Tumor-Specific Localization of Multivariate Nanoparticles

Fusion of ultrafine particles (nanoparticles-assembly) and target ligands possessing specific recognition affinity towards cellular receptors provides transformative nanocarriers capable of overcoming the intrinsic physiological barriers of clearance through the innate immune system and ensuring safe delivery of therapeutics to tumor sites. The active cellular targeting and site-selective drug-delivery can be further enhanced by co-conjugating anticancer drugs on nanocarriers, which is an important determinant of the therapeutic index. In this study, a fluorescent anticancer drug (doxorubicin) was co-conjugated with a target ligand capable of specifically binding to a membrane glycoprotein (folate receptor) that is over-expressed in several tumors and can thus enhance the selective uptake and enrichment of drug-loaded nanocarriers at the tumor site. Through the covalent coupling of folic acid (FA)-attached hematite (α-Fe₂O₃) nanocrystals and doxorubicin (DOX)-coated magnetite (Fe₃O₄) particles, a dual-action nanocarrier (<b>FA-α-Fe₂O₃@Fe₃O₄-DOX</b>) was developed for single-stage tumor targeting and localized drug delivery. The efficiency and specificity of the dual-mode nanocarriers in cell-mediated delivery of drugs at tumor location were verified by both <i>in-vitro</i> and <i>in-vivo </i>(Breast cancer mice models) studies. Experimental data confirmed the preferential uptake and accumulation of nanoparticles containing both target ligand and anti-cancer drug on a single carrier particle when compared to control particles not bearing target ligands (negative control). In addition, these particles showed 99 % radiolabeling yield and optimal stability with a radionuclide (¹⁷⁷Lu) in human serum. In addition, the apoptosis study showed an enhanced therapeutic effect to the cells after the incorporation of radionuclides into these carriers. The minimization of off-target effects and effective ligand-driven in-vivo delivery of doxorubicin to the mice tumors illustrate the therapeutic potential of this approach. The facile chemical conjugation and small size of folic acid make the co-conjugate, <b>FA-α-Fe₂O₃@Fe₃O₄-DOX</b> an attractive drug-delivery platform for folate-mediated targeting.<br/><br/><b>Keywords:</b> iron oxide, silica, carbodiimide, folic acid, doxorubicin, biodistribution, therapeutic