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DNA-Functionalized Metal-Organic Framework Nanoparticles for Intracellular Delivery of Proteins Shunzhi Wang, Yijing Chen, Shuya Wang, Peng Li, Chad A. Mirkin, and Omar K. Farha J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jan 2019 Downloaded from http://pubs.acs.org on January 23, 2019

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Journal of the American Chemical Society

DNA-Functionalized Metal-Organic Framework Nanoparticles for Intracellular Delivery of Proteins Š—œŠ‹ƒ‰ǡȘǡ͓ ‹Œ‹‰Š‡ǡȘǡ͓Š—›ƒƒ‰ǡș‡‰‹ǡ͓Šƒ†Ǥ‹”‹ǡȗ͓ƒ”Ǥ ƒ”Šƒȗ͓ ͓‡’ƒ”–‡–‘ˆŠ‡‹•–”›ƒ†–Š‡ –‡”ƒ–‹‘ƒŽ •–‹–—–‡ˆ‘”ƒ‘–‡…Š‘Ž‘‰›ǡ‘”–Š™‡•–‡”‹˜‡”•‹–›ǡʹͳͶͷŠ‡”‹†ƒ

‘ƒ†ǡ˜ƒ•–‘ǡ ŽŽ‹‘‹•͸ͲʹͲͺǡ‹–‡†–ƒ–‡• ș –‡”†‡’ƒ”–‡–ƒŽ‹‘Ž‘‰‹…ƒŽ…‹‡…‡•ǡʹʹͲͷ‡…Š”‹˜‡ǡ˜ƒ•–‘ ŽŽ‹‘‹•͸ͲʹͲͺǡ‹–‡†–ƒ–‡• 

Supporting Information ABSTRACT:—‡–‘–Š‡‹”Žƒ”‰‡•‹œ‡ǡ…Šƒ”‰‡†•—”ˆƒ…‡•ǡƒ†‡Ǧ ˜‹”‘‡–ƒŽ •‡•‹–‹˜‹–›ǡ ’”‘–‡‹• †‘ ‘– ƒ–—”ƒŽŽ› …”‘•• …‡ŽŽǦ ‡„”ƒ‡•‹‹–ƒ…–ˆ‘”ƒ†ǡ–Š‡”‡ˆ‘”‡ǡƒ”‡†‹ˆˆ‹…—Ž––‘†‡Ž‹˜‡” ˆ‘”„‘–Š†‹ƒ‰‘•–‹…ƒ†–Š‡”ƒ’‡—–‹…’—”’‘•‡•Ǥ ƒ•‡†—’‘–Š‡ ‘„•‡”˜ƒ–‹‘ –Šƒ– …Ž—•–‡”‡† ‘Ž‹‰‘—…Ž‡‘–‹†‡• …ƒ ƒ–—”ƒŽŽ› ‡Ǧ ‰ƒ‰‡ •…ƒ˜‡‰‡” ”‡…‡’–‘”• –Šƒ– ˆƒ…‹Ž‹–ƒ–‡ …‡ŽŽ—Žƒ” –”ƒ•ˆ‡…–‹‘ǡ —…Ž‡‹…ƒ…‹†Ǧ‡–ƒŽ‘”‰ƒ‹…ˆ”ƒ‡™‘”ƒ‘’ƒ”–‹…Ž‡ȋ Ȍ …‘Œ—‰ƒ–‡•Šƒ˜‡„‡‡†‡•‹‰‡†ƒ†•›–Š‡•‹œ‡†ˆ”‘ǦͳͲͲͲ ƒ† ǦʹʹʹȀ ǦͷͶͷǡ ”‡•’‡…–‹˜‡Ž›ǡ ƒ† ’Š‘•’Šƒ–‡Ǧ–‡”‹Ǧ ƒ–‡†‘Ž‹‰‘—…Ž‡‘–‹†‡•ǤŠ‡›Šƒ˜‡„‡‡…Šƒ”ƒ…–‡”‹œ‡†•–”—…–—”Ǧ ƒŽŽ›ƒ†™‹–Š”‡•’‡…––‘–Š‡‹”ƒ„‹Ž‹–›–‘‡–‡”ƒƒŽ‹ƒ…‡ŽŽ•Ǥ Š‡  • ƒ…– ƒ• ’”‘–‡‹ Š‘•–•ǡ ƒ† –Š‡‹” †‡•‡Ž› ˆ—…–‹‘ƒŽǦ ‹œ‡†ǡ ‘Ž‹‰‘—…Ž‡‘–‹†‡Ǧ”‹…Š •—”ˆƒ…‡• ƒ‡ –Š‡ …‘ŽŽ‘‹†ƒŽŽ› •–ƒǦ „Ž‡ƒ†‡•—”‡ˆƒ…‹Ž‡…‡ŽŽ—Žƒ”‡–”›Ǥ‹–Š‹•—Ž‹ƒ•ƒ‘†‡Ž’”‘Ǧ –‡‹ǡŠ‹‰ŠŽ‘ƒ†‹‰ƒ†ƒͳͲǦˆ‘Ž†‡Šƒ…‡‡–‘ˆ…‡ŽŽ—Žƒ”—’–ƒ‡ ȋƒ•…‘’ƒ”‡†–‘–Šƒ–‘ˆ–Š‡ƒ–‹˜‡’”‘–‡‹Ȍ™‡”‡ƒ…Š‹‡˜‡†Ǥ Ǧ ’‘”–ƒ–Ž›ǡ–Š‹•ƒ’’”‘ƒ…Š…ƒ„‡‰‡‡”ƒŽ‹œ‡†–‘ˆƒ…‹Ž‹–ƒ–‡–Š‡†‡Ǧ Ž‹˜‡”›‘ˆƒ˜ƒ”‹‡–›‘ˆ’”‘–‡‹•ƒ•„‹‘Ž‘‰‹…ƒŽ’”‘„‡•‘”’‘–‡–‹ƒŽ –Š‡”ƒ’‡—–‹…•Ǥ ”‘–‡‹•’Žƒ›‡›”‘Ž‡•‹Ž‹˜‹‰•›•–‡•ǡƒ†–Š‡ƒ„‹Ž‹–›–‘ †‡Ž‹˜‡”ƒ…–‹˜‡’”‘–‡‹•–‘…‡ŽŽ•‹•ƒ––”ƒ…–‹˜‡ˆ‘”„‘–Š†‹ƒ‰‘•–‹… ƒ†–Š‡”ƒ’‡—–‹…’—”’‘•‡•Ǥͳ‘–‡–‹ƒŽ—•‡•‹˜‘Ž˜‡–Š‡‡˜ƒŽ—ƒǦ –‹‘‘ˆ‡–ƒ„‘Ž‹…’ƒ–Š™ƒ›•ǡʹ”‡‰—Žƒ–‹‘‘ˆ…‡ŽŽ—Žƒ”’”‘…‡••‡•ǡ͵ ƒ†–”‡ƒ–‡–‘ˆ †‹•‡ƒ•‡‹˜‘Ž˜‹‰’”‘–‡‹†‡ˆ‹…‹‡…‹‡•ǤͶǦ͸—”Ǧ ‹‰–Š‡’ƒ•–†‡…ƒ†‡ǡƒ•‡”‹‡•‘ˆ–‡…Š‹“—‡•Šƒ˜‡„‡‡†‡˜‡Ž‘’‡†

