Hyaluronic Acid-Modified Micelles Encapsulating Gem‑C₁₂ and HNK for Glioblastoma Multiforme Chemotherapy

Glioblastoma multiforme (GBM), a prevalent brain cancer with high mortality, is resistant to the conventional single-agent chemotherapy. In this study, we employed a combination chemotherapy strategy to inhibit GBM growth and addressed its possible beneficial effects. The synergistic effect of lauroyl-gemcitabine (Gem-C₁₂) and honokiol (HNK) was first tested and optimized using U87 cells in vitro. Then, the hyaluronic acid-grafted micelles (HA-M), encapsulating the optimal mole ratio (1:1) of Gem-C₁₂ and HNK, were prepared and characterized. Cell-based studies demonstrated that HA-M could be transported into cells by a CD44 receptor-mediated endocytosis, which could penetrate deeper into tumor spheroids and enhance the cytotoxicity of payloads to glioma cells. In vivo, drug-loaded HA-M significantly increased the survival rate of mice bearing orthotopic xenograft GBM compared with the negative control (1.85-fold). Immunohistochemical analysis indicated that the enhanced efficacy of HA-M was attributed to the stronger inhibition of glioma proliferation and induction of apoptosis. Altogether, our findings showed advantages of combination chemotherapy of GBM using HA-grafted micelles

Development a hyaluronic acid ion-pairing liposomal nanoparticle for enhancing anti-glioma efficacy by modulating glioma microenvironment

<p>Glioma, one of the most common brain tumors, remains a challenge worldwide. Due to the specific biological barriers such as blood–brain barrier (BBB), cancer stem cells (CSCs), tumor associated macrophages (TAMs), and vasculogenic mimicry channels (VMs), a novel versatile targeting delivery for anti-glioma is in urgent need. Here, we designed a hyaluronic acid (HA) ion-pairing nanoparticle. Then, these nanoparticles were encapsulated in liposomes, termed as DOX-HA-LPs, which showed near-spherical morphology with an average size of 155.8 nm and uniform distribution (PDI = 0.155). HA was proven to specifically bind to CD44 receptor, which is over-expressed on the surface of tumor cells, other associated cells (such as CSCs and TAMs) and VMs. We systematically investigated anti-glioma efficacy and mechanisms <i>in vivo</i> and <i>in vitro</i>. The strong anti-glioma efficacy could attribute to the accumulation in glioma site and the regulation of tumor microenvironment with depletion of TAMs, inhibition of VMs, and elimination of CSCs.</p