) in different organs of H22 tumor-bearing mice at various time points after intravenous injection; Data are represented as mean ± SD (n = 3).
Figure 10
Figure 10
(a) In vivo tumor growth curves of H22 tumor-bearing mice that received different treatments. Data are represented as mean ± SD (n = 10); (b) Tumor weight changes of mice after 7-day treatment; (c) image of H22 graft tumors at the end of the treatment; ** represents P < 0.01; * represents P < 0.05.
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