Targeted pharmacokinetics of polymeric micelles modified with glycyrrhetinic acid and hydrazone bond in H22 tumor-bearing mice

Abstract

Liver cancer is one of the most common malignant tumors. Chemotherapy drugs have been widely used in the anti-hepatoma research. However, low targeting efficiency and serious adverse reaction are their main drawbacks. Liver tumor was proved to have a slightly acidic microenvironment (pH 4.5–5.5) and many glycyrrhetinic-acid-specific binding sites. Therefore, in the present study, the glycyrrhetinic acid- and hydrazone bond-modified micelles were designed. mPEG-HZ-PLA and GA-PEG-PLA copolymer were synthesized to prepare glycyrrhetinic-acid-modified pH-sensitive polymeric micelles (GA-PEG-HZ-PLA). The targeted pharmacokinetics was used to evaluate the effect in hepatoma 22 tumor-bearing mice after the micelles were administered intravenously. The contents of coumarin-6 in blood and tissues were determined through high-performance liquid chromatography using a fluorescence detection (HPLC-FLD) with coumarin-30 as inner standard. The micelles have shown long-circulation effects and two-department models. In the targeting pharmacokinetics, the relative intake efficiency, targeted efficiency, relative targeting efficiency, and concentration ratio of GA-PEG-HZ-PLA in the tumor were 3.24, 4.04, 3.00, and 2.47, respectively. We have demonstrated that GA-PEG-HZ-PLA was more effectively accumulated in the liver and tumor. Thus, the prepared active-targeted and pH-sensitive micelles modified with glycyrrhetinic acid structure and hydrazone bond are promising tools for effective liver cancer therapy.

Synergistic effect of doxorubicin lauroyl hydrazone derivative delivered by α-tocopherol succinate micelles for the treatment of glioblastoma

“…Previous results highlighted how C12 chain can enhance the cytotoxicity of drugs in the context of GBM treatment ( Bastiancich et al, 2019 ). The hydrazone-based linking chemistry used to prepare DOXC 12 has been selected due to its easy preparation method, pH sensitivity allowing DOX release without forming a new chemical entity ( Malfanti et al, 2022 ; Zheng et al, 2019 ). Moreover, even though Hao et al developed TPGS 2000 micelles loaded with DOX base, DOXC 12 not only provides higher affinity to the lipophilic core of micelles but also enables DOX release by the breakage of hydrazone bond in acidic pH ( Hao et al, 2015 ).…”

A nano-preparation approach to enable the delivery of daphnoretin to potentiate the therapeutical efficacy in hepatocellular cancer

“…Referring to the literature proportional feeding GA-PEG-PLA block copolymer ( Zheng et al, 2019 ; Pan et al, 2020 ), one-ninth of GA-PEG 3400 -PLA 2000 block copolymer was added to PEG 3400 -PLA 2000 to prepare GPP/PP-DAP according to the result of the Box–Behnken design. Afterward, three samples of PP-DAP and GPP/PP-DAP were prepared in parallel to verify the process.…”

Recent Advances in Glycyrrhetinic Acid-Functionalized Biomaterials for Liver Cancer-Targeting Therapy

“…Hydrazone bonds, formed by the carbonyl group with hydrazine, have an acid-sensitive chemical structure; they are stable under physiological pH conditions but are rapidly hydrolyzed in the slightly acidic microenvironment of hepatoma cells. Zheng and coworkers tested the pharmacokinetics of GA liver-targeted delivery using a pH-sensitive polymeric DDS based on PEG-PLA hydrazone bond-modified micelles (GA-PEG-HZ-PLA) [ 63 ] loaded with coumarin-6 as a fluorescent tracer. The micelles have shown in vivo long-circulation properties and relative intake and targeted efficiency since GA-PEG-HZ-PLA were more successfully accumulated in the liver and tumor in H22 tumor-bearing mice when compared to PEG-PLA and PEG-HZ-PLA.…”