–‘ˆƒ…‹Ž‹–ƒ–‡’”‘–‡‹‹–‡”ƒŽ‹œƒ–‹‘„›Ž‹˜‡…‡ŽŽ•ǡ ‹…Ž—†‹‰–Š‡ —•‡‘ˆ…‘’Ž‡‡–ƒ”›–”ƒ•ˆ‡…–‹‘ƒ‰‡–•ǡƒ‘…ƒ””‹‡”•ǡ͹Ǧͻƒ† ’”‘–‡‹•—”ˆƒ…‡‘†‹ˆ‹…ƒ–‹‘•ǤͳͲǦͳ͵Ž–Š‘—‰Š‡ƒ…Š•–”ƒ–‡‰›Šƒ• ‹–•‘™‡”‹–ǡ‘‡ƒ”‡’‡”ˆ‡…–•‘Ž—–‹‘•Ǣ–Š‡›…ƒ…ƒ—•‡…›–‘Ǧ –‘š‹…‹–›ǡ”‡†—…‡’”‘–‡‹ƒ…–‹˜‹–›ǡƒ†•—ˆˆ‡”ˆ”‘Ž‘™†‡Ž‹˜‡”› ’ƒ›Ž‘ƒ†•ǤͳͶ ‘” ‡šƒ’Ž‡ǡ ™‡ Šƒ˜‡ ƒ†‡ –Š‡ ‘„•‡”˜ƒ–‹‘ –Šƒ– ‘‡…ƒ–ƒ‡ƒŽ‘•–ƒ›’”‘–‡‹ƒ†ˆ—…–‹‘ƒŽ‹œ‡‹–••—”ˆƒ…‡ ™‹–Š–‘…”‡ƒ–‡‡–‹–‹‡•–Šƒ–™‹ŽŽƒ–—”ƒŽŽ›‡‰ƒ‰‡–Š‡…‡ŽŽǦ •—”ˆƒ…‡”‡…‡’–‘”•‹˜‘Ž˜‡†‹•’Š‡”‹…ƒŽ—…Ž‡‹…ƒ…‹†ȋȌ—’Ǧ –ƒ‡Ǥͳ͵ǡͳͷǦͳ͹Š‹Ž‡–Š‹•‡–Š‘†‹•‡š–”‡‡Ž›—•‡ˆ—Ž‹…‡”–ƒ‹•‹–Ǧ —ƒ–‹‘•ǡ‹–”‡“—‹”‡•†‹”‡…–‘†‹ˆ‹…ƒ–‹‘‘ˆ–Š‡’”‘–‡‹ƒ†Žƒ”‰‡ ƒ‘—–•‘ˆ—…Ž‡‹…ƒ…‹†ǡ‘ƒ’‡”Ǧ’”‘–‡‹„ƒ•‹•ǡ–‘‡ˆˆ‡…––”ƒ•Ǧ ˆ‡…–‹‘Ǥ †‡ƒŽŽ›ǡ‘‡™‘—Ž†Ž‹‡–‘†‡Ž‹˜‡”‹–ƒ…–ǡˆ—…–‹‘ƒŽ’”‘Ǧ –‡‹•™‹–Š‘—––Š‡‡‡†–‘…Š‡‹…ƒŽŽ›‘†‹ˆ›–Š‡ǡƒ†–‘†‘•‘ ‹ƒ—…Ž‡‹…Ǧƒ…‹†‡ˆˆ‹…‹‡–ƒ‡”Ǥ  •Šƒ˜‡‡‡”‰‡†ƒ•ƒ…Žƒ••‘ˆ’”‘‹•‹‰ƒ–‡”‹ƒŽ•ˆ‘”–Š‡ ‹‘„‹Ž‹œƒ–‹‘ƒ†•–‘”ƒ‰‡‘ˆˆ—…–‹‘ƒŽ’”‘–‡‹•ǤͳͺŠ‡‹”‡•Ǧ ‘’‘”‘—••–”—…–—”‡•ƒŽŽ‘™ˆ‘” ‡š…‡’–‹‘ƒŽŽ›Š‹‰Š’”‘–‡‹Ž‘ƒ†Ǧ ‹‰•ǡ ƒ† –Š‡‹” ˆ”ƒ‡™‘” ƒ”…Š‹–‡…–—”‡• …ƒ •‹‰‹ˆ‹…ƒ–Ž› ‹Ǧ ’”‘˜‡–Š‡–Š‡”ƒŽƒ†…Š‡‹…ƒŽ•–ƒ„‹Ž‹–‹‡•‘ˆ–Š‡‡…ƒ’•—Žƒ–‡† ’”‘–‡‹•ǤͳͻǦʹͶ ‘™‡˜‡”ǡ ƒŽ–Š‘—‰Š   • Šƒ˜‡ „‡‡ ”‡…‘‰Ǧ ‹œ‡† ƒ• ’‘–‡–‹ƒŽŽ› ‹’‘”–ƒ– ‹–”ƒ…‡ŽŽ—Žƒ” †‡Ž‹˜‡”› ˜‡Š‹…Ž‡• ˆ‘” ’”‘–‡‹•ǡʹͷǦʹ͹ –Š‡‹” ’‘‘” …‘ŽŽ‘‹†ƒŽ •–ƒ„‹Ž‹–› ƒ† ’‘•‹–‹˜‡Ž› …Šƒ”‰‡†•—”ˆƒ…‡•ǡʹͺǦʹͻ ‹Š‹„‹––Š‡‹”…‡ŽŽ—Žƒ”—’–ƒ‡ƒ†Šƒ˜‡Ž‡† –‘ —ˆƒ˜‘”ƒ„Ž‡ „‹‘ƒ˜ƒ‹Žƒ„‹Ž‹–‹‡•Ǥ͵ͲǦ͵͵ Š‡”‡ˆ‘”‡ǡ –Š‡ †‡˜‡Ž‘’Ǧ ‡–‘ˆ‰‡‡”ƒŽƒ’’”‘ƒ…Š‡•ˆ‘””‡†—…‹‰ ƒ‰‰”‡‰ƒ–‹‘ǡ

Scheme 1ǤȋȌ…Š‡ƒ–‹…‹ŽŽ—•–”ƒ–‹‘‘ˆ‹•—Ž‹‡…ƒ’•—Žƒ–‹‘‹–Š‡‡•‘’‘”‘—•…Šƒ‡Ž•‘ˆ •ˆ‘ŽŽ‘™‡†„› •—”ˆƒ…‡ ˆ—…–‹‘ƒŽ‹œƒ–‹‘ǤȋȌ”›•–ƒŽ•–”—…–—”‡•‘ˆ–™‘‡•‘’‘”‘—•” •ǣǦͳͲͲͲƒ†ǦʹʹʹȀ ǦͷͶͷƒ†–Š‡‹””‡•’‡…–‹˜‡‘”‰ƒ‹… Ž‹‡”•ǤȋȌˆ—…–‹‘ƒŽ‹œƒ–‹‘‘ˆ‹•—Ž‹‡…ƒ’•—Žƒ–‡† •—•‹‰͵̵–‡”‹ƒŽ’Š‘•’Šƒ–‡‘†‹ˆ‹‡†—…Ž‡‹…ƒ…‹†•Ǥ

