Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and one of the leading causes of cancer-related death worldwide. Advanced HCC displays strong resistance to chemotherapy, and traditional chemotherapy drugs do not achieve satisfactory therapeutic efficacy. Sorafenib is an oral kinase inhibitor that inhibits tumor cell proliferation and angiogenesis and induces cancer cell apoptosis. It also improves the survival rates of patients with advanced liver cancer. However, due to its poor solubility, fast metabolism, and low bioavailability, clinical applications of sorafenib have been substantially restricted. In recent years, various studies have been conducted on the use of nanoparticles to improve drug targeting and therapeutic efficacy in HCC. Moreover, nanoparticles have been extensively explored to improve the therapeutic efficacy of sorafenib, and a variety of nanoparticles, such as polymer, lipid, silica, and metal nanoparticles, have been developed for treating liver cancer. All these new technologies have improved the targeted treatment of HCC by sorafenib and promoted nanomedicines as treatments for HCC. This review provides an overview of hot topics in tumor nanoscience and the latest status of treatments for HCC. It further introduces the current research status of nanoparticle drug delivery systems for treatment of HCC with sorafenib.

Keywords: Hepatocellular carcinoma; Nanomaterials; Nanomedicine.; Nanoparticles; Sorafenib.

Figure 1

Research directions in the development of SOR-NPs for HCC. (Top left) Improving the biocompatibility of SOR using various nanocarriers. (Top right) Modification methods to increase the targeting and responsiveness of SOR-NPs. (Bottom) Enhancing treatment efficacy through combination therapies. HCC: hepatocellular carcinoma; PDT: photodynamic therapy; PEG: Polyethylene glycol; PLGA: poly (lactic-co-glycolic acid); PTT: photothermal therapy; NLC: nanostructured lipid carriers; NP: nanoparticle; SLN: solid lipid nanoparticles; SOR: sorafenib.

Figure 2

Structures of polymer SOR-NPs for targeted treatment of HCC. MRI: magnetic resonance imaging.

Figure 3

Structures of silica SOR-NPs modified with surface groups for targeted delivery and pH-responsive drug release in HCC. CS: sensitive chitosan; LA: lactic acid; MSN: mesoporous silica nanoparticles; NH2: amino; VEGF: vascular endothelial growth factor.

Figure 4

Structures of SOR-LBNPs for targeted treatment of HCC. LBNP: lipid-based nanoparticle.

Figure 5

CXCR4-targeted lipid-coated PLGA NPs loaded with SOR and AZD6244 for targeted treatment of HCC. (A) Confocal microscopy images of NP uptake by activated HCC cells. (B) Quantification of (A). (C) The NPs prevented spontaneous development of HCC. (D) Schematic of the structure and mechanisms of action of the NPs. SOR increases TAMs infiltration and tumor metastasis, while NPs reduces TAMs infiltration and metastasis in the tumor microenvironment. (E) In vitro cellular uptake of the NPs in HCC cells and HUVECs. (F) The NPs achieved potent tumor growth inhibition. AZD6244: selumetinib; C6: coumarin 6; CTCE9908: CXCR4 antagonist; CXCR4: C-X-C chemokine receptor type 4; DOP: 1,2-dioleoyl-sn-glycero-3-phosphocholine; DSPE: distearoyl phosphatidylethanolamine; TAM: tumor-associated macrophage. Adapted with permission from , copyright 2018, Ivyspring International Publisher and , copyright 2017, Nature Publishing Group.

Figure 6

Co-delivery of SOR and metapristone in PLGA-PEG NPs for synergistic treatment of HCC. (A) Synthesis scheme and proposed mechanism of action. SOR up-regulates the expression of CXCR4 and SDF-1, while Meta and LFC131 increase tumor cell apoptosis by inhibiting CXCR4 and SDF-1. (B) Cumulative drug release profile. (C) Colony formation assay of SMMC-7721 cells. (D) Confocal microscopy images of the intracellular distribution of coumarin 6 (green) in SMMC-7721 cells after 2 h incubation with the indicated formulations. Nuclei were stained with DAPI (blue). (E) Tumor volumes and weights from the start of treatment to the endpoint. AKT: protein kinase B; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell leukemia/lymphoma 2; DAPI: 4',6-diamidino-2-phenylindole; LFC131: a peptide inhibitor of CXCR4; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ERK: extracellular regulated protein kinases; MAPK: mitogen-activated protein kinase; Meta: metapristone; NHS: N-hydroxysuccinimide; PARP: poly ADP-ribose polymerase; SDF-1: stromal cell-derived factor-1. Adapted with permission from , copyright 2019, BioMed Central.

Figure 7

Lactosylated pH-responsive nanoparticles for co-delivery of SOR and curcumin. (A) Reaction scheme and 1H NMR spectrum of the NPs. (LAC, lactobionic acid; ADH, adipic acid dihydrazide). (B) TEM images of the NPS with and without lactosylation, revealing their different morphologies (CCM, curcumin). (C, D) Cumulative release of SOR and CCM in vitro. (E) Antitumor activity of the indicated NPs in a subcutaneous tumor model. ADH: adipic acid dihydrazide; CCM: curcumin; CHO: cyclohexanone oxime; LAC: lactobionic acid; NMR: nuclear magnetic resonance; PCL: polycaprolactone; TEM: transmission electron microscope. Adapted with permission from , copyright 2020, Dove Medical Press Ltd.

Figure 8

NPs encapsulating SOR, SPIONs, and Cy7-Hex for induction of lipid hydroperoxides and ferroptosis in therapy-resistant cancer. (A) Schematic illustration of the preparation of the NPs. (B) TEM images of the disassembling self-assembled NPs after incubation with 10 mM GSH for 0 h, 2 h, 8 h and 12 h. (C) Hysteresis loops of SPIONs and the NPs in self-assembly solution. (D) Confocal microscopy images of the NPs after pretreatment with 1 mM N-ethylmaleimide (NEM) and 10 mM GSH. (E) TEM image of 4T1 cells treated with the NPs for observation of ferroptosis. i-v. The mitochondria seemed smaller than normal with increased membrane density and decreased or absent mitochondrial ridges. (F) Immunofluorescence images of GPX-4 in 4T1 tumor tissues after treatment with the indicated NPs. (scale bar, 5 μm). (G) Tumor volumes from the start of treatment to the endpoint. CSO: chitosan oligosaccharide; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethyl formamide; GPX-4: glutathione peroxidase 4; GSH: glutathione; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NEM: N-ethylmaleimide; POCl3: phosphorus oxychloride; SPION: superparamagnetic iron oxide nanoparticle; Srfn: sorafenib. Adapted with permission from , copyright 2019, Ivyspring International Publisher.

Figure 9

siGRP78-modified exosomes for the suppression of SOR resistance in HCC. (A) Transwell assay showing that the combination treatment inhibited the invasion ability of SOR-sensitive and -resistant cells. (B) MTT assay showing that the growth of HepG2 and PLC cells was inhibited by siGRP78-modified exosomes with or without SOR. (C) Tumor size in a subcutaneous model after the indicated treatments (control, SOR, Exo-scramble siRNA + SOR, and Exo-siGRP78 + SOR). (D) Metastasis of SOR-resistant cancer cells after the indicated treatments (control, SOR, Exo-scramble siRNA + SOR, and Exo-siGRP78 + SOR). GRP78: glucose-regulated protein, 78kDa; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide; PBS: phosphate buffer saline; SR: sorafenib resistant. Adapted with permission from , copyright 2018, BioMed Central.