Decoration of pH-sensitive copolymer micelles with tumor-specific peptide for enhanced cellular uptake of doxorubicin

Abstract

To improve the targeting efficacy of hyaluronic acid (HA)-based micelles, pH-sensitive mixed micelles based on HA-g-poly(L-histidine) (PHis) and d-α-tocopheryl polyethylene glycol 2000 copolymers were prepared and decorated with human epidermal growth factor receptor 2 (Her2) peptide, a tumor cell-specific peptide ligand, on their surface. The doxorubicin-loaded micelles (HA-PHis/peptide–d-α-tocopheryl polyethylene glycol 2000 mixed micelles [PHTM]) were characterized to have a unimodal size distribution and pH-dependent drug release pattern. In vitro tumor targeting studies demonstrated that PHTM exhibited the pronounced cytotoxicity and efficient internalization in MDA-MB-231 cells overexpressing CD44 and Her2 receptors. In vivo investigation into micelles in MDA-MB-231 tumor-bearing mice confirmed that PTHM could reach the tumor site more effectively and exert excellent tumor killing activity. In general, Her2 peptide decoration can enhance the selective cytotoxicity and antitumor activity of HA-based micelles.

<p>Cellular uptake, intracellular distribution and degradation of Her2-targeting silk nanospheres</p>

“…Our results are consistent with research by Chen et al, which used specific inhibitors of endocytosis to assess the cellular uptake of micelles decorated with the same Her2-binding peptide. 30 The receptor-mediated endocytosis, both clathrin-and caveola-mediated, is the predominant pathway of micelle entry into cells. 30 Moreover, Chen et al indicated that macropinocytosis was not closely involved in the internalization of these particles.…”

“…30 The receptor-mediated endocytosis, both clathrin-and caveola-mediated, is the predominant pathway of micelle entry into cells. 30 Moreover, Chen et al indicated that macropinocytosis was not closely involved in the internalization of these particles. 30 EGF receptors utilize multiple endocytotic pathways, possibly depending upon the ligand type and its concentration in the extracellular milieu.…”

“…30 Moreover, Chen et al indicated that macropinocytosis was not closely involved in the internalization of these particles. 30 EGF receptors utilize multiple endocytotic pathways, possibly depending upon the ligand type and its concentration in the extracellular milieu. 31 At a low concentration of ligand, the EGF-type receptors are internalized through clathrin-dependent endocytosis, and at high ligand concentration, a caveola-dependent endocytotic pathway is also used.…”

Design of Soft Nanocarriers Combining Hyaluronic Acid with Another Functional Polymer for Cancer Therapy and Other Biomedical Applications

“…Poly(amino acids) are the most common enzymatically degradable polymers which are conjugated to HA for the fabrication of nanocarriers [28,29,30,35,57,58,59,60]. Lecommandoux et al used poly(benzyl- l -glutamate) (PBLG) for the synthesis of HA-based polymersomes (Figure 3) with a size around 200 nm to convey different chemotherapeutic drugs such as DOX [29,30] and docetaxel (DOC) [28], with a high drug loading capacity (see Table 1).…”

Polymer-Based Nanocarriers for Co-Delivery and Combination of Diverse Therapies against Cancers

“…According to the enhanced permeability and retention (EPR) effect, nanocarriers have passive targeting property (tend to enter tumors from irregular microvasculature and stay there for a longer period than small molecule drugs) [ 42 , 43 ]. Equipped with targeting ligands, nanocarriers are imparted with active targeting property (tend to actively accumulate in specific tumor tissues), reducing systematic toxicity and enhancing therapeutic effects [ 44 , 45 ]. Moreover, if triggered by external stimuli within tumor tissues or cells, nanocarriers may release the loaded drugs, directly exerting antitumor effects [ 43 , 46 ].…”