ACS Paragon Plus Environment

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Figure 1Ǥ…ƒ‹‰‡Ž‡…–”‘‹…”‘•…‘’›ȋŽ‡ˆ–Ȍƒ†–”ƒ•‹••‹‘‡Ž‡…–”‘‹…”‘•…‘’›ȋ”‹‰Š–Ȍ‹ƒ‰‡•‘ˆƒ•Ǧ•›–Š‡•‹œ‡†ǦͳͲͲͲ• ȋȌƒ†Ǧʹʹʹ•ȋȌǤȋǦȌ‘ŽŽ‘‹†ƒŽ•–ƒ„‹Ž‹–›‘ˆǦͳͲͲͲƒ†Ǧʹʹʹ•‹…‡ŽŽ‡†‹—ǡƒ•†‡–‡”‹‡†„›™‹–Š‘—–ȋŽ‡ˆ–Ȍ ƒ†™‹–Š•—”ˆƒ…‡‘†‹ˆ‹…ƒ–‹‘ȋ”‹‰Š–ȌǤ…ƒŽ‡„ƒ”•αͳͲͲǤ ‹‹‹œ‹‰’‘•‹–‹˜‡…Šƒ”‰‡ȋ™Š‹…Š…ƒ…ƒ—•‡…›–‘–‘š‹…‹–›Ȍǡƒ† ˆƒ…‹Ž‹–ƒ–‹‰…‡ŽŽ—Žƒ”—’–ƒ‡‹•†‡•‹”ƒ„Ž‡Ǥ͵ͶǦ͵ͷ ‡”‡‹ǡ™‡”‡’‘”–ƒ‡™‡–Š‘†ˆ‘”–Š‡‹–”ƒ…‡ŽŽ—Žƒ”†‡Ž‹˜‡”› ‘ˆ ’”‘–‡‹• –Šƒ– ”‡Ž‹‡• ‘ —…Ž‡‹… ƒ…‹†Ǧ   …‘Œ—‰ƒ–‡• ȋ…Š‡‡ͳȌǤ͵ͶǦ͵͹ –Š‹•’”‘–‘…‘Žǡ–™‘™ƒ–‡”•–ƒ„Ž‡œ‹”…‘‹— ‡•‘’‘”‘—•  •ǡ ǦͳͲͲͲ ȋ”͸ȋρ͵ǦȌͶȋρ͵Ǧ ȌͶȋȌͶȋʹȌͶȋ›Ȍʹǡ ͶǦ› α ͶǡͶǯǡͶǯǯǡͶǯǯǯǦȋ’‘”’Š‹‡Ǧ ͷǡͳͲǡͳͷǡʹͲǦ–‡–”ƒ›ŽȌ–‡–”ƒ‹•ȋ„‡œ‘‹…ƒ…‹†ȌȌƒ†ǦʹʹʹȀ Ǧ ͷͶͷ(”͸ȋρ͵ǦȌͶȋρ͵ǦȌͶȋȌͶȋʹȌͶȋǦʹȌʹH4-TCPP-H2 = tetrakis(4-carboxyphenyl)porphyrin)ǡ͵ͺǦͶͲ ™‡”‡ •›–Š‡•‹œ‡† ‹ ƒ‘’ƒ”–‹…Ž‡ ˆ‘” ƒ† —•‡† –‘ ‡…ƒ’•—Žƒ–‡ ‹•—Ž‹ǡ ƒ ‘†‡Ž ’”‘–‡‹ˆ‘”–Š‡•–—†‹‡•†‡•…”‹„‡†Š‡”‡‹ȋ…Š‡‡ͳȌǤͶͳǦͶʹ‡š–ǡ ˜‹ƒ‘†‹ˆ‹…ƒ–‹‘‘ˆŽ‹–‡”ƒ–—”‡’”‘…‡†—”‡•ǡ –Š‡•‡‹•—Ž‹̷  • ™‡”‡ •—”ˆƒ…‡ ˆ—…–‹‘ƒŽ‹œ‡† ™‹–Š –‡”‹ƒŽ ’Š‘•’Šƒ–‡Ǧ ‘†‹ˆ‹‡†–‘›‹‡Ž†‹•—Ž‹̷Ǧ •ȋ…Š‡‡ͳȌǤ͵͸ Š‡͵‘Ž‹‰‘—…Ž‡‘–‹†‡•Š‡ŽŽ…”‡ƒ–‡•ƒ•–‡”‹…ƒ†‡Ž‡…–”‘•–ƒ–‹… „ƒ””‹‡”–‘•–ƒ„‹Ž‹œ‡ •‹Š‹‰Š†‹‡Ž‡…–”‹…‡†‹ƒƒ†”‡Ǧ †‡”•–Š‡ˆ—…–‹‘ƒŽ™‹–Š”‡•’‡…––‘…‡ŽŽ—Žƒ”‡–”›Ǥ͵Ͷ ’”‹…‹Ǧ ’Ž‡ǡ –Š‹• •–”ƒ–‡‰› …ƒ „‡ ‰‡‡”ƒŽ‹œ‡† –‘  • ™‹–Š †‹ˆˆ‡”‡– ’‘”‡ •‹œ‡• ƒ† –‘’‘Ž‘‰‹‡•ǡ –Š‡”‡„› …”‡ƒ–‹‰ ƒ ƒ”•‡ƒŽ ‘ˆ —Ǧ …Ž‡‹… ƒ…‹†Ǧ Ǧ„ƒ•‡† †‡Ž‹˜‡”› ˜‡Š‹…Ž‡• ˆ‘” –”ƒ•’‘”–‹‰ ˆ—…Ǧ –‹‘ƒŽ‡œ›‡•ƒ…”‘••…‡ŽŽ—Žƒ”‡„”ƒ‡•™‹–ŠŠ‹‰Š’ƒ›Ž‘ƒ†•Ǥ  •›–Š‡•‡•Ͷ͵ǦͶͶƒ†‹•—Ž‹‡…ƒ’•—Žƒ–‹‘•Ͷͳ™‡”‡”‡Ǧ ƒŽ‹œ‡†˜‹ƒŽ‹–‡”ƒ–—”‡’”‘–‘…‘Ž•Ǥ’‡…‹ˆ‹…ƒŽŽ›ǡǦͳͲͲͲ • ȏͳͺͲȋʹͲȌέ͹ͲȋͳͲȌȐ™‡”‡•›–Š‡•‹œ‡†˜‹ƒƒ•‘Ž˜‘–Š‡”ƒŽ”‡Ǧ ƒ…–‹‘ ‘ˆ œ‹”…‘‹— …ŠŽ‘”‹†‡ ȋ”ŽͶȌ ™‹–Š ͶǦ› Ž‹‰ƒ†•ǡ ‘†—Žƒ–‡†„›ƒ…‡–‹…ƒ…‹†‹ǡǦ‹‡–Š›Žˆ‘”ƒ‹†‡ȋ Ȍƒ– ͻͲιȋ ‹‰—”‡ͳȌǤ‹‹Žƒ”Ž›ǡǦʹʹʹ•ȏʹͳͲȋ͵ͲȌέͷͲȋͳͲȌ Ȑ™‡”‡•›–Š‡•‹œ‡†˜‹ƒƒ•‘Ž˜‘–Š‡”ƒŽ”‡ƒ…–‹‘„‡–™‡‡œ‹”Ǧ …‘›Ž…ŠŽ‘”‹†‡‘…–ƒŠ›†”ƒ–‡ȋ”ŽʹȉͺʹȌƒ†ͶǦǦʹŽ‹‰Ǧ ƒ†•ǡ‘†—Žƒ–‡†„›†‹…ŠŽ‘”‘ƒ…‡–‹…ƒ…‹†‹ ƒ–ͳ͵Ͳιȋ ‹‰Ǧ —”‡ͳȌǤ‡š–ǡ–Š‡–Š‡”ƒŽŽ›ƒ…–‹˜ƒ–‡†…”›•–ƒŽ•‘ˆǦͳͲͲͲ™‡”‡ –”‡ƒ–‡†™‹–Šƒ„‹•Ǧ–”‹•Ǧ’”‘’ƒ‡„—ˆˆ‡”ȋǡ’α͹Ȍ•‘Ž—–‹‘‘ˆ ‹•—Ž‹ ȋͲǤͶ ‰ȀȌǤ Š‡    ‹•—Ž‹ ‡…ƒ’•—Žƒ–‹‘ ‡ˆˆ‹Ǧ …‹‡…‹‡•™‡”‡†‡–‡”‹‡†„›‡ƒ•—”‹‰–Š‡ȏˆ‘”‹•—Ž‹Ȑƒ†

”ȋˆ‘” •Ȍ…‘–‡–•„›‹†—…–‹˜‡Ž›…‘—’Ž‡†’Žƒ•ƒǦ‘’–‹…ƒŽ ‡‹••‹‘ •’‡…–”‘•…‘’›Ǥ  Š‡ ƒš‹—‹•—Ž‹ Ž‘ƒ†‹‰•‘ˆ ͵Ͷ ƒ†͸͵™–Ψ™‡”‡†‡–‡”‹‡†ˆ‘”ǦͳͲͲͲƒ†Ǧʹʹʹ•ǡ ”‡•’‡…–‹˜‡Ž›ǡ™Š‹…Šƒ”‡…‘•‹•–‡–™‹–Š‘—”’”‡˜‹‘—•”‡’‘”–ǤͶͳ

Figure 2Ǥ ȋȌ ‡’”‡•‡–ƒ–‹˜‡ …‘ˆ‘…ƒŽ ˆŽ—‘”‡•…‡…‡ ‹…”‘Ǧ ‰”ƒ’Š•‘ˆͳͲρ‹•—Ž‹̷ǦǦͳͲͲͲ’ƒ”–‹…Ž‡•˜‡”‹ˆ‹‡†–Š‡ …‘Ž‘…ƒŽ‹œƒ–‹‘ ‘ˆ ‹•—Ž‹ ȋ ͸Ͷ͹ …Šƒ‡ŽȌ ƒ†  ȋ …Šƒ‡ŽȌǤȋȌǦ•–ƒ…‹ƒ‰‡‘ˆƒ•‹‰Ž‡ͳͲρ‹•—Ž‹̷ǦǦ ͳͲͲͲ …”›•–ƒŽǤ ȋȌ ‡‰”ƒ†ƒ–‹‘ ’”‘ˆ‹Ž‡• ‘ˆ ǦǦͳͲͲͲ • ƒ† ǦǦʹʹʹ • ‹…—„ƒ–‡† ‹ ‡š–”ƒ…‡ŽŽ—Žƒ” ‡†‹— ȋ†ƒ•Š‡† Ž‹‡•Ȍ ƒ† ‹ •‹—Žƒ–‡† ‹–”ƒ…‡ŽŽ—Žƒ” ‡†‹— ȋ•‘Ž‹† Ž‹‡•Ȍƒ–͵͹ι™‹–ŠͶͲͲ”’•Šƒ‹‰Ǥ

2 ACS Paragon Plus Environment

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Journal of the American Chemical Society Š‡‡š…‡••‹•—Ž‹‹–Š‡•—’‡”ƒ–ƒ–™ƒ•”‡‘˜‡†„›•‡“—‡Ǧ –‹ƒŽ™ƒ•Š‹‰•–‡’•™‹–Š ™ƒ–‡”Ǥ Š‡‹•—Ž‹̷ •™‡”‡ˆ—…–‹‘ƒŽ‹œ‡†™‹–Š—…Ž‡‹…ƒ…Ǧ ‹†•„›…‘‘”†‹ƒ–‹‰–Š‡–‡”‹ƒŽ’Š‘•’Šƒ–‡Ǧ‘†‹ˆ‹‡†‘Ž‹‰‘—Ǧ …Ž‡‘–‹†‡•–‘–Š‡•—”ˆƒ…‡”•Ǥ͵͸ǡͶͷŠ‡•‡“—‡…‡—•‡†Š‡”‡ǡ ͷ̵ȋ†

