Seite - 99 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Pearsonetal. Nanoparticlebiomoleculecorona decreased therapeuticefficacyofNPs fordiseases suchaspancre- atic cancer that requirenanotherapieswithparticles sizes smaller than50nm(Cabral etal., 2011). Consideringthosechangescausedbythebiomolecularcorona, it appears essential to characterize the therapeutic and target- ing efficacies of NPs under relevant conditions. Silicon dioxide (SiO2)NPs were functionalized with Tf to validate their ability tomaintain targeted interactions in physiologically relevant cell cultureconditions.InFBS-containingmedium,Tf-functionalized NPs lost their ability to selectively target A549 lung cancer cells (Figures1C,D) (Salvati et al., 2013).Mirshafiee et al., prepared 75nmSiO2NPsand studied their ability to reactwith synthetic, surface-bound azide groups using copper-free click chemistry (Mirshafiee et al., 2013). The results of this study confirmed that the biomolecular corona creates a barrier that screens the interactionof the ligandandits targetonaseparate surface. While NP characteristics, such as size, shape, and surface charge, change due to biomolecular corona formation, drug releasekineticsfromtheNPscaneitherbeenhancedordisrupted. Liposomescanundergoshrinkageduetoosmotic forcesandmay undergoaburst-release effectuponentering theblood, resulting inrapiddrugrelease (Wolframetal., 2014b). Incontrast,protein bindingonNPshasbeenshowntodelaydrugrelease,whichpre- venteddrugdiffusion through theNPmatrix (Paula et al., 2013) andreducedthebursteffect (Behzadietal., 2014). The biomolecular corona may alter the toxicity profiles of NPs in a positive manner as well. Evidence has accumulated that the biomolecular corona may mitigate NP-induced toxic- ities. Decreased negative cellular impacts of carbon nanotubes were observed when they were coated with plasma proteins. Nanotubes with a higher protein density displayed less toxic- ity than those with a lower protein density (Ge et al., 2011). The effect of the biomolecular corona of 22nm silicaNPswith different surface charges on toxicity was also evaluated. The corona formed on each NP was confirmed to be unique, and SiO2-COOHNPs exhibited lower toxicity than bare SiO2 and SiO2-NH2 (Mortensen et al., 2013). These results indicated that NP-protein interactions can be utilized to reduce toxicities of some NPs that are otherwise known to be toxic to biological systems. CONCLUSIONSANDFUTUREDIRECTIONS Thebiomolecularcoronahasbeendemonstrated tohaveamajor impactonthebiologicalbehaviorsofNPs.Physicochemicalprop- erties ofNPs including size, surface charge, and hydrophobicity affect the relative amounts, types, andconformationsofproteins thatadsorbontotheNP. NPs functionalizedwith disease-specific targeting ligands are positioned to revolutionize the treatment of debilitating dis- eases such as cancer by achieving targeted and selective cellular interactions.However, thebiomolecularcoronadiminishes those cellular interactions bymaking the ligands inaccessible at their surfaces. Therefore, development of strategies to overcome the negative impact of the protein corona onNP targeting is neces- sary. Recently, attaching targeting ligands to longer PEG tethers in combination with backfilling of the remaining bare surface withshortPEGchainshasbeenshowntopromote the formation of targeted interactions in vitro (Dai et al., 2014). It is seem- ingly obvious that characterization and biological evaluations NPsmust be performed in the presence of physiologically rele- vant protein levels, whichwill ultimately result in the enhanced invivoefficacyof targeteddrugdeliveryplatforms. ACKNOWLEDGMENTS This work was partially supported by National Science Foundation(NSF)underthegrant#DMR-1409161andNational Cancer Institute (NCI) under the grant # R01 CA182580-01. Ryan M. Pearson also acknowledges partial support from the Dean’sScholarshipofUICforhisgraduateeducation. REFERENCES Aggarwal, P.,Hall, J. B.,McLeland,C.B.,Dobrovolskaia,M.A., andMcNeil, S. E. (2009). Nanoparticle interactionwith plasma proteins as it relates to particle biodistribution,biocompatibilityandtherapeuticefficacy.Adv.DrugDeliv.Rev. 61,428–437.doi:10.1016/j.addr.2009.03.009 Amoozgar, Z., andYeo, Y. (2012). Recent advances in stealth coating of nanopar- ticledrugdelivery systems.Wiley Interdiscip.Rev.Nanomed.Nanobiotechnol.4, 219–233.doi:10.1002/wnan.1157 Ashby, J., Pan, S., and Zhong, W. (2014). Size and surface functionalization of iron oxide nanoparticles influence the composition and dynamic nature of their protein corona. ACS Appl. Mater. 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