Activation of CYP3A by Accelerated Blood Clearance Phenomenon Potentiates the Hepatocellular Carcinoma-Targeting Therapeutic Effects of PEGylated Anticancer Prodrug Liposomes

Abstract

Reduced enzyme activity in hepatocellular carcinoma (HCC) and poor targeting limit the application of enzyme-activating prodrugs, which is also detrimental to the effective treatment of HCC. Here, we investigated whether accelerated blood clearance (ABC) phenomenon occurs in HCC models following repeated injections of PEGylated liposomes (PEG-L), thus inducing prodrugs accumulation and activation in the liver and exerting highly effective and low-toxicity therapeutic effects on HCC. Firstly, PEGylated liposomal cyclophosphamide (PEG-CP-L) was prepared by solvent injection and characterized. Importantly, pre-injection of PEG-L induced ABC phenomenon and activation of CYP3A in both HCC rats and HCC mice by investigating the effects of repeated injections of PEG-L on pharmacokinetics and tissue distribution. Next, the efficacy and toxicity of repeated injections of PEG-L in HCC mice were examined, and our data indicate that repeated injections are administered in a manner that significantly enhances the antitumor effect compared to controls with little or no toxicity to other organs. To further reveal the pharmacokinetic mechanism of PEG-L repeated administration for the treatment of HCC, the protein expression of hepatic CYP3A and the concentration of CP in the liver and spleen of HCC mice by inhibiting CYP3A were analyzed. These results revealed that inducing CYP3A to accelerate the rapid conversion of prodrugs that accumulate significantly in the liver is a key mechanism for the treatment of HCC with repeated injections of PEG-L. Collectively, this work taps into the application potential of the ABC phenomenon and provides new insights into the clinical application of PEGylated nanoformulations.

The application strategy of liposomes in organ targeting therapy

“…Reproduced with permission from Dhawan et al (2022), Copyright 2022, Elsevier. (d) Multiple injections of polyethylene glycol liposomes (PEG‐L) accelerated blood clearance, optimizing the accumulation and activation of drugs in the liver (Zhang, Pan, et al, 2023). Reproduced with permission from Zhang, Pan, et al (2023), Copyright 2023, the Author(s).…”

“…Additionally, agarose‐based ligands and FZD1 antibodies were also modified on the surface of liposomes to efficiently deliver drugs to the liver (Figure 2c) (Dhawan et al, 2022; Negro et al, 2023). Multiple injections of polyethylene glycol liposomes (PEG‐L) accelerated blood clearance, increasing drug accumulation and activation in the liver, thereby amplifying the therapeutic efficacy of the drug in hepatocellular carcinoma (Zhang, Pan, et al, 2023).…”