ȌͳͲǦ’Š‘•’Šƒ–‡͵̵ǡ™ƒ•…Š‘•‡„‡…ƒ—•‡‹–‹•‘™™‹–Š • –Šƒ– ƒ Ǧ”‹…Š •Š‡ŽŽǡ ”‡Žƒ–‹˜‡ –‘ ’‘Ž› † •Š‡ŽŽ•ǡ ˆƒ…‹Ž‹–ƒ–‡• Š‹‰Š‡” …‡ŽŽ—Žƒ” —’–ƒ‡ǤͶ͸  ƒ –›’‹…ƒŽ  ˆ—…–‹‘ƒŽ‹œƒ–‹‘ ‡šǦ ’‡”‹‡–ǡ ‡š…‡•• ‘Ž‹‰‘—…Ž‡‘–‹†‡• ™‡”‡ ƒ††‡† –‘ ƒ …‘ŽŽ‘‹†ƒŽ †‹•’‡”•‹‘‘ˆ •ƒ†‹…—„ƒ–‡†ˆ‘”ͶŠ‘—”•ȋ—’’‘”–‹‰ ˆ‘”ƒ–‹‘ȌǤ ƒ”–‹…Ž‡  …‘˜‡”ƒ‰‡ ™ƒ• “—ƒ–‹–‹˜‡Ž› †‡–‡”Ǧ ‹‡† „› ‡ƒ•—”‹‰ –Š‡  –‘ ” ”ƒ–‹‘ „› Ǧ ȋͺ ά ͳ ‘ŽȀ‰ˆ‘”ǦͳͲͲͲ•ƒ†ͳͲάͳ‘ŽȀ‰ˆ‘”Ǧʹʹʹ •ȌǤ‘™†‡”Ǧ”ƒ›†‹ˆˆ”ƒ…–‹‘ȋȌƒ†•…ƒ‹‰‡Ž‡…–”‘ ‹…”‘•…‘’› ȋȌ …‘ˆ‹”‡† –Šƒ– –Š‡ …”›•–ƒŽŽ‹‹–› ƒ† ‘”Ǧ ’Š‘Ž‘‰‹‡•‘ˆ–Š‡ •™‡”‡ƒ‹–ƒ‹‡†ǡ’‘•–Ǧˆ—…–‹‘Ǧ ƒŽ‹œƒ–‹‘ȋ ‹‰—”‡ ʹƒ†͵ȌǤ ’‘”–ƒ–Ž›ǡ†›ƒ‹…Ž‹‰Š– •…ƒ–Ǧ –‡”‹‰ȋȌ˜‡”‹ˆ‹‡†–Šƒ–•—”ˆƒ…‡ˆ—…–‹‘ƒŽ‹œƒ–‹‘•‹‰‹ˆǦ ‹…ƒ–Ž› ‹…”‡ƒ•‡•    …‘ŽŽ‘‹†ƒŽ •–ƒ„‹Ž‹–› ‹ …‡ŽŽ—Žƒ” ‡†‹ƒ ȋͻͲΨ„—ˆˆ‡”ΪͳͲΨˆ‡–ƒŽ„‘˜‹‡•‡”—Ȍˆ‘”ƒ–Ž‡ƒ•–ʹͶ Š‘—”•Ǣˆ‘”…‘’ƒ”‹•‘ǡ —ˆ—…–‹‘ƒŽ‹œ‡†ǦͳͲͲͲ• ƒ‰‰”‡Ǧ ‰ƒ–‡†‹Ž‡••–Šƒ‘‡Š‘—”ǡŠƒ’‡”‹‰ˆ—”–Š‡”in vitro—•‡ȋ ‹‰Ǧ —”‡ͳƒ†ͳǡ‹ƒ‰‡‘ˆƒ‰‰”‡‰ƒ–‡†•ǣ ‹‰—”‡ͷȌǤ ƒ††‹–‹‘–‘…‘ŽŽ‘‹†ƒŽ•–ƒ„‹Ž‹–›ǡ–Š‡‹–”ƒǦƒ†‡š–”ƒ…‡ŽŽ—Žƒ” •–ƒ„‹Ž‹–›‘ˆ’”‘–‡‹†‡Ž‹˜‡”›˜‡Š‹…Ž‡•‹•‡”—ƒ†•‡”—ˆ”‡‡ „—–„‹‘Ž‘‰‹…ƒŽŽ›”‡Ž‡˜ƒ–ƒ–”‹…‡•‹•‹’‘”–ƒ–Ǥ †‡‡†ǡ–Š‡ƒ„‹ŽǦ ‹–›–‘…‘–”‘Ž†‡‰”ƒ†ƒ–‹‘…‘—Ž†„‡—•‡ˆ—Ž‹–Š‡†‡˜‡Ž‘’‡– ‘ˆ –‡’‘”ƒŽŽ›Ǧ…‘–”‘ŽŽ‡† †”—‰ †‡Ž‹˜‡”› ƒ’’Ž‹…ƒ–‹‘•Ǥ †‡” ’Š›•‹‘Ž‘‰‹…ƒŽ …‘†‹–‹‘•ǡ ‹–”ƒ…‡ŽŽ—Žƒ” ˆŽ—‹† ‡šŠ‹„‹–• •‹‰‹ˆ‹Ǧ …ƒ–Ž› Š‹‰Š‡” ‹‘”‰ƒ‹… ’Š‘•’Šƒ–‡ …‘…‡–”ƒ–‹‘ ȋͷ̱ͳͲ Ȍ ƒ•…‘’ƒ”‡†–‘–Šƒ–‘ˆ•‡”—ȋ̱ͳȌǤͶ͹ǦͶͺŠ‡”‡ˆ‘”‡ǡ–Š‡†‡‰Ǧ ”ƒ†ƒ–‹‘ ’”‘ˆ‹Ž‡• ‘ˆ ‹•—Ž‹̷ǦǦͳͲͲͲ • ƒ† ‹•—Ǧ Ž‹̷ǦǦʹʹʹ • ™‡”‡ ‡˜ƒŽ—ƒ–‡† „› ‡š’‘•‹‰ –Š‡ –‘ •‘Ž—–‹‘•†‡•‹‰‡†–‘‡—Žƒ–‡„‘–Š‡š–”ƒ…‡ŽŽ—Žƒ”ƒ†‹–”ƒ…‡ŽǦ Ž—Žƒ”…‘†‹–‹‘•ȋ—’’‘”–‹‰ ˆ‘”ƒ–‹‘ȌǤ‘•‹—Žƒ–‡•‡”—ǡ  •™‡”‡‹…—„ƒ–‡†™‹–ŠͻͲΨ„—ˆˆ‡”ΪͳͲΨ„Ž‘‘† •‡”—ȋ’α͹ǤͲȌƒ–͵͹ι™‹–Š‰‡–Ž‡•Šƒ‹‰ȋͶͲͲ”’Ȍǡ™Š‡”‡ Ž‡••–ŠƒͷΨ‘ˆ†‡‰”ƒ†ƒ–‹‘‘……—””‡†™‹–Š‹ͳʹŠ‘—”•ˆ‘”„‘–Š ˜‡Š‹…Ž‡•ǡƒ†Ž‡••–ŠƒʹͲΨ™‹–Š‹ͻ͸Š‘—”•ǡ•—‰‰‡•–‹‰Ǧ  •‡šŠ‹„‹–‡š…‡ŽŽ‡–•–ƒ„‹Ž‹–›ƒ†ƒ›„‡…‘’ƒ–‹„Ž‡™‹–Š „Ž‘‘†ȋ ‹‰—”‡ʹǡ†ƒ•Š‡†ȌǤ …‘–”ƒ•–ǡ™Š‡–Š‡•ƒ‡ • ™‡”‡‹…—„ƒ–‡†‹ƒ‹–”ƒ…‡ŽŽ—Žƒ”‡†‹—•‹—Žƒ–ȋͳέ’Š‘•Ǧ ’Šƒ–‡„—ˆˆ‡”‡†•ƒŽ‹‡ǡ’α͹ǤͲȌƒ–͵͹ι™‹–Š‰‡–Ž‡•Šƒ‹‰ǡ –Š‡’ƒ”–‹…Ž‡•†‡‰”ƒ†‡ƒ–—…Šˆƒ•–‡””ƒ–‡•ȋ ‹‰—”‡ʹǡ•‘Ž‹†Ȍ†—‡ –‘–Š‡Š‹‰Š’Š‘•’Šƒ–‡…‘–‡–ǡ™Š‹…Š…‘’‡–‹–‹˜‡Ž›„‹†•–‘” …Ž—•–‡”•Ǥ –‡”‡•–‹‰Ž›ǡǦǦʹʹʹ•‡šŠ‹„‹–ƒˆƒ•–‡”†‡‰Ǧ ”ƒ†ƒ–‹‘”ƒ–‡ȋŠƒŽˆǦŽ‹ˆ‡αͳŠȌ™Š‡…‘’ƒ”‡†–‘–Šƒ–‘ˆǦ ǦͳͲͲͲ•ȋŠƒŽˆǦŽ‹ˆ‡αͶͲŠȌǤ—…Š†‡‰”ƒ†ƒ–‹‘‹‡–‹…•…‘—Ž† „‡—•‡ˆ—Žˆ‘”in vivo’—”’‘•‡•„›’”‘˜‹†‹‰ƒ‡ƒ•–‘…‘–”‘Ž –Š‡ –‡’‘”ƒŽ ”‡Ž‡ƒ•‡ ‘ˆ ’”‘–‡‹• ˆ”‘ ’ƒ”–‹…Ž‡•ǡ ‘…‡ ‹•‹†‡ …‡ŽŽ•Ǥ ‘†‹”‡…–Ž›˜‹•—ƒŽ‹œ‡—…Ž‡‹…ƒ…‹†Ǧ‘†‹ˆ‹‡†ǡ‹•—Ž‹‡…ƒ’•—Ǧ Žƒ–‡† •ǡ™‡‡’Ž‘›‡†…‘ˆ‘…ƒŽŽƒ•‡”•…ƒ‹‰‹…”‘•Ǧ …‘’›–‘‹ƒ‰‡–Š‡Ǥ—‡–‘–Š‡”‡•‘Ž—–‹‘Ž‹‹–•‘ˆ…‘ˆ‘…ƒŽ‹Ǧ …”‘•…‘’›ǡ Žƒ”‰‡” ’ƒ”–‹…Ž‡• ȋʹǤͺ ρ έ ͳͲ ρ ˆ‘” ǦͳͲͲͲȌǡ Ž‡šƒ Ž—‘” ͸Ͷ͹ †›‡ ȋ ͸Ͷ͹ȌǦŽƒ„‡Ž‡† ‹•—Ž‹ǡ ƒ† Ǧ Žƒ„‡Ž‡†™‡”‡—•‡†Ǥ‹–Š•—…Š’ƒ”–‹…Ž‡•ǡ–Š‡…‘ǦŽ‘…ƒŽ‹œƒ–‹‘ ‘ˆ ͸Ͷ͹ƒ†•‹‰ƒŽ•…ƒ„‡…Ž‡ƒ”Ž›‘„•‡”˜‡†ǡ˜‡”‹ˆ›‹‰ –Š‡‡…ƒ’•—Žƒ–‹‘‘ˆ‹•—Ž‹ƒ†•—”ˆƒ…‡ˆ—…–‹‘ƒŽ‹œƒ–‹‘ ‘ˆ–Š‡ ȋ ‹‰ʹȌǤ‘‘„–ƒ‹†‡–ƒ‹Ž‡†‹ˆ‘”ƒ–‹‘”‡‰ƒ”†‹‰ ”‡Žƒ–‹˜‡†‹•–”‹„—–‹‘‘ˆ‹•—Ž‹ƒ†ǡǦ•–ƒ…‹ƒ‰‡•‘ˆƒ•‹Ǧ ‰Ž‡ ’ƒ”–‹…Ž‡™‡”‡–ƒ‡ǡ™Š‡”‡•‹‰ƒŽȋȌ™ƒ•

