Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy

doi:10.1016/j.nano.2016.11.012

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 13, Issue 3, April 2017, Pages 987-998

https://doi.org/10.1016/j.nano.2016.11.012 Get rights and content

Abstract

Designing active targeting nanocarriers with increased cellular accumulation of chemotherapeutic agents is a promising strategy in cancer therapy. Herein, we report a novel active targeting strategy based on the large amino acid transporter 1 (LAT1) overexpressed in a variety of cancers. Glutamate was conjugated to polyoxyethylene stearate as a targeting ligand to achieve LAT1-targeting PLGA nanoparticles. The targeting efficiency of nanoparticles was investigated in HeLa and MCF-7 cells. Significant increase in cellular uptake and cytotoxicity was observed in LAT1-targeting nanoparticles compared to the unmodified ones. More interestingly, the internalized LAT1 together with targeting nanoparticles could recycle back to the cell membrane within 3 h, guaranteeing sufficient transporters on cell membrane for continuous cellular uptake. The LAT1 targeting nanoparticles exhibited better tumor accumulation and antitumor effects. These results suggested that the overexpressed LAT1 on cancer cells holds a great potential to be a high-efficiency target for the rational design of active-targeting nanosystems.

Graphic Abstract

Large amino acid transporter 1 highly expressed in tumor cells is selected as a novel target for tumor active-targeting nanoformulation. Glutamate modified LAT1 targeting nanoparticles significantly improve the cytotoxicity, cellular uptake and in vivo antitumor effects. Recycled LAT1 guarantee sufficient transporters on cell membrane for continuous cellular uptake. LAT1 holds a great potential to be used as a high-efficiency target for the rational design of active-targeting nanosystems.

Section snippets

Materials

Polyoxyethylene stearate 10 and 25 (SP₁₀, SP₂₅) were purchased from Aladdin (Shanghai, China). Polyoxyethylene stearate 40 (SP₄₀), coumarin-6 (C6) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma (St. Louis, MO, USA). N-carbobenzyloxy-glutamate-α-benzyl ester (Z-Glu-Obzl) was gained from GL Biochem Ltd. (Shanghai China). Poly (lactic-co-glycolic acid) (PLGA, lactide:glycolide = 75:25, Mw 38,000) was purchased from Daigang Biomaterial Co., Ltd.

Synthesis of SPG_n

The synthetic scheme of glutamate-modified polyoxyethylene stearate copolymers (SPG_n) is presented in Figure 1S. The chemical structures of SPG_n were confirmed by ¹H -NMR and the spectrum of SPG₁₀ is shown in Figure 2. The peaks of both glutamate and SP₁₀ in Figure 2, D proved successful synthesis of SPG₁₀. The detailed analysis of ¹H -NMR spectra is exhibited in SI.

Characterizations of SPG_n PTX NPs

Paclitaxel-loaded SPG_n decorated PLGA nanoparticles (SPG_n PTX NPs) were prepared by the emulsion solvent evaporation method. The

Discussion

More and more attention is paid to developing new targets for tumor treatment because the types of receptors expressed in tumor cells are limited and ligands are certainly unstable in vivo. In comparison, simple amino acids modifications are enough to satisfy amino acid transporters targeting, and the amino acids are stable in vivo and have no steric hindrance. In this work, large amino acid transporter 1 highly expressed in tumors is selected as the target. Then glutamate modified PLGA

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: Support information: This work was supported by the National Nature Science Foundation of China (No. 81273450, 81373336, 81473164), by the National Basic Research Program of China (973 Program), No. 2015CB932100, and by the Program for New Century Excellent Talents in University (No. NCET-12-1015).

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Original ArticleTargeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy

Abstract

Graphic Abstract

Section snippets

Materials

Synthesis of SPGn

Characterizations of SPGn PTX NPs

Discussion

Bioconjug Chem

Adv Drug Deliv Rev

Cancer Lett

Biomaterials

Biomaterials

Biochim Biophys Acta

Mol Aspects Med

J Biol Chem

Cancer Lett

Biomaterials

Acta Biomater

Biomaterials

Biomaterials

J Control Release

Adv Drug Deliv Rev

Original Article
Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy

Synthesis of SPG_n

Characterizations of SPG_n PTX NPs