Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells.

Stephen L Hayward,Srivatsan Kidambi,Christina L Wilson

doi:10.18632/oncotarget.8926

Stephen L Hayward, Srivatsan Kidambi + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.8926

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Abstract

Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency. In summary, novel CD44 targeted lipid based nanocarriers appear to be proficient in mediating site-specific delivery of drugs via CD44 receptors in GBM cells, with an improved therapeutic margin and safety.

Highlights

Glioblastoma Multiforme (GBM) is the most aggressive, lethal, and prevalent brain malignancy with over 10,000 new cases diagnosed in the United States each year [1, 2] GBM is a grade IV astrocytoma histologically defined by abnormal cellularity, mitotic activity, vascular proliferation, and necrosis leading to a highly mobile and invasive phenotype capable of infiltrating surrounding brain tissue [3]
We demonstrated that encapsulation of a range of molecular weight of FITC-tagged Dextran (FD) (10, 20, and 70 kDa) as model drugs did not change the hyaluronic acid coated liposomes (HALNPs) size
No studies to date have performed an in-depth analysis probing the true merit of hyaluronic acid (HA) as a natural ligand to favorably target GBM cells over healthy glial cells

Summary

Introduction

Glioblastoma Multiforme (GBM) is the most aggressive, lethal, and prevalent brain malignancy with over 10,000 new cases diagnosed in the United States each year [1, 2] GBM is a grade IV astrocytoma histologically defined by abnormal cellularity, mitotic activity, vascular proliferation, and necrosis leading to a highly mobile and invasive phenotype capable of infiltrating surrounding brain tissue [3]. Current widespread clinical treatment options for GBM include radiation therapy, chemotherapy with antineoplastic agents, and maximal tumor resection [5] These treatment measures instigate systemic toxic effects to healthy tissue, are limited in potency by intrinsic resistance pathways, require regular invasive dose regimens, and overall do not provide improved long-term quality of life for the patient. CD44 has been found to be increased in glioma cells compared to healthy astrocytes [23, 24], and has been implicated to directly impact glioma invasion [24, 25] These findings are extremely exciting, only a few studies involving an HA decorated nanocarrier have been examined as a potential CD44 targeted GBM therapy [26, 27]. No studies to date have performed an in-depth analysis probing the true merit of HA as a natural ligand to preferentially bind and internalize into GBM cells over healthy glial cells

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