‘„•‡”˜‡†–‘’”‡ˆ‡”‡–‹ƒŽŽ›‘……—’›–Š‡’‡”‹’Š‡”›™Š‹Ž‡ ͸Ͷ͹ ȋ‹•—Ž‹Ȍ™ƒ•’”‡•‡– –Š”‘—‰Š‘—– –Š‡’ƒ”–‹…Ž‡ȋ ‹‰—”‡ʹ ƒ† ‹‰—”‡͹ȌǤ”‹‰Š–‡” ͸Ͷ͹•‹‰ƒŽ•™‡”‡‘„•‡”˜‡†ƒ–„‘–Š‡†• ‘ˆ–Š‡’ƒ”–‹…Ž‡ ƒ•…‘’ƒ”‡†–‘–Š‡…‡–‡”•‡…–‹‘‘ˆ–Š‡ ǡ …‘•‹•–‡–™‹–Š–Š‡’”‡˜‹‘—•‘„•‡”˜ƒ–‹‘–Šƒ–’”‘–‡‹•†‹ˆˆ—•‡ ‹–‘ǦͳͲͲͲ–Š”‘—‰Š‹–•ͳ…Šƒ‡Ž•ǤͶʹ—‡–‘–Š‡Žƒ”‰‡†‹ƒǦ ‡–‡”‘ˆ–Š‡ ’‘”‡•ȋ͵Ǥʹˆ‘”ǦͳͲͲͲƒ†͵Ǥ͹ˆ‘”Ǧ ʹʹʹȌǡͶͲ •‹‰Ž‡ •–”ƒ†‡†  ™ƒ• ƒŽ•‘ ‡š’‡…–‡† –‘ ’‡‡–”ƒ–‡ –Š”‘—‰Š–Š‡ ’‘”‡•ƒ†ˆ—…–‹‘ƒŽ‹œ‡–Š‡‹–‡”ƒŽ•—”ˆƒ…‡ǡ Ž‡ƒ†‹‰–‘ˆŽ—‘”‡•…‡…‡•‹‰ƒŽ‹•‹†‡–Š‡’ƒ”–‹…Ž‡•Ǥ•˜‡”‹ˆ‹‡† „› ʹ ƒ†•‘”’–‹‘ ‹•‘–Š‡”•ǡ ”‡†—…‡† ʹ —’–ƒ‡ …ƒ’ƒ…‹–› ™ƒ• ‘„•‡”˜‡† ’‘•–Ǧ‹•—Ž‹ ‡…ƒ’•—Žƒ–‹‘ ˆ‘” „‘–Š  •ǡ ƒ† ˆ—”Ǧ –Š‡”Ž‘••‘ˆ’‘”‘•‹–›™ƒ•‘„•‡”˜‡†’‘•–Ǧˆ—…–‹‘ƒŽ‹œƒ–‹‘ ȋ ‹‰—”‡ͻƒ†ͳͲȌǤ —”–Š‡”‘”‡ǡƒ‡œ›‡ǦŽ‹‡†‹—‘Ǧ •‘”„‡–ƒ••ƒ›ȋ Ȍ™ƒ•‡’Ž‘›‡†–‘†‡–‡”‹‡™Š‡–Š‡”‹Ǧ •—Ž‹™‘—Ž†Ž‡ƒ…Šˆ”‘–Š‡ ’‘”‡•ƒ†Ȁ‘”Ž‘•‡…ƒ–ƒŽ›–‹… ƒ…–‹˜‹–› †—”‹‰ –Š‡  ˆ—…–‹‘ƒŽ‹œƒ–‹‘ ’”‘…‡••Ǥ  „‘–Š …ƒ•‡•ǡ‘ƒ’’”‡…‹ƒ„Ž‡Ž‡ƒ…Š‹‰ƒ†Ȁ‘”‹•—Ž‹ƒ…–‹˜‹–›Ž‘••™ƒ• ‘„•‡”˜‡† ˆ‘” ‹•—Ž‹̷ǦǦͳͲͲͲ ƒ† ‹•—Ž‹̷ǦǦ ʹʹʹ…‘•–”—…–• ȋ ‹‰—”‡ͺȌǤ •’”‡˜‹‘—•Ž›•–ƒ–‡†ǡƒ‡›…Šƒ”ƒ…–‡”‹•–‹…‘ˆǦ…‘Œ—Ǧ ‰ƒ–‡• ‹• –Š‡‹” ƒ„‹Ž‹–› –‘ ‡ˆˆ‡…–‹˜‡Ž› ‡–‡” …‡ŽŽ•Ǥ Š‡”‡ˆ‘”‡ǡ ™‡ –‡•–‡† ™Š‡–Š‡” ‹•—Ž‹̷Ǧ  • ‡šŠ‹„‹–‡† ‡Šƒ…‡† …‡ŽŽ—Žƒ”—’–ƒ‡Ǥ’‡…‹ˆ‹…ƒŽŽ›ǡǦͳͲͲͲƒ†Ǧʹʹʹ•™‡”‡ ‡…ƒ’•—Žƒ–‡† ™‹–Š  ͸Ͷ͹ǦŽƒ„‡Ž‡† ‹•—Ž‹ ƒ† ˆ—…–‹‘ƒŽ‹œ‡† ™‹–ŠǦŽƒ„‡Ž‡†ƒ†‹…—„ƒ–‡†™‹–ŠŠ—ƒ‘˜ƒ”‹ƒ ƒ†‡‘…ƒ”…‹‘ƒ…‡ŽŽ•ǡǦ͵ǡˆ‘”ͲǤͷŠǡʹŠǡ͸Šǡƒ†ʹͶŠȋ—’Ǧ ’‘”–‹‰ ˆ‘”ƒ–‹‘ȌǤ • ƒ …‘–”‘Ž ‰”‘—’ǡ ƒ ‹š–—”‡ ‘ˆ ˆ”‡‡ ǦŽƒ„‡Ž‡†  ƒ†  Ǧ͸Ͷ͹ǦŽƒ„‡Ž‡† ‹•—Ž‹ ™ƒ• ‹…—Ǧ „ƒ–‡†™‹–Š…‡ŽŽ•ƒ––Š‡•ƒ‡…‘…‡–”ƒ–‹‘Ǥ‘ˆ‘…ƒŽŽƒ•‡”•…ƒǦ ‹‰‹…”‘•…‘’›…‘ˆ‹”•–Š‡‡”‹…Š‡–‘ˆ‹•—Ž‹‹…‡ŽŽ—Žƒ” ˜‡•‹…Ž‡•ǡ ƒ• ‡˜‹†‡…‡† „› •–”‘‰ …‘Ž‘…ƒŽ‹œƒ–‹‘ ‘ˆ  ͸Ͷ͹ ƒ† •‹‰ƒŽ•‹…‡ŽŽ—Žƒ”˜‡•‹…Ž‡•ȋ ‹‰—”‡•͵ǦȌǤŠ‡Ǧ•–ƒ… ‹ƒ‰‡• …‘ˆ‹” –Šƒ– –Š‡ ‹•—Ž‹̷Ǧ  • ƒ”‡ ‹–‡”ƒŽǦ ‹œ‡†„›–Š‡…‡ŽŽ•ǡƒ•‘’’‘•‡†–‘ƒ––ƒ…Š‡†–‘–Š‡‹”‡„”ƒ‡•Ǥ

