Anti-EGFR Targeted Multifunctional I-131 Radio-Nanotherapeutic for Treating Osteosarcoma: In Vitro 3D Tumor Spheroid Model

Abstract

The systemic delivery of doxorubicin (DOX) to treat osteosarcoma requires an adequate drug concentration to be effective, but in doing so, it raises the risk of increasing organ off-target toxicity and developing drug resistance. Herein, this study reveals a multiple therapeutic nanocarrier delivery platform that overcomes off-target toxicity by providing good specificity and imparting enhanced tumor penetration in a three-dimensional (3D) human MG-63 spheroid model. By synthesizing PEG-PLGA nanoparticles by the double emulsion method, encapsulating DOX and Na131I in the inner core, and conjugating with an epidermal growth factor receptor (EGFR) antibody, it is intended to specifically target human MG-63 cells. The nanocarrier is biocompatible with blood and has good stability characteristics. Na131I encapsulation efficiency was >96%, and radiochemical purity was >96% over 96 h. A DOX encapsulation efficacy of ~80% was achieved, with a drug loading efficiency of ~3%, and a sustained DOX release over 5 days. The nanocarrier EGFR antibody achieved a ~80-fold greater targeting efficacy to MG-63 cells (EGFR+) than fibroblast cells (EGFR−). The targeted multiple therapeutic DIE-NPs have a higher penetration and uptake of Na131I to the 3D model and a ~3-fold higher cytotoxicity than the DOX monotherapy (D-NPs). The co-administration of DOX and Na131I (DIE-NPs) disrupts DNA repair and generates free radicals resulting in DNA damage, triggering the activation of apoptosis pathways. This leads to inhibition of MG-63 cell proliferation and promotes cell cycle arrest in the G0/G1 phase. Furthermore, the PEGylated anti-EGFR functionalized DIE-NPs were found to be biocompatible with red blood cells and to have no adverse effects. This anti-EGFR targeted multifunctional I-131 radio-nanotherapeutic signifies a customizable specific targeted treatment for osteosarcoma.

Enhanced Biomimetics of Three-Dimensional Osteosarcoma Models: A Scoping Review

“…The full search is illustrated in the PRISMA flowchart ( Figure 2 ) . Finally, 70 studies fulfilling the inclusion/exclusion criteria were included in this review [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 6...…”

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model

“…Furthermore, Lee et al [ 31 ] found that gefitinib at concentrations of up to 20 μM did not reduce the viability of several other osteosarcoma cell lines, confirming their robust resistance to gefitinib. Recently, Marshall et al [ 36 ], in order to value EGFR expression as a target in osteosarcoma, designed a complex nanoparticle that was able to deliver doxorubicin (a DNA-damaging agent) using a conjugated EGFR antibody. ZR2002 without encapsulation targets EGFR, damages DNA and exhibits superior cytotoxicity when compared with all the drugs in all cell lines.…”

Advances of Osteosarcoma Models for Drug Discovery and Precision Medicine

“…This intriguing finding revealed a paradoxical relationship between tumor elimination and bone regeneration, thus contributing to the development of more effective therapeutic strategies for OS [ 52 ]. In a separate study, Marshall et al put forth a nanocarrier delivery platform with improved tumor specificity and penetration in a 3D human MG-63 spheroid model [ 56 ]. They employed the double emulsion method to synthesize PEG-PLGA nanoparticles, encapsulating DOX and Na 131 I within the inner core [ 56 ].…”

“…In a separate study, Marshall et al put forth a nanocarrier delivery platform with improved tumor specificity and penetration in a 3D human MG-63 spheroid model [ 56 ]. They employed the double emulsion method to synthesize PEG-PLGA nanoparticles, encapsulating DOX and Na 131 I within the inner core [ 56 ]. These were further conjugated with an epidermal growth factor receptor (EGFR) antibody for targeted delivery to human MG-63 cells [ 56 ].…”

“…They employed the double emulsion method to synthesize PEG-PLGA nanoparticles, encapsulating DOX and Na 131 I within the inner core [ 56 ]. These were further conjugated with an epidermal growth factor receptor (EGFR) antibody for targeted delivery to human MG-63 cells [ 56 ]. This multifunctional I 131 radio-nanotherapeutic targeting anti-EGFR provides a tailored treatment option for OS, underlining the potential of 3D multicellular spheroid models in anticancer drug discovery and development [ 56 ].…”