4.6 Article

Size-shrinkable and protein kinase Cα-recognizable nanoparticles for deep tumor penetration and cellular internalization

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ELSEVIER
DOI: 10.1016/j.ejps.2020.105693

Keywords

Enhanced permeability and retention (EPR) effect; Deep tumor penetration; Hyaluronidase (HAase); Glycyrrhetinic acid (GA); Tumor targeting

Funding

  1. National Natural Science Foundation of China Fund [81541060]
  2. Science and Technology Projects from the Science Technology and Innovation Committee of Shenzhen Municipality [JCJY20170818110340383, JCJY2017030 7163529489]

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The study successfully integrated the functions of enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis into a single platform, resulting in the development of DGL-GA-CDA-DOX-HA nanoparticles with improved antitumor efficiency. The pre-degraded nanoparticles showed better penetration in vitro multicellular tumor spheroids compared to untreated nanoparticles.
In the present study, the three functions, including enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis, were integrated into a single platform in order to improve antitumor efficiency. A novel nanoparticle (dendrigraft poly-L-lysine@glycyrrhetinic acid@cyclohexane dicarboxylic anhydride@doxorobicin@ hyaluronic acid composite) has been successfully developed and was denoted as DGL-GA-CDA-DOX-HA. The transmission electron microscope (TEM), dynamic light scattering (DLS), polymer dispersity index (PDI), fourier transform infrared spectrometer (FTIR), and zeta potentials were used to characterize the physicochemical properties of the nanoparticles. According to the results of TEM and DLS, the DGL-GA-CDA-DOX-HA nanoparticles could be rapidly degraded with a size shrink from 182.5 nm to 47.7 nm by hyaluronidase (HAase) added in the medium. The loading amount of DOX reached 252.03 +/- 36.38 mg/g for DGL-GA-CDA-DOX nanoparticles. When the nanoparticles were in a medium with HAase at pH 5.0, the drug quickly released. However, when the nanoparticles were exposed to a medium without HAase at pH 5.0, or a neutral medium containing HAase, drug release slowed down. The modification of GA on nanoparticles significantly enhanced their affinity and cytotoxicity to hepatocellular carcinoma HepG2 cells. The study showed that the penetrability of DGL-GA-CDA-DOX and DGL-GA-CDA DOX-HA nanoparticles pre-degraded by HAase in vitro multicellular tumor spheroids were always better than that of DGL-GA-CDA-DOX-HA nanoparticles untreated by HAase. The imaging in vivo and ex vivo exhibited that DGL-GA-CDA-DOX-HA nanoparticles could preferentially accumulate in the tumor site. Correspondingly, the DGL-GA-CDA-DOX-HA displayed the preferable antitumor efficiency to other experimental groups in H22 tumor-bearing mice, with a tumor inhibition rate of 71.6%. In short, these results suggested that DGL-GA-CDA-DOX-HA nanoparticles could promote therapeutic effects by modulating particle size and GA receptor-mediated endocytosis.

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