Figure 3ǤȋǦȌ Ž‘™…›–‘‡–”›’Ž‘–•ƒ†…‘ˆ‘…ƒŽˆŽ—‘”‡•…‡…‡ ‹…”‘‰”ƒ’Š•‘ˆǦ…‡ŽŽ•ƒˆ–‡”͸Š–”‡ƒ–‡–™‹–Šˆ”‡‡‹•—Ž‹ ΪȋȌǡ‹•—Ž‹̷ǦǦͳͲͲͲȋȌǡƒ†‹•—Ž‹̷ǦǦ ʹʹʹȋȌǤȋȌ‡ŽŽ—Žƒ”—’–ƒ‡‘ˆ‹•—Ž‹†‡Ž‹˜‡”‡†‹†‹ˆˆ‡”‡–…‘Ǧ •–”—…–•ƒ•†‡–‡”‹‡†„›ˆŽ‘™…›–‘‡–”›Ǥ Ž—‘”‡•…‡…‡ƒ–͸Ͷ͹ ™ƒ•‡ƒ•—”‡†‹Ǧ…‡ŽŽ•ƒˆ–‡”–”‡ƒ–‡–™‹–Š‹•—Ž‹ƒ– ˜ƒ”‹‘—•‹…—„ƒ–‹‘–‹‡ȋͲǤͷŠƒ†ʹŠȌǤȋȌƒ••ƒ›˜‡”‹ˆ‹‡• ‘ƒ’’”‡…‹ƒ„Ž‡…›–‘–‘š‹…‹–›‹†—…‡†„›‹•—Ž‹̷ǦǦʹʹʹ ƒ†‹•—Ž‹̷ǦǦͳͲͲͲ•Ǥ…ƒŽ‡„ƒ”αͳͲρǤ

3 ACS Paragon Plus Environment

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‘•‹•–‡–™‹–Š–Š‹•…‘…Ž—•‹‘ǡˆŽ‘™…›–‘‡–”›•Š‘™‡†ƒͳͲǦ ˆ‘Ž† ‹…”‡ƒ•‡ ‹ ˆŽ—‘”‡•…‡…‡ ‹ …‡ŽŽ• –”‡ƒ–‡† ™‹–Š ‹•—Ǧ Ž‹̷Ǧ •ƒ•…‘’ƒ”‡†–‘–Š‘•‡–”‡ƒ–‡†™‹–Š–Š‡ˆ”‡‡ ‹•—Ž‹ Ϊ  …‘–”‘Ž ‰”‘—’ ȋ ‹‰—”‡ ͵ȌǤ Š‡ ‹•—Ž‹̷Ǧ  •‡šŠ‹„‹–••‹‹Žƒ”Ž‡˜‡Ž•‘ˆ‡Šƒ…‡‡–‹…‡ŽŽ—Žƒ”—’Ǧ –ƒ‡ǡƒ•…‘’ƒ”‡†–‘–Šƒ–‘ˆ…‘˜‡–‹‘ƒŽǦ…‘Œ—‰ƒ–‡•ǤͶͻ ‹ƒŽŽ›ǡƒ••ƒ›••Š‘™–Šƒ––Š‡’ƒ”–‹…Ž‡•”‡•—Ž–‹‘ƒ’’ƒ”Ǧ ‡–…›–‘–‘š‹…‹–›‘”ƒ–‹Ǧ’”‘Ž‹ˆ‡”ƒ–‹˜‡‡ˆˆ‡…–•ȋ ‹‰—”‡•͵ȌǤ …‘…Ž—•‹‘ǡ™‡Šƒ˜‡†‡˜‡Ž‘’‡†ƒˆƒ…‹Ž‡•–”ƒ–‡‰›ˆ‘”—•‹‰ —…Ž‡‹…Ǧƒ…‹†‘†‹ˆ‹‡† •–‘†‡Ž‹˜‡”’”‘–‡‹•ƒ…”‘••…‡ŽŽ ‡„”ƒ‡•ƒ–Š‹‰Š’ƒ›Ž‘ƒ†•ƒ†‡‰Ž‹‰‹„Ž‡…›–‘–‘š‹…‹–›ǤŠ‹• ™‘”‹•‹’‘”–ƒ–•‹…‡‹–Š‹‰ŠŽ‹‰Š–•Š‘™…Ž—•–‡”‡†•—”ˆƒ…‡‘Ž‹Ǧ ‰‘—…Ž‡‘–‹†‡•‘–Š‡•‡‘†—Žƒ”ƒ–‡”‹ƒŽ•…ƒ„‡—•‡†–‘ƒ‡ –Š‡…‘ŽŽ‘‹†ƒŽŽ›•–ƒ„Ž‡‹’Š›•‹‘Ž‘‰‹…ƒŽ‡˜‹”‘‡–•ƒ†—•‡Ǧ ˆ—Žˆ‘”‹–”ƒ…‡ŽŽ—Žƒ”„‹‘Ž‘‰‹…ƒŽƒ’’Ž‹…ƒ–‹‘•Ǥ —–—”‡†‡•‹‰‹–‡”ƒǦ –‹‘• ™‹ŽŽ ƒŽŽ‘™ ˆ‘” ‡…ƒ’•—Žƒ–‹‰ ˜ƒ”‹‘—• ’”‘–‡‹• „› –—‹‰ –Š‡ ’‘”‡•‹œ‡•ǡͶʹǡͷͲǦͷͳƒ†’‘–‡–‹ƒŽŽ›…‘Ǧ†‡Ž‹˜‡”›‘ˆ’”‘Ǧ –‡‹ƒ†—…Ž‡‹…ƒ…‹†–ƒ”‰‡–•–Šƒ–ƒ”‡‹’‘”–ƒ–ˆ‘”ƒ›’—”Ǧ ’‘•‡•ǡ‹…Ž—†‹‰in vivo‹ƒ‰‹‰ǡʹ‰‡‡”‡‰—Žƒ–‹‘ǡ͵ͷ–Š‡”ƒ’‡—Ǧ –‹…•ǡͷƒ†–Š‡•–—†›‘ˆˆ—†ƒ‡–ƒŽ…‡ŽŽ—Žƒ”’”‘…‡••‡•ǤͶ

ASSOCIATED CONTENT Supporting Information Š‡—’’‘”–‹‰ ˆ‘”ƒ–‹‘‹•ƒ˜ƒ‹Žƒ„Ž‡ˆ”‡‡‘ˆ…Šƒ”‰‡‘–Š‡ —„Ž‹…ƒ–‹‘•™‡„•‹–‡Ǥ  š’‡”‹‡–ƒŽ ƒ–‡”‹ƒŽ•ǡ ‡–Š‘†•ǡ    •›–Š‡•‡•ǡ  ’ƒ––‡”•ǡ  •‡“—‡…‡•ǡ ‹–”‘‰‡ •‘”’–‹‘ ‹•‘–Š‡”•ǡ ƒ† •—’’Ž‡‡–ƒŽˆ‹‰—”‡•ȋ Ȍ

AUTHOR INFORMATION Corresponding Author ȗ‘Ǧˆƒ”Šƒ̷‘”–Š™‡•–‡”Ǥ‡†— ȗ…Šƒ†ƒ‘̷‘”–Š™‡•–‡”Ǥ‡†—

Author Contributions ȘŠ—œŠ‹ǤǤƒ†ǤǤ…‘–”‹„—–‡†‡“—ƒŽŽ›Ǥ



Notes Š‡ƒ—–Š‘”•†‡…Žƒ”‡‘…‘’‡–‹‰ˆ‹ƒ…‹ƒŽ‹–‡”‡•–•Ǥ

ACKNOWLEDGMENT Š‹•ƒ–‡”‹ƒŽ‹•„ƒ•‡†—’‘™‘”•—’’‘”–‡†„›–Š‡ˆ‘ŽŽ‘™‹‰ ƒ™ƒ”†•ǣ‹” ‘”…‡ˆˆ‹…‡‘ˆ…‹‡–‹ˆ‹…‡•‡ƒ”…Š ͻͷͷͲǦͳͶǦͳǦ Ͳʹ͹Ͷǡ ƒ–‹‘ƒŽ …‹‡…‡ ‘—†ƒ–‹‘ǯ•  ’”‘‰”ƒ ȋǦ ͳͳʹͳʹ͸ʹȌƒ†ƒ†‡—•‡‘ˆ‹–•Šƒ”‡† ƒ…‹Ž‹–‹‡•ƒ––Š‡ƒ–‡”‹ƒŽ• ‡•‡ƒ”…Š‡–‡”‘ˆ‘”–Š™‡•–‡”‹˜‡”•‹–›ǤǤǤ Ǥ‰”ƒ–‡ˆ—ŽŽ› ƒ…‘™Ž‡†‰‡–Š‡‡ˆ‡•‡Š”‡ƒ–‡†—…–‹‘‰‡…›ˆ‘”ˆ‹ƒǦ …‹ƒŽ •—’’‘”– ȋͳǦͳͶǦͳǦͲͲͳͶȌǤ Š—œŠ‹ǤǤ ƒ…‘™Ž‡†‰‡• •—’’‘”–ˆ”‘–Š‡  ‡ŽŽ‘™•Š‹’ǤŠ—›ƒǤǤƒ…‘™Ž‡†‰‡••—’Ǧ ’‘”–ˆ”‘–Š‡›ƒ ‡ŽŽ‘™•Š‹’ƒ–‘”–Š™‡•–‡”‹˜‡”•‹–›ƒ† –Š‡ Š‡‹•–”› ‘ˆ ‹ˆ‡ ”‘…‡••‡• ȋȌ ”‡†‘…–‘”ƒŽ ”ƒ‹‹‰ ”‘‰”ƒƒ–‘”–Š™‡•–‡”‹˜‡”•‹–›Ǥ

