Tumor Microenvironment Triggered Cascade‐Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NP Lap/TPZ ) is prepared based on -lapachone ( -Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NP Lap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H 2 O 2 -triggered disassembly to release -Lap and TPZ. The released -Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NP Lap/TPZ nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

“…Due to the particular redox potential properties of quinone compounds, they can produce semiquinones or hydroquinones via one or two-electron reduction, respectively [ 328 ]. For example, the elimination of indolequinones can be achieved under hypoxic environments with the aid of the DT-diaphorase NQO1, which is overexpressed in various cancer cells and plays a crucial role in bioreduction [ 329 , 330 ]. Taking advantage of this property, Tanabe et al [ 331 ] designed 19 F nuclear magnetic resonance (NMR) monitor nanoprobes to detect the biological reduction effects of indolequinones.…”

Tailored Beta‐Lapachone Nanomedicines for Cancer‐Specific Therapy

“…Xin et al encapsulated LAP and tirapazamine (TPZ) in an aptamer-targeted hybrid polymer lipid nanocarrier for liver cancer treatment. [117] The action of LAP in terms of ROS production would consume oxygen and increase the degree of hypoxia. Under hypoxic conditions, TPZ was reduced, forming •OH and benzotriazinyl radical, followed In contrast, the neutral pH in normal cells enabled the decomposition of H 2 O 2 by nanozyme to prevent the cytotoxicity of LAP.…”

“…[116] Xin et al conjugated a targeting aptamer (TLS11a) with a lipid (DSPE-PEG-N 3 ) via the click chemistry and co-assembly of the targeting lipid together with an amphiphilic polymer produced a hybrid micelle that showed enhanced cellular uptake and tumor treatment in a liver cancer model. [117] Likewise, the AS1411 aptamer was utilized to aid the targeting of LAP-loaded paclitaxelzidovudine conjugate micelles to B16 cells. [95] Liu et al employed folate to modify the surface of a red blood cell membrane-coated hybrid nanocarrier, resulting in the enhanced efficacy of LAP in a 4T1 tumor model because of the active targeting.…”

Emerging Strategies in Stimuli-Responsive Prodrug Nanosystems for Cancer Therapy

“…N-Oxide is one of the most extensively studied hypoxia-responsive structures; until now, more than 30 kinds of N-oxide compounds have been developed as HAPs. Among them, the most representative cases are tirapazamine (TPZ) 99 and banoxantrone (AQ4N). 100 To increase their tumor availability, current studies focus on delivering them through specially designed nanovehicles.…”