Selective Accumulation of Galactomannan Amphiphilic Nanomaterials in Pediatric Solid Tumor Xenografts Correlates with GLUT1 Gene Expression

Abstract

In this work, we designed, characterized, and investigated the performance of hydrolyzed galactomannan (hGM)-based amphiphilic nanoparticles for selective intratumoral accumulation in pediatric patient-derived sarcomas. To create a self-assembly amphiphilic copolymer, the side chain of hGM was hydrophobized with poly­(methyl methacrylate) (PMMA) by utilizing a graft free radical polymerization reaction. Different hGM and MMA weight feeding ratios were used to adjust the critical aggregation concentration and the size and size distribution of the nanoparticles. The ability to actively target glucose transporter-1 (GLUT-1) was studied by fluorescence confocal microscopy and imaging flow cytometry in vitro on Rh30 (rhabdomyosarcoma) and patient-derived Ewing sarcoma (HSJD-ES-001) cell lines with different expression levels of GLUT-1. Results confirmed that the nanoparticles are internalized by ∼100% of the cells at 37 °C. Furthermore, we investigated the biodistribution of the nanoparticles in pediatric patient-derived models of two deadly musculoskeletal tumors, rhabdomyosarcoma and Ewing sarcoma. Outstandingly, the intratumoral accumulation of the nanoparticles correlated very well with the expression level of GLUT1 gene in each patient-derived tumor (P = 0.0141; Pearson’s correlation test). Finally, we demonstrated the encapsulation capacity of these nanoparticles by loading 7.5% (w/w) of the hydrophobic first-generation tyrosine kinase inhibitor imatinib. These findings point out the potential of this new type of nanoparticle to target GLUT-1-expressing tumors and selectively deliver anticancer agents.

Glucosylated Polymeric Micelles Actively Target a Breast Cancer Model

“…The design and development of nanomedicines for the passive and active targeting of anticancer agents to solid tumors became one of the areas of major research interest and efforts. [ 2,13,33–35 ]…”

“…The design and development of nanomedicines for the passive and active targeting of anticancer agents to solid tumors became one of the areas of major research interest and efforts. [2,13,[33][34][35] PMs which are core-shell nanoparticles of relatively simple, scalable and fast production are key players in the field. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] In the context of anticancer therapy, PMs have been mainly attempted for the passive targeting of chemotherapy by capitalizing on the so-called enhanced permeation and retention effect (EPR).…”

Multicellular Organoids of the Neurovascular Blood-Brain Barrier: A New Platform for Precision Neuronanomedicine

“…[55] In a previous work, we demonstrated that the accumulation of hGM-PMMA28 nanoparticles in pediatric sarcomas correlates well with the overexpression of GLUT1. [51] Our LSFM results show that these inherently sugared nanoparticles are actively transported into the organoids, most probably by activated microglia and astrocytes. hGM-PMMA28 and other carbohydrate-based nanoparticles investigated in this work such as crosslinked mixed CS-PMMA30:PVA-PMMA17 and CS-PMMA33 could be also taken up through the mannose receptor that is expressed in microglia and astrocytes and that displays a carbohydrate recognition domain.…”

“…In this work, we used four polymeric NPs produced by the self-assembly of chitosan (CS)-, [49] poly(vinyl alcohol) (PVA)- [50] and hydrolyzed galactomannan (hGM)-based graft copolymers [51] synthesized by the hydrophobization of the polymer backbone with poly(methyl methacrylate) (PMMA) and displaying size between 92 ± 4 to 463 ± 73 nm and from positive to negative Z-potential ( Supplementary Table S4); these two properties govern the interaction of nanoparticulate matter with cells [52] and were measured immediately before the biological experiments.…”

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

“…GLUT1-targeted NDDS strategy could also be used for tumor-targeting drug delivery. Zaritski et al designed hydrolyzed galactomannan (hGM)-based amphiphilic nanoparticles for the selective tumoral accumulation of drugs in pediatric patient-derived sarcomas [ 94 ]. The nanoparticles could be internalized into the cells about 100% at 37 °C.…”