REFERENCES ȋͳȌ ̵•–‘Žˆ‘ǡǤǤǢƒ‰Ž‹‡”‘ǡǤ ǤǢ”ƒ•ǡǤǢƒ”–Šƒ—•ǡǤǤǢŽ‡˜‡”•ǡǤǢ ”ƒ•ƒ†ǡ ǤǢ ‡„„‹ǡ Ǥ ǤǢ ‡Šƒǡ ǤǢ ‡‹Œ•‡ǡ Ǥ ˆˆ‹…‹‡– –”ƒ…‡ŽŽ—Žƒ”‡Ž‹˜‡”›‘ˆƒ–‹˜‡”‘–‡‹•ǤCell 2015,161ǡ͸͹ͶǦ͸ͻͲǤ

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ȋʹȌ ‘ˆˆƒǡ Ǥ Ǥ ”‡‡ ˆŽ—‘”‡•…‡– ’”‘–‡‹ ‹ƒ‰‹‰ ‘ˆ –—‘—” ‰”‘™–Šǡ ‡–ƒ•–ƒ•‹•ǡ ƒ† ƒ‰‹‘‰‡‡•‹• ‹ ‘—•‡ ‘†‡Ž•Ǥ Lancet Oncol. 2002,3ǡͷͶ͸Ǧͷͷ͸Ǥ ȋ͵Ȍ ‘”…Š‹Ž‹ǡ Ǥ –”ƒ…‡ŽŽ—Žƒ” †‡Ž‹˜‡”› ‘ˆ ’”‘–‡‹ ƒ† ’‡’–‹†‡ –Š‡”ƒ’‡—–‹…•ǤDrug Discovery Today: Technol. 2008,5ǡ‡ͻͷǦ‡ͳͲ͵Ǥ ȋͶȌ ‡•‹…ǡ Ǥ ǤǢ …Š—…Šƒǡ Ǥ Ǥ œ›‡ ”‡’Žƒ…‡‡– ƒ† ‡Šƒ…‡‡––Š‡”ƒ’‹‡•ǣ‡••‘•ˆ”‘Ž›•‘•‘ƒŽ†‹•‘”†‡”•Ǥ Nat. Rev. Genet. 2002,3ǡͻͷͶǦͻ͸͸Ǥ ȋͷȌ ‡ƒ†‡”ǡ ǤǢ ƒ…ƒǡ Ǥ ǤǢ ‘Žƒǡ Ǥ Ǥ ”‘–‡‹ –Š‡”ƒ’‡—–‹…•ǣ  •—ƒ”› ƒ† ’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ …Žƒ••‹ˆ‹…ƒ–‹‘Ǥ Nat. Rev. Drug Discovery 2008,7ǡʹͳǦ͵ͻǤ ȋ͸Ȍ ‡–”‘•ǡ Ǥ ǤǢ ‡‹‘‡ǡ Ǥ Ǥ –”ƒ–‡‰‹‡• ‹ –Š‡ †‡•‹‰ ‘ˆ ƒ‘’ƒ”–‹…Ž‡• ˆ‘” –Š‡”ƒ’‡—–‹… ƒ’’Ž‹…ƒ–‹‘•Ǥ Nat. Rev. Drug Discovery 2010,9ǡ͸ͳͷǦ͸ʹ͹Ǥ ȋ͹Ȍ Š‘•ŠǡǤǢƒ‰ǡǤǤǢ”˜‹œ‘ǡǤǢŠ—ǡǤ ǤǢ‰ƒ•–‹ǡǤǤǢ‘ǡǤǤǢ ‘–‡ŽŽ‘ǡǤǤ –”ƒ…‡ŽŽ—Žƒ”‡Ž‹˜‡”›‘ˆƒ‡„”ƒ‡Ǧ ’‡”‡ƒ„Ž‡ œ›‡‹…–‹˜‡ ‘”•‹‰ —…–‹‘ƒŽ‹œ‡† ‘Ž†ƒ‘’ƒ”–‹…Ž‡•Ǥ J. Am. Chem. Soc. 2010,132ǡʹ͸ͶʹǦʹ͸ͶͷǤ ȋͺȌ —ǡ ǤǢ ‹•™ƒ•ǡ ǤǢ Šƒ‘ǡ ǤǢ ƒ‰ǡ Ǥ ƒ‹Ž‘”‹‰ ƒ‘…ƒ””‹‡”• ˆ‘” ‹–”ƒ…‡ŽŽ—Žƒ” ’”‘–‡‹ †‡Ž‹˜‡”›Ǥ Chem. Soc. Rev. 2011, 40ǡ ͵͸͵ͺǦ ͵͸ͷͷǤ ȋͻȌ —ǡ Ǥ ǤǢ ‘•–ƒǡ ǤǢ —”‰‡••ǡ Ǥ Ǥ ”‘–‡‹ …ƒ’•—Žƒ–‹‘ ‹ ‹Žƒ‡ŽŽƒ” ‹’‘•‘‡•ǣ ‹‰Š …ƒ’•—Žƒ–‹‘ ˆˆ‹…‹‡…› ƒ†  ‘˜‡Ž‡…Š‹“—‡–‘••‡••‹’‹†Ǧ”‘–‡‹ –‡”ƒ…–‹‘ǤPharm. Res. 2012,29ǡͳͻͳͻǦͳͻ͵ͳǤ ȋͳͲȌ …Š™ƒ”œ‡ǡ Ǥ ǤǢ ‘ǡ ǤǢ ‘…‡”‘Ǧ„ƒ‹ǡ ǤǢ ‘™†›ǡ Ǥ Ǥ  ˜‹˜‘ ’”‘–‡‹–”ƒ•†—…–‹‘ǣ‡Ž‹˜‡”›‘ˆƒ„‹‘Ž‘‰‹…ƒŽŽ›ƒ…–‹˜‡’”‘–‡‹‹–‘ –Š‡‘—•‡ǤScience 1999,285ǡͳͷ͸ͻǦͳͷ͹ʹǤ ȋͳͳȌ ƒ™”‡…‡ǡ Ǥ ǤǢ Š‹ŽŽ‹’•ǡǤ ǤǢ ‹—ǡ ǤǤ—’‡”…Šƒ”‰‹‰ ’”‘–‡‹• …ƒ‹’ƒ”–——•—ƒŽ”‡•‹Ž‹‡…‡ǤJ. Am. Chem. Soc. 2007,129ǡͳͲͳͳͲǦ ΪǤ ȋͳʹȌ ”‘‹…ƒǡ Ǥ ǤǢ Š‘’•‘ǡ Ǥ ǤǢ ‡‹‡”ǡ Ǥ ǤǢ …ƒ—‰Š–‘ǡ Ǥ ǤǢ ‡’‘ǡǤǤǢ‹—ǡǤǤ‘–‡–‡Ž‹˜‡”›‘ˆ —…–‹‘ƒŽ”‘–‡‹•‹–‘ ƒƒŽ‹ƒ ‡ŽŽ• ‹ ‹–”‘ ƒ† ‹ ‹˜‘ •‹‰ ƒ —’‡”…Šƒ”‰‡† ”‘–‡‹ǤACS Chem. Biol. 2010,5ǡ͹Ͷ͹Ǧ͹ͷʹǤ ȋͳ͵Ȍ ”‘†‹ǡ Ǥ ǤǢ ’”ƒ‰‡”•ǡ Ǥ ǤǢ …‹ŽŽƒǡ Ǥ ǤǢ ‹”‹ǡ Ǥ Ǥ Ǧ ‡†‹ƒ–‡† ‡ŽŽ—Žƒ” ‡Ž‹˜‡”› ‘ˆ —…–‹‘ƒŽ œ›‡•Ǥ J. Am. Chem. Soc. 2015,137ǡͳͶͺ͵ͺǦͳͶͺͶͳǤ ȋͳͶȌ —ǡǤǤǢƒ‰ǡǤǢƒ”†‹‡ǡ ǤǢ ƒ”ƒ•ǡǤǤǢ‘–‡ŽŽ‘ǡǤǤ”‘‹•‡• ƒ† ‹–ˆƒŽŽ• ‘ˆ –”ƒ…‡ŽŽ—Žƒ” ‡Ž‹˜‡”› ‘ˆ ”‘–‡‹•Ǥ Bioconjugate Chem. 2014,25ǡͳ͸ͲʹǦͳ͸ͲͺǤ ȋͳͷȌ ‹”‹ǡ Ǥ ǤǢ ‡–•‹‰‡”ǡ Ǥ ǤǢ —…‹…ǡ Ǥ ǤǢ –‘”Š‘ˆˆǡ Ǥ Ǥ  Ǧ „ƒ•‡† ‡–Š‘† ˆ‘” ”ƒ–‹‘ƒŽŽ› ƒ••‡„Ž‹‰ ƒ‘’ƒ”–‹…Ž‡• ‹–‘ ƒ…”‘•…‘’‹…ƒ–‡”‹ƒŽ•ǤNature 1996,382ǡ͸Ͳ͹Ǧ͸ͲͻǤ ȋͳ͸Ȍ ƒ–‡ŽǡǤǤǢ ‹ŽŒ‘ŠƒǡǤǤǢƒ‹‡ŽǡǤǤǢŠ‡‰ǡǤǢ”‹‰‘†‹…ŠǡǤ ǤǢ‹”‹ǡǤǤ…ƒ˜‡‰‡”‡…‡’–‘”•‡†‹ƒ–‡‡ŽŽ—Žƒ”’–ƒ‡‘ˆ ‘Ž›˜ƒŽ‡– Ž‹‰‘—…Ž‡‘–‹†‡Ǧ —…–‹‘ƒŽ‹œ‡† ‘Ž† ƒ‘’ƒ”–‹…Ž‡•Ǥ Bioconjugate Chem. 2010,21ǡʹʹͷͲǦʹʹͷ͸Ǥ ȋͳ͹Ȍ Š‘‹ǡǤǤ ǤǢƒ‘ǡǤǤǢƒ”ƒ›ƒǡǤǤǢ—›‡—‰ǡǤǢ‹”‹ǡǤǤ ‡…Šƒ‹• ˆ‘” –Š‡ ‡†‘…›–‘•‹• ‘ˆ •’Š‡”‹…ƒŽ —…Ž‡‹… ƒ…‹† ƒ‘’ƒ”–‹…Ž‡…‘Œ—‰ƒ–‡•ǤProc. Natl. Acad. Sci. U. S. A. 2013,110ǡ ͹͸ʹͷǦ͹͸͵ͲǤ ȋͳͺȌ ‹ƒǡǤǤǢ ƒ‰ǡǤǢ ‘•‡’ŠǡǤǢƒ‰ǡǤǢ‹ǡ ǤǤǢƒ‡”Œ‡‡ǡǤǢ‘ŽŽƒ”ǡ ǤǢƒ‰ǡǤǢŠ‘—ǡǤǤœ›‡Ǧ ȋ‡–ƒŽǦ‘”‰ƒ‹…ˆ”ƒ‡™‘”Ȍ …‘’‘•‹–‡•ǤChem. Soc. Rev. 2017,46ǡ͵͵ͺ͸Ǧ͵ͶͲͳǤ ȋͳͻȌ ›‘—”‹‘—ǡǤǢŠ‡ǡǤǢƒ‰ǡǤǤǢ‡‰ǡǤǢ‘ƒ‰ǡǤǢ‹‰ǡǤ

