'

Specific'uptake'and'affinity,'washout'and'clearance,'imaging'and'therapeutic'value'are'all' important;' they' have' been' extensively' explained' in' the' previous' paragraphs.' When' the' goal' is' to' design' a' new' (radio)Rligand,' all' these' characteristics' need' to' be' evaluated' a!

priori'(Fig.'17).''

( Figure( 17:' Summary' of' important' characteristics' of' monomers,' multimers' and'

polymers/dendrimers.((Although'the'monomers'offer'best'imaging'properties,'dendrimers' and'highly'branched'multimers'have'the'best'therapeutic'applications.'They'are'able'to' deliver'a'payload'to'tumors.'''

NANOTECHNOLOGIES(AND(NEW(PERSPECTIVES(

The'thermodynamic'and'kinetic'characteristics'of'multivalent'interactions'have'influenced' the'field'of'supramolecular'nanofabrication'dramatically.'It'has'been'demonstrated'that' selfRassembled' hybrid' monolayers' as' well' as' nanoparticles' and' dendrimers' prefer' multivalent'binding'and'intermolecular'binding'(25).'

61

Multivalency'is'one'of'the'most'extensively'studied'themes'of'nanotechnology.'Recently,' supramolecular'multivalent'interactions'have'been'studied'systematically'by'Stoddart'et' al.'(91).'By'increasing'the'number'of'repeats'of'the'original'sequence,'multivalency'may' play' an' important' role' in' modifying' the' binding' activity' of' a' given' peptide.' Such' multimerization' can' be' accomplished' using' the' simple' tandem' repeat' of' the' original' sequence.'''

Oren' and' Notman' applied' a' multipleRrepeatRbased' strategy' on' both' phage' display' selected'platinum'and'quartz'binder'(7'and'12'amino'acid'sequences'respectively)'and'cell' surface'selected'gold'binders'of'14'aminoacids'each'(92).'They'showed'that'the'increase' of'the'number'of'repeated'peptides'was'not'always'associated'with'an'enhancement'of' binding' activity' and,' interestingly,' that' peptides' were' changed' when' used' in' multipleR repeat'forms.'So,'one'may'assume'that'the'molecular'structure'is'relevant'and'that'there' is' a' correlation' between' conformational' arrangement' and' binding' ability' (93).' Linkers' must'be'incorporated'between'two'or'more'following'sequences'to'conform'the'overall' multipleRrepeated'peptides'for'binding'and'other'biological'functions.'

Potentially' the' soRcalled' dock' and' lock' (DNL)' method' may' provide' a' large' number' of' bioactive' molecules' by' multivalency' (94).' This' approach' may' not' only' overcome' the' limitations'of'current'technologies'with'regards'the'production'of'antibodyRbased'agents,' but' also' be' useful' for' multimerization' in' general.' The' limitations' of' the' DNLRmethod' include'high'manufacturing'cost,'low'expression'yields,'instability'in'serum,'formation'of' aggregates'or'dissociated'subunits,'undefined'batch'composition'due'to'the'presence'of' multiple' product' forms,' contaminating' sideRproducts,' reduced' functional' activities' or' binding'affinity/avidity'attributed'to'steric'factors'or'altered'conformations.'

A'very'new'approach'is'nanoRengineering'by'gold'probes.'Gold'nanoparticles'are'similar'in' size'to'proteins,'biocompatible,'and'can'be'modified'using'functional'groups.'Rotello'et!al.' made' libraries' of' gold' nanoparticles' by' ligand' exchange' reactions' of' several' aminoacidR' and' peptideRfunctionalized' alkene' thiols' on' 1RpentanethiolRcoated' gold' nanoparticles' (95).'Changes'in'the'charge,'hydrophobic'index,'and/or'chirality'of'the'pending'moieties' caused'different'binding'affinity'capacity'toward'protein'surfaces.''

62

Recently,' a' potent' inhibition' of' HIV' fusion' by' gold' nanoparticles' coated' with' a' therapeutically'inactive'small'molecule'related'to'TAKR779'has'been'described'(96).'TAKR 779' is' a' specific' inhibitor' of' HIVR1' entry.' This' study' demonstrates' how' small' organic' molecules'can'be'converted'into'highly'active'drugs'by'conjugating'them'to'multivalent' gold' nanoparticles' as' scaffold.' So,' multivalent' attachment' of' small' molecules' to' nanoparticles'can'be'a'valid'tool'to'increase'specific'binding'affinity.'This'tool'may'also' facilitate' the' development' of' ' nanomaterials' for' potential' application' in' drug' discovery' and'drug'delivery'as'well'as'in'the'diagnosis'and'treatment'of'human'diseases'in'general'' Undoubtedly,'nanomaterials'will'also'be'developed'for'designing'novel'anticancer'drugs' (95);'(97);'(98).''Several'are'already'commercially'available'and'used'to'attach'peptides'as' diagnostic'imaging'agents'for'targeting'inflammation,'and'other'angiogenic'processes.'

CONCLUSIONS(

In'the'future,'multivalency'may'become'a'prominent'tool'for'designing'and'developing'a' wide' library' of' new' compounds' to' use' as' targeting' agents' for' radioimaging' and' radionuclide' therapy.' This' review' described' and' evaluated' parameters' which' play' a' critical'role'in'designing'a'functional'construct.'Knowing'that'in'the'next'future'the'design' principles' and' the' basics' of' multivalency' need' extensive' investigations,' the' results' reported'by'many'research'groups'show'that'both'homoR'and'heteroRmultimers'provide' higher' binding' affinities' than' the' respective' monomeric' counterparts.' The' designing' strategies'all'requires'series'of'computational'studies'to'distinguish'within'the'multitude' of'known'backbones,'linkers,'receptors'and'especially'ligands.''

' ' ' ' ' ' '

63

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