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. 2018 Jul 27:13:4379-4389.
doi: 10.2147/IJN.S142668. eCollection 2018.

Folic acid-conjugated mesoporous silica nanoparticles for enhanced therapeutic efficacy of topotecan in retina cancers

Wei Qu  1 , Bo Meng  1 , Yangyang Yu  2 , Shaowei Wang  1
Affiliations

Folic acid-conjugated mesoporous silica nanoparticles for enhanced therapeutic efficacy of topotecan in retina cancers

Wei Qu et al. Int J Nanomedicine. .

Abstract

In this study, topotecan-loaded mesoporous silica nanoparticles were prepared and surface conjugated with folic acid (FTMN) to enhance the therapeutic efficacy of topotecan for the treatment of retinoblastoma (RB) cancers. The particles were nano-sized and exhibited a sustained release of drug in the physiological conditions. The folic acid-conjugated nanoformulations exhibited a remarkable uptake in RB cells compared to that of non-targeted nanoparticles. These results clearly indicate that receptor-mediated endocytosis is the mechanism of cellular internalization. The greater cellular uptake of FTMN resulted in significantly higher cytotoxic effect in Y79 cancer cells compared to that of other formulations. The results were well corroborated with the live/dead assay and nuclear fragmentation assay. FTMN consistently induced apoptosis of cancer cells with an efficiency of ~58%. Our results clearly showed that nanoparticulate encapsulation of TPT exhibited superior anticancer efficacy in Y79 cancer cells compared to that of free drug or non-targeted nanoparticles. As expected, FTMN exhibited a remarkable reduction in the overall tumor volume compared to any other group with less presence of tumor cells in histology staining. Overall, folic acid-conjugated nanoparticulate system could provide an effective platform for RB treatment.

Keywords: anticancer effect; apoptosis; mesoporous silica nanoparticles; retinoblastoma; topotecan.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic presentation of preparation of folic acid-conjugated mesoporous silica nanoparticles loaded with topotecan. Abbreviation: FA, folic acid.
Figure 2
Figure 2
(A) TEM image of FTMN; (B) In vitro release profile of TPT from TMN and FTMN. The release study was performed in physiological media under 37°C. Abbreviations: TEM, transmission electron microscopy; TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid.
Figure 3
Figure 3
In vitro cellular uptake study of TMN and FTMN in Y79 cancer cells. The cellular uptake was studied by flow cytometer. Abbreviations: PE-A, phycoerythrin; TPT, topotecan; TMN, TPT-loaded mesoporous silica nano particles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid.
Figure 4
Figure 4
Colocalization of TMN and FTMN in Y79 cancer cells. The study was performed by CLSM. Scale bar: 20 µm. Abbreviations: CLSM, confocal laser-scanning microscopy; DAPI, 4′, 6-diamidino-2-phenylindole; TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid; Rho-B, Rhodamine B.
Figure 5
Figure 5
(A) Cytotoxicity analysis of blank nanoparticles; (B) In vitro cytotoxicity of blank NP, TPT, TMN, and FTMN in Y79 cancer cells after 24 h incubation. The cells were treated with respective formulations studied using MTT assay. Abbreviations: NP, nanoparticle; TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid.
Figure 6
Figure 6
Hoechst 33342 based nuclear staining of Y79 cancer cells. The assay was performed by fluorescence microscopy.
Figure 7
Figure 7
(A) Morphological imaging of Y79 cancer cells after treatment with TPT, TMN, and FTMN; (B) live dead assay of Y79 cancer cells after treating with respective formulations. Abbreviations: TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid.
Figure 8
Figure 8
Induction of apoptosis in Y79 cancer cells by treatment with TPT, TMN, and FTMN. The cells were treated with respective formulations and stained with Annexin V and PI. Abbreviations: PE-A, phycoerythrin; TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid; PI, propidium iodide; FITC, fluorescein isothiocyanate.
Figure 9
Figure 9
In vivo antitumor efficacy analysis in animal mode. (A) tumor volume and (B) H&E staining. Abbreviations: TPT, topotecan; TMN, TPT-loaded mesoporous silica nanoparticles; FTMN, TPT-loaded mesoporous silica nanoparticles surface conjugated with folic acid.
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