Cell Microenvironment-Controlled Antitumor Drug Releasing-Nanomicelles for GLUT1-Targeting Hepatocellular Carcinoma Therapy

Abstract

In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…DHAA can be specifically recognized by GLUT1 contributing to its structural similarity to d-glucose 133 and rapidly reduced to ascorbic acid (AA) in cells. 134 Therefore, Guo et al 135 developed DHAA-modified PEG-pLys-pPhe nanomicelle for efficient therapy of HCC. The cellular uptake in vitro showed that the internalization of DHAA-modified PEG-pLys-pPhe nanomicelle was significantly enhanced compared with that of PEG-pLys-pPhe …”

Dehydroascorbic Acids-modified Polymer Micelles Target Cancer Cells to Enhance Anti-tumor Efficacy of Paclitaxel

“…These polymeric compounds can be applied for graft-modification, and further used in wide range of applications 33, 34 . The modification of DHA ligands and covalent cross-linked disulfide bonds can not only endow the active targeting for cancer cells and tissues, but also strengthen stability and avoid drugs leaking in the blood circulation, which reduces the toxicity to non-target tissues and increases safety of PTX-loaded polymeric micelles in vivo use simultaneously 27, 35, 36 .…”

Micelles Formed by Polypeptide Containing Polymers Synthesized Via N-Carboxy Anhydrides and Their Application for Cancer Treatment

“…One year later, the same group [54] reported the synthesis of similar polymers featuring the dehydroascorbic acid (DHA) that formed micelles modified with disulfide cross-links for the hepatocellular carcinoma (HCC) treatment. These micelles were consisted of DHA-PEGb-PLL(SS)-b-Phe polymers, in which the amino groups of PLL were crosslinked.…”

“…1 H NMR and SEC analysis revealed that the polymer had the expected molecular weight and low polydispersity index, like its precursor. Stepwise synthesis, GLUT1-mediated endocytosis and GSH-triggered intracellular drug release of DPL(SS)P/DOX micelles [54].…”