Engineering an Anthrax Toxin inspired protein-ligand for Nanoparticle-Mediated Treatment of Malignant Melanoma

BackgroundMalignant melanoma is a highly aggressive cancer that presents significant treatment challenges, especially in metastatic stages where conventional therapies often fail due to resistance. Targeting the tumors supportive environment rather than the cancer cells themselves offers a promising strategy. The tumor endothelial marker 8 (TEM8), also known as anthrax toxin receptor 1, is overexpressed in tumor neovasculature endothelial cells and their precursors, making it an attractive therapeutic target. This study introduces PA17, a protein ligand derived from the anthrax toxin binding domain and specifically engineered to target TEM8, aiming to enhance the precision and effectiveness of nanomedicine. ResultsRecombinant and purified PA17 ligand protein exhibited high affinity for TEM8 both in vitro and in vivo in preclinical melanoma models, demonstrating significant intrinsic antitumor activity and no detectable off-target effects. When PA17 was used to functionali ze doxorubicin-loaded mesoporous silica nanoparticles, it resulted in a 65% reduction in tumor mass with a single local administration and a 55% reduction after three systemic administrations. This treatment was significantly more effective than free doxorubicin or non-targeted doxorubicin-loaded nanoparticles and was associated with a marked decrease in tumor vascularization. ConclusionsThis study highlights the potential of toxin-derived ligands as novel targeti ng agents for tumor neovasculature in aggressive cancers such as malignant melanoma. PA17, with its intrinsic antitumor properties and exceptional targeting efficacy, enhances the efficacy of nanomedicine and addresses common challenges such as drug resistance. The use of natural ligands represents a transformative approach to nanomedicine delivery and offers a promising strategy to advance cancer nanotherapy. Graphical abstract image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/626996v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@ae5f6dorg.highwire.dtl.DTLVardef@1fb115borg.highwire.dtl.DTLVardef@309f9eorg.highwire.dtl.DTLVardef@3f53b5_HPS_FORMAT_FIGEXP M_FIG C_FIG