Mussel-Inspired Hyaluronic Acid Derivative Nanostructures for Improved Tumor Targeting and Penetration.

An amphiphilic hyaluronic acid-ceramide-dopamine (HACE-d) conjugate was prepared, and HACE-d-based nanoparticles (NPs) including phloretin (as an inhibitor of glucose transporter (GLUT1)) were fabricated. Mussel-inspired property of d was introduced to HACE NPs, and it may improve tumor targetability and penetration in addition to passive (based on enhanced permeability and retention effect) and active (interaction between HA and CD44 receptor) tumor targeting effects. HACE-d/phloretin NPs with 279 nm mean diameter, ∼0.2 polydispersity index, and -18 mV zeta potential were successfully fabricated, and a sustained drug release pattern was observed. HACE-d/phloretin NPs exhibited enhanced cellular accumulation efficiency and antiproliferation property, compared with HACE/phloretin NPs, in MDA-MB-231 cells (GLUT1 and CD44 receptor-expressed human breast adenocarcinoma cells). In a MDA-MB-231 spheroid model, HACE-d NPs group showed better tumor penetration efficiency and spheroid growth inhibitory effect rather than HACE NPs group. According to the optical imaging test in MDA-MB-231 tumor-xenografted mouse, HACE-d NPs group exhibited more selective distribution in tumor region and deeper infiltration into the inner part of tumor compared with HACE NPs group. After intravenous injection, HACE-d/phloretin NPs group also exhibited improved antitumor efficacies rather than the other experimental groups in MDA-MB-231 tumor-xenografted mouse. All these findings suggested that HACE-d/phloretin NP may be a promising tumor targetable and penetrable nanosystem for the therapy and imaging of GLUT1 and CD44 receptor-expressed cancers.