ǤǢ —••‡Žƒǡ Ǥ ǤǢ ƒǡ Ǥ Ǥ ‘„‹Ž‹œƒ–‹‘ ‘ˆ Ǧͳͳ ‹–‘ ƒ ‡•‘’‘”‘—• ‡–ƒŽǦ”‰ƒ‹… ”ƒ‡™‘”ǡ Ǧͳͳ̷‡•‘ ǣ  ‡™Žƒ–ˆ‘”ˆ‘”œ›ƒ–‹…ƒ–ƒŽ›•‹•ǤJ. Am. Chem. Soc. 2011,133ǡ ͳͲ͵ͺʹǦͳͲ͵ͺͷǤ ȋʹͲȌ Š‹ŠǡǤǤǢ‘ǡǤǤǢƒ‰ǡǤǤǢ‹‰…‘ǡǤǢŠ‡‰ǡǤ ǤǢ—ǡǤǤǢ Šƒ‰ǡ Ǥ ǤǢ —ƒ‰ǡ ǤǤǢ ‹ǡǤ Ǥ ”›’•‹Ǧ ‘„‹Ž‹œ‡† ‡–ƒŽǦ ”‰ƒ‹… ”ƒ‡™‘” ƒ• ƒ ‹‘…ƒ–ƒŽ›•–  ”‘–‡‘‹…• ƒŽ›•‹•Ǥ Chempluschem 2012,77ǡͻͺʹǦͻͺ͸Ǥ ȋʹͳȌ ‹ƒ‰ǡǤǢ‹……‘ǡǤǢ‘Š‡”–›ǡǤǤǢ–›Ž‡•ǡǤ ǤǢ‡ŽŽǡǤǢ‹”„›ǡǤǢ —†‹‡ǡ ǤǢ ƒ›Ž‘…ǡ ǤǢ ‹ŽŽǡ Ǥ ǤǢ ‘‘ƒǡ Ǥ ǤǢ ƒŽ…ƒ”‘ǡ Ǥ ‹‘‹‡–‹… ‹‡”ƒŽ‹œƒ–‹‘ ‘ˆ ‡–ƒŽǦ‘”‰ƒ‹… ˆ”ƒ‡™‘”• ƒ• ’”‘–‡…–‹˜‡…‘ƒ–‹‰•ˆ‘”„‹‘ƒ…”‘‘Ž‡…—Ž‡•ǤNat. Commun. 2015, 6ǡ͹ʹͶͲǤ ȋʹʹȌ ‹ǡǤǢ‘‘ǡǤǤǢ —‡Ž–ƒǡǤǤǢƒ”˜‡›ǡǤǤǢ—’’ǡ ǤǤǢ ƒ”ŠƒǡǤ Ǥ …ƒ’•—Žƒ–‹‘ ‘ˆ ƒ ‡”˜‡ ‰‡– ‡–‘š‹ˆ›‹‰ œ›‡ „› ƒ

4 ACS Paragon Plus Environment

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‡•‘’‘”‘—• ‹”…‘‹— ‡–ƒŽǦ”‰ƒ‹… ”ƒ‡™‘” ‰‡†‡”• Š‡”ƒŽ ƒ† ‘‰Ǧ‡” –ƒ„‹Ž‹–›Ǥ J. Am. Chem. Soc. 2016, 138ǡ ͺͲͷʹǦͺͲͷͷǤ ‘‘ƒǡǤǢ ‹……ÖǡǤǢ‹ƒ‰ǡǤǢ”ƒ†•Šƒ™ǡǤǢ ƒŽ…ƒ”‘ǡǤ‡–ƒŽȂ ”‰ƒ‹… ”ƒ‡™‘”•ƒ––Š‡‹‘‹–‡”ˆƒ…‡ǣ›–Š‡–‹…–”ƒ–‡‰‹‡•ƒ† ’’Ž‹…ƒ–‹‘•ǤAcc. Chem. Res. 2017,50ǡͳͶʹ͵ǦͳͶ͵ʹǤ

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ǤǢ ‘—ǡ Ǥ ǤǢ Š‘—ǡ Ǥ Ǥ –ƒ„Ž‡ ‡–ƒŽǦ‘”‰ƒ‹… ˆ”ƒ‡™‘”• …‘–ƒ‹‹‰•‹‰Ž‡Ǧ‘Ž‡…—Ž‡–”ƒ’•ˆ‘”‡œ›‡‡…ƒ’•—Žƒ–‹‘ǤNat. Commun. 2015,6Ǥ ‹ǡ ǤǢ Š‡ǡ ǤǢ ƒ‰ǡ Ǥ ǤǢ ‡”‡—Ž‡ǡ Ǥ ǤǢ ‡Š†‹ǡ Ǥ ǤǢ ‘ŠƒŽ‘˜ƒǡǤǢ”‘™‹‰ǡǤǤǢŠ‡ǡǤǢ†‡”•‘ǡǤǢ ‘‡œǦ

—ƒŽ†”‘ǡǤǤǢ‡–‹ǡ ǤǤǢ ƒ‰‹‡ŽŽ‘ǡ ǤǢ•‹”‹ǡǤǤǢ–‘††ƒ”–ǡ Ǥ ǤǢ ƒ”ŠƒǡǤǤ‹‡”ƒ”…Š‹…ƒŽŽ›‰‹‡‡”‡†‡•‘’‘”‘—•‡–ƒŽǦ”‰ƒ‹… ”ƒ‡™‘”• –‘™ƒ”† ‡ŽŽǦˆ”‡‡ ‘„‹Ž‹œ‡† œ›‡ ›•–‡•Ǥ Chem 2018,4ǡͳͲʹʹǦͳͲ͵ͶǤ 

   

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