Seite - 98 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Pearsonetal. Nanoparticlebiomoleculecorona Anumberof studieshavebeendedicatedtocharacterizing the interactionof albuminwithNPs.AuNPs, for example,modified albumin from its stable secondary conformation to its unsta- ble tertiary conformation (Shang et al., 2007). In the case of charged-PSt NPs, it was observed that albuminmaintained its native secondary structure while associated with carboxylated NPsenabling its interactionwith thealbuminreceptor.However, amine-terminatedNPsdenatured albumin and subsequently led to a loss of specificity toward the albumin receptor in favor for scavenger receptors, indicating that the transition to unstable proteins alters their activity in the body (Fleischer and Payne, 2014). This illustrated that themisfolding of proteins can result in an alteration of the cell surface receptors targeted by NPs, whichcoulddecreasetheirtargetingefficacy(FleischerandPayne, 2014). Mortimer et al., investigated the role of scavenger receptors in NP-protein interactions (Mortimer et al., 2014). Albumin binding to synthetic layered silicateNPs (LSNs) inducedprotein unfolding akin to heat denaturation of albumin. Class A scav- engerreceptors,whicharethedominantreceptors involvedinthe mononuclear phagocyte system(MPS), required thepresence of thealbumincoronatorecognize theLSNs. The conformational changes of albumin can not only lead to increased NP clearance, but also alter their cellular uptake. A study characterized the biomolecular corona of negatively charged disulfide-stabilized poly (methacrylic acid) nanoporous polymer particles (PMASH NPPs) following incubation in complete media containing 10% fetal bovine serum (FBS). Adsorption of BSA, a major component in FBS, onto the sur- faceof theNPPswas found to result in a conformational change from its native state.Notably, denaturedBSAonNPPs caused a reduction in the internalizationefficiencyof theNPs intohuman monocytic cells, compared to the bare particles, due to reduced cell membrane adhesion. However, a different conformation of BSA, triggered class A scavenger receptor-mediated phagocyto- sis in differentiated macrophage-like cells (dTHP-1) without a significant impact on the overall degree of cell internalization. Recognizingthatbothcompositionandorientationoftheprotein coronaareimportantfortheassessmentofbiological interactions may lead to the prevention of off target cellular interactions of NPs(Yanetal., 2013). CONSIDERATIONSOFTHEBIOMOLECULARCORONAFOR NP-BASEDTARGETEDDRUGDELIVERY NPinteractionswithbiomoleculescansignificantlyaffecttheeffi- caciesofnanomedicine.Alterationsinconformationsoractivities ofbiomolecules candramatically impairNP-baseddrugdelivery. These alterationsmay result in changes in cellular uptake, drug release, and biodistribution profiles. Importantly, newmethods tostudythoseNP-cell interactionsatthemolecular levelwillyield insight intohowthebiomoleculecoronacanalter the fateofNPs (Bertoli etal., 2014). In Table1, we have summarized the major considerations onemust takewhendesigning and evaluating targetedNPdrug delivery systemstoachieveoptimumefficacy. Size isanimportantpropertyofNPsthataffects theirdistribu- tionwithinthebody.Biomolecularcoronaformationcanincrease theoriginalsizeandalterthepharmacokineticsofNPs(Lundqvist et al., 2008). In some cases, this size increase could be benefi- cial since NPs smaller than 5nm are readily excreted through renal filtration (Choi et al., 2007; Sunoqrot et al., 2014). Yet, the size increase caused by biomolecule adsorptionmay result in a Table1 |Considerationsof thebiomolecularcoronatodesignmoreeffectiveNPs. References PHYSICOCHEMICALPROPERTIESOFNPsANDTHEIREFFECTONBIOMOLECULARCORONAFORMATION Size LargerNPsadsorbmoreproteins to their surfaces Shannahanetal., 2013 Surfacecharge ChargedNPsadsorbmoreproteins to their surfaces.Alterationofparticle zeta potential Lundqvistet al., 2008 Hydrophobicity MorehydrophobicNPsadsorbmoreproteins to their surfaces. Cedervall et al., 2007; Lindmanetal., 2007 IMPACTOFPEGLAYERSONBIOMOLECULARCORONAFORMATION HighdensitybrushPEGconformationadsorbed lessprotein thanmushroomconformations Walkeyetal., 2011;Perry et al., 2012 CONFORMATIONALCHANGESOFADSORBEDPROTEINSCAUSEDBYNPs Results inproteinmisfolding (changes insecondarystructure) Karlssonetal., 2000;Shang etal., 2007;Fleischerand Payne,2014 Crypticepitopeexposureuponprotein interactionwithNP Mortimeret al., 2014 Inappropriate receptor recognitionafterNP-protein interaction Yanetal., 2013 CONSIDERATIONSOFTHEBIOMOLECULARCORONAFORNP-BASEDTARGETEDDRUGDELIVERY In vitroexperimentsshouldbecarriedout inphysiologically relevant conditions Mirshafieeetal., 2013;Salvati et al., 2013 PEGbackfillingmaybeused toovercomethenegativeeffectsof theproteincoronaon targeteddrugdeliverysystems Daiet al., 2014 Biomolecular corona formationcanenhancepharmacokineticsofNPs Pengetal., 2013 Biomolecular corona formationmitigates the toxicityofNPs Geetal., 2011;Mortensen etal., 2013 Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article108 | 98