Polymeric nanomedicines for the treatment of hepatic diseases

Abstract

The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.

Keywords: Hepatic fibrosis; Hepatitis B virus; Hepatocellular carcinoma; Host-versus-graft disease; Liver targeting; Nonalcoholic steatohepatitis; Polymeric nanomedicines.

Fig. 1

Scheme illustrating the application of polymeric nanomedicines in the treatment of various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and host-versus-graft disease

Fig. 2

Structural illustration of polymer-based nanoplatforms. a Polymer conjugates, b dendrimers, c nanogels, d micelles, e nanocapsules, and f lipid-polymer hybrid nanoparticles

Fig. 3

Structure of the liver. a The blood and bile systems of the liver. b The hepatic lobule is a functional and structural unit of the liver. c The hepatic sinusoid is the main area of material exchange in the liver

Fig. 4

List of specific receptors expressed on different liver cell types

Fig. 5

Strategies for targeting nanomedicines loaded with various cargoes to the liver. Nanomedicines first enter the liver by passive targeting, and then are internalized by liver cells through ligand-mediated endocytosis (active targeting)

Fig. 6

A Schematic illustration of Nifedipine nanoparticles (NFD-NPs) for preventing NAFLD. B NFD-NPs alleviate high-fat diet (HFD)-induced obesity and hepatic steatosis. C and D NFD-NPs improve insulin sensitivity and glucose tolerance. (Reprinted with permission from Ref. [105], Copyright 2019, Elsevier Ltd)

Fig. 7

A Schematic illustration showing the preparation of polymeric micelles and their proposed destinations in vivo. B Cellular uptake of polymeric micelles through anti-collagen I barrier activity in vitro. C Fluorescence intensity in the liver of normal mice and mice treated with CCl4 for 4 weeks, expressed as average radiant efficiency units. D Colocalization of DiI and DiI-labelled polymeric micelles with activated HSCs in the liver of fibrotic mice. (Reprinted with permission from Ref. [165], Copyright 2019, Elsevier Ltd)

Fig. 8

A Preparation of GC-FU/miR-122 and hepatoma-targeted codelivery of miR-122 and 5-Fu. B Viability of HepG2 cells after incubation with various treatment constructs. C The expression of Bcl-2 and ADAM17 in the HepG2 cells and quantitative analysis. (Reprinted with permission from Ref. [184], Copyright 2019, American Chemical Society)

Fig. 9

Proposed elimination mechanism of biodegradable nanoparticle (NP) in the liver. Intravenously injected NPs enter the liver and into hepatic sinusoids. A Kupfer cells (KCs) take up the majority of circulating NPs on the basis of NP size. B NPs can escape from KCs. C, D NPs that are smaller than the diameter of liver sinusoidal fenestrations (up to 100–200 nm) can enter the space of Disse through LSECs or fenestrations. E NPs then collect in the space of Disse, where hepatocytes slowly internalize and process them for transport into the bile canaliculus. F Larger NPs may not be able to enter fenestrations or access by LSECs and thus continue to circulate throughout the body. (Reprinted with permission from Ref. [200], Copyright 2019, American Chemical Society)