Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells.

Abstract

Simple SummaryGlioblastoma multiforme is the most aggressive malignant brain tumor with poor patient prognosis. The presence of the blood-brain barrier and the complex tumor microenvironment impair the efficient accumulation of drugs and contrast agents, causing late diagnosis, inefficient treatment and monitoring. Functionalized theranostic nanoparticles are a valuable tool to modulate biodistribution of active agents, promoting their active delivery and selective accumulation for an earlier diagnosis and effective treatment, and provide simultaneous therapy and imaging for improved evaluation of treatment efficacy. In this work, we developed angiopep-2 functionalized crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and irinotecan (Thera-ANG-cHANPs) that were shown to boost relaxometric properties of Gd-DTPA by the effect of Hydrodenticity, improve the uptake of nanoparticles by the exploitation of angiopep-2 improved transport properties, and accelerate the therapeutic effect of Irinotecan.Glioblastoma multiforme (GBM) has a mean survival of only 15 months. Tumour heterogeneity and blood-brain barrier (BBB) mainly hinder the transport of active agents, leading to late diagnosis, ineffective therapy and inaccurate follow-up. The use of hydrogel nanoparticles, particularly hyaluronic acid as naturally occurring polymer of the extracellular matrix (ECM), has great potential in improving the transport of drug molecules and, furthermore, in facilitatating the early diagnosis by the effect of hydrodenticity enabling the T1 boosting of Gadolinium chelates for MRI. Here, crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and the chemotherapeutic agent irinotecan (Thera-cHANPs) are proposed as theranostic nanovectors, with improved MRI capacities. Irinotecan was selected since currently repurposed as an alternative compound to the poorly effective temozolomide (TMZ), generally approved as the gold standard in GBM clinical care. Also, active crossing and targeting are achieved by theranostic cHANPs decorated with angiopep-2 (Thera-ANG-cHANPs), a dual-targeting peptide interacting with low density lipoprotein receptor related protein-1(LRP-1) receptors overexpressed by both endothelial cells of the BBB and glioma cells. Results showed preserving the hydrodenticity effect in the advanced formulation and internalization by the active peptide-mediated uptake of Thera-cHANPs in U87 and GS-102 cells. Moreover, Thera-ANG-cHANPs proved to reduce ironotecan time response, showing a significant cytotoxic effect in 24 h instead of 48 h.