Nanoparticle-Based Therapeutics to Overcome Obstacles in the Tumor Microenvironment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is still a main health concern around the world, with a rising incidence and high mortality rate. The tumor-promoting components of the tumor microenvironment (TME) play a vital role in the development and metastasis of HCC. TME-targeted therapies have recently drawn increasing interest in the treatment of HCC. However, the short medication retention time in TME limits the efficiency of TME modulating strategies. The nanoparticles can be elaborately designed as needed to specifically target the tumor-promoting components in TME. In this regard, the use of nanomedicine to modulate TME components by delivering drugs with protection and prolonged circulation time in a spatiotemporal manner has shown promising potential. In this review, we briefly introduce the obstacles of TME and highlight the updated information on nanoparticles that modulate these obstacles. Furthermore, the present challenges and future prospects of TME modulating nanomedicines will be briefly discussed.

Keywords: hepatocellular carcinoma; immunosuppression; nanoparticles; tumor microenvironment.

Figure 1

Schematic of the obstacles and their crosstalk in the dynamic TME of HCC. Complex connections affect the growth of HCC and hinder the immune system’s ability to fight it by promoting the activation of immune cells with immunosuppressive qualities. The growth and progression of HCC induce tumor abnormal vasculature and hypoxia, which negatively impacts the infiltration of immune cells and impairs host immunity. Immune suppressive cell types in the TME (MDSC, regulatory Tregs, and M2-TAM) secrete factors that establish immune tolerance to block cancer cell destruction. HCC: hepatocellular carcinoma; TME: tumor microenvironment; CAFs: cancer-associated fibroblasts; ECM: extracellular matrix; TAM: tumor-associated macrophages; MDSC: myeloid-derived suppressor cells; Tregs: regulatory T cells; GM-CSF: granulocyte-macrophage colony-stimulating factor; IL-6: interleukin-6; TGF-β: transforming growth factor-β; IFN-γ: Interferon-γ; HIF: hypoxia-inducible factor; VEGF: vascular endothelial growth factor; IFG-2: insulin-like growth factor-2; ANG-1: angiopoietin-1.

Figure 2

(A) Schematic illustration of synthesis procedure of SO/siVEGF@MSN-LA NPs and (B) inhibiting effect on the proliferation of cancer cells. MSN: mesoporous silica nanoparticles; SO: sorafenib; LA: lactobionic acid; siVEGF: vascular endothelial growth factor small interfering RNA. (Copyright © 2017 Elsevier B.V. All rights reserved, https://doi.org/10.1016/j.ejps.2017.10.036).

Figure 3

MMF-LA@DSPE-PEG inhibited HCC growth by depleting CAF. Mice were orally administrated with free MMF (20 mg/kg) or intravenously injected with MMF-LA NPs (at 20 mg/kg MMF-equivalent dose) every other day four times. (A), Tumor images of different groups, (n = 6). (B), Tumor growth curves of different groups, ** p < 0.01. (C), Tumor inhibition rates of different treatments. (n = 6), ** p < 0.01, *** p < 0.001. (D), Bodyweights (mean ± SD, n = 6) of mice in different groups. (E), Expression levels of α-SMA, FAP, collagen IV, and CD31 determined by Immunohistochemistry. The scale bars: 200 µm. (F), Quantitative analysis of panel E (Image J software), data are shown as the mean ± SD, (n = 3), ** p < 0.01, *** p < 0.001. MMF-LA: Mycophenolate mofetil-linoleic acid; DSPE-PEG: 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly (ethylene glycol); CAF: cancer-associated fibroblast; α-SMA: alpha-smooth muscle actin; FAP: fibroblast activation protein. (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://doi.org/10.1111/jcmm.16434).

Figure 4

Schematic representation of the mechanism of immunogene therapy by TT-LDCP NPs containing siRNA against the immune checkpoint PD-L1 and Pdna encoding the immunostimulating cytokine IL-2. Active tumor targeting was achieved through the addition of the HCC-targeted SP94 peptide to the surface of the NPs.