Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis

Abstract

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H 2 O 2 - and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H 2 O 2 and pH-responsive properties by coupling a wide range of drugs containing o -diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

Dual‐Responsive Nanogels with Cascaded Gentamicin Release and Lysosomal Escape to Combat Intracellular Small Colony Variants for Peritonitis and Sepsis Therapies

“…The intrinsic fluorescence of phenylboronic acid would be quenched after reacting with catechol groups. [ 23 ] As shown in Figure 1g, the fluorescence quenching became more significant with the increase of tannic acid contents, indicating the successful formation of phenylboronic esters. In addition, phenylboronic acid mostly reacted with the outer catechol groups of tannic acid due to the existence of steric hindrance for the inner groups.…”

“…The binding behavior between pba‐ePL and tannic acid was monitored from fluorescence quenching of phenylboronic acid moieties by fluorescence spectrophotometry (Hitachi F‐7000, Japan). [ 23 ] The GEN loading level in mHA NPs was examined after incubation in pH 3.0 buffers to totally release GEN, and the released GEN was mixed with ortho‐phthalaldehyde to obtain GEN derivatives, which was determined by UV–vis spectrophotometry (Shimadzu UV‐2550, Japan) at 330 nm. [ 45 ] To detect the respective G1 and G2 levels, NG@G1‐mHA G2 NGs were degraded after incubation with H 2 O 2 (5 mM) to release G1 and mHA G2 NPs, and then the mHA G2 NPs were incubated with pH 3.0 buffers to release G2.…”

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

“…[185] Inhibition of mTOR signaling and accelerating mitochondrial depolarization increase mitophagy as well. [207,208] The engineered IL-10-loaded EVs (IL-10 + EVs) from macrophages could protect the tubular from ischemia injury by inducing mitophagy via suppressing rapamycin signaling to preserve mitochondrial function. Simultaneously, IL-10 + EVs efficiently drove M2 macrophage polarization in the tubulointerstitium for tissue repair as a synergetic measure to counteract AKI.…”

“…Alda-1 loaded N-alkyl-O-HTCC micelles [ 301] Positive charge -221 ± 3.70 45.6 ± 0.64 Alda-1; Chitosan Renal fibrosis CeNP-PEG [302] --12.73 ± 1.32 -9.00 ± 0.66 Ceria NPs Acute liver injury SIL/BSA NPs [ 316] --9 0 ± 29 -Silibinin APAP-induced liver injury TSCs [57] -Tannic acid ≈50 −11.28 SOD; CAT Drug-induced hepatitis cPBA-BE [208] TBI H 2 O 2 and pH response ≈100 -Baicalein…”

Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury

“…Studies have shown that ruthenium nanoparticles with antioxidant activity can be exploited to treat APAP-induced ALI ( Xia et al, 2022 ). In addition, nanoparticles formed by coupling cyclic phenylboronic acid with baicalein can target the liver for efficacious treatment of hepatitis ( Zhang et al, 2021 ). Although those novel nanomedicines show excellent liver-targeting properties and good therapeutic effects, their safety and toxic effects merit further evaluation ( Zhao and Castranova, 2011 ).…”