Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles

Abstract

Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, <10 kDa) HA has been reported to provoke inflammatory responses, such as induction of cytokines, chemokines, reactive nitrogen species and growth factors. Herein, we prepared and characterized two types of HA coated (LMw and HMw) lipid-based targeted and stabilized nanoparticles (tsNPs) and tested their binding to tumor cells expressing the HA receptor (CD44), systemic immunotoxicity, and biodistribution in tumor bearing mice. In vitro, the Mw of the surface anchored HA had a significant influence on the affinity towards CD44 on B16F10 murine melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer chemotherapy, entrapped in HMw HA-tsNPs slowly diffused from the particles with a half-life of 13.75 days, and improved the therapeutic outcome in a murine B16F10 melanoma model compared with NPs suggesting an active cellular targeting beyond the Enhanced Permeability and Retention (EPR) effect. Taken together, these findings have major implications for the use of high molecular weight HA in nanomedicine as a selective and safe active cellular targeting moiety.

Perspectives of CD44 targeting therapies

“…Their non-modified counterparts showed no such advantages. For example, coupling of high molecular weight HA to lipid-based NPs enhanced their circulation time and improved the specificity of tumor targeting (Mizrahy et al 2014). Interestingly, coupling of sHA did not show this effect.…”

Harnessing nanomedicine for therapeutic intervention in glioblastoma

“…The addition of targeting moieties on the surface of the NPs can enable a specific recognition of malignant cells compared to healthy cells. One such targeting moiety is hyaluronan (HA), which is a ligand for CD44, a cell surface glycoprotein, that was previously shown to be overexpressed on many types of malignant cells [58][59][60] in general and glioma cells 61 in particular.…”

Targeting tumor microenvironment: crossing tumor interstitial fluid by multifunctional nanomedicines

“…These researchers also showed high encapsulation capacity of high MW HA decorated NPs for anticancer cytotoxic agent methotrexate (MTX), whose liberation from NPs tend to be slow with a half-life of 13.75 days, mainly because of the active cellular targeting rather than EPR effect. 89 …”