University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Publications -- Chemistry Department Published Research - Department of Chemistry 2019 BRUSH-ARM STAR POLYMER IMAGING AGENTS AND USES THEREOF Jeremiah A. Johnson Hung Vanthanh Nguyen Andrzej Rajca Follow this and additional works at: https://digitalcommons.unl.edu/chemfacpub Part of the Analytical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, and the Other Chemistry Commons This Article is brought to you for free and open access by the Published Research - Department of Chemistry at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Publications -- Chemistry Department by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. US 20190038782A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 / 0038782 A1 Johnson et al . (43 ) Pub . Date : Feb . 7 , 2019 ( 54 ) BRUSH -ARM STAR POLYMER IMAGING (52 ) U . S . CI. AGENTS AND USES THEREOF CPC . .. .. A61K 49 / 124 (2013 . 01 ) ; A61K 49 / 186 ( 2013 . 01 ) ; A61K 49 / 1881 (2013 .01 ) ; B82Y (71 ) Applicant : Massachusetts Institute of 5700 (2013 .01 ) ; A61K 49 / 0093 ( 2013 .01 ) ; Technology , Cambridge , MA (US ) A61K 2123/ 00 ( 2013. 01 ) ; A61K 49 / 0054 (72 ) Inventors : Jeremiah A . Johnson , Boston , MA (2013 .01 ) ( US ) ; Hung Vanthanh Nguyen , Cambridge , MA (US ); Andrzej Rajca , Lincoln , NE (US ) ( 57 ) ABSTRACT ( 21 ) Appl. No .: 16 / 024 ,643 (22 ) Filed : Jun . 29 , 2018 Disclosed are methods, compositions , reagents, systems, and kits to prepare nitroxide- functionalized brush - arm star Related U . S . Application Data polymer organic radical contrast agent ( BASP - ORCA ) as (60 ) Provisional application No. 62 /528 , 026 , filed on Jun . well as compositions and uses thereof. Various embodiments 30 , 2017 . show that BASP -ORCA display unprecedented per- nitrox ide and per -molecule transverse relaxivities for organic Publication Classification radical contrast agents , exceptional stability , high water ( 51 ) Int. Ci. solubility , low in vitro and in vivo toxicity , and long blood A6IK 49 / 12 ( 2006 . 01 ) compartment half - life . These materials have the potential to A61K 49 / 18 ( 2006 .01 ) be adopted for tumor imaging using clinical high - field ' H A61K 49 /00 ( 2006 .01 ) MRI techniques. brush - first ROMP : tolal equiv MM : chex - MM ( 0 .01 ) equiv ) 1 ) Grubbs lll ( 1 equiv ) 2 ) Acetal- XL (Nequiv ) 1 , 4 - dioxane , 20 min ,RT slow addition , 4 h , RT * . ** * ** + 1 O .. .. , NO MAMMAMUN * * * om Nettet BASP -ORCA Patent Application Publication Feb . 7 , 2019 Sheet 1 of 16 US 2019 /0038782 A1 structures used in this study : branchen initiator : macromonoiner: pys -- -Ruang - - - Grubbs {I } (pyr pyridine ) Crosslinker : chex -MM Acetal- XL FigureFigure 1A1A brush - first ROMA : total equiv MM : chex -MM 1 } Grubbs (il ( 1 equiv ) 2 ) Acetal- XL ( N equiv ) 1 , 4 - dioxane , 20 min , RTL slow addition , 4 h , RT 399 *** *** * * * * ** ** * 22 *** * * ** * ** ** * BASPORCA Figure 1B Patent Application Publication Feb . 7 , 2019 Sheet 2 of 16 US 2019 /0038782 A1 www . BASP - ORCA1 www Chex -MM . 340 345 350 BASP -ORCAT Field strength / mt Figure 2A Figure 2B BASP -ORCA1 chex -MM BS TOULOUD chex concentration chex concentration chex - bottlebrush PEG - BASA (no chex ) chex concentration BASP concentration Figure 2C Patent Application Publication Feb . 7 , 2019 Sheet 3 of 16 US 2019 /0038782 A1 wwww am 1 min A os mwanan 40 min B wwwwwwww . 180 min 0 NY * Www . Figure 3A ** Normalizedpeakheight: * * * * * * * * * chex - bottlebrush 0 . 0 musasewwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww pasasaapasasayasos que se passenyususnyasszusasemansasjonsasayasosasyon Figure 3B Emissionat700nmincrease1% # 40 equiv ASC $ 60 equiv ASC A 120 equiv Aso Y 60 equiv ASC 60 equiv GSH Os 10 15 20 Figure 3C Patent Application Publication Feb . 7 , 2019 Sheet 4 of 16 US 2019 /0038782 A1 . pre - inject 20 h post- inject . 20 h post - inject . ' . ' . ' ' heart. : . ' ' . ' ' . ' VWWX . ' ' . ' ' . ' . ' ' . ' . ? . lung. : '. .liver : . ' . ' . ' radiantefficiency/x109 ' kidney12 : radiantefficiency/x10% spleen : W Figure 4A Figure 4B Patent Application Publication Feb . 7 , 2019 Sheet 5 of 16 US 2019 /0038782 A1 . WWWWWWWWWW . w . W . wooow00000000000000* . W000000000000000 . WWW. Figure5B Figure5A . lowdose(0.16mmolchex/kg):20hpost-injection highdose(0.23mmolchex/kg):20hpost-injection . tumor tumor . pre-injection: pre-injection: . Patent Application Publication Feb . 7 , 2019 Sheet 6 of 16 US 2019 /0038782 A1 pre - injection : tumors . .. .: . : .: . : . : . : . : .: . : . high dose :# 20 :h post- injection. Figure 5C A D low dose .' . ma B . high dose Contrastchange1% : ? WWWWWWWWWWWWWWWWWWW AAAAAAAAAAAAAAAAAAAAAAAAAAAAA ?? Time0 post- injection 12 16of BASP 20-ORCA1 20 / h Figure 5D Patent Application Publication Feb . 7 , 2019 Sheet 7 of 16 US 2019 /0038782 A1 . 21 . A www .muscle . heart . 20TL mkidney . *. www . " . mliver . tratamentulmasomowa . tumor. Vierten . .. ** . : . .- . 340 . 345 350. Field strength /MT Figure 6A . 57 umol chex / g protein. C . radiant efficiency' . ' . - . ws . Normalizedsignal . ' ' ' muscleheart kidney liver tumor Figure 6B Patent Application Publication Feb . 7 , 2019 Sheet 8 of 16 US 2019 /0038782 A1 m 9 ,99 , N = 15 m = 5 .05 , N = 20 mm 7 ,07 , N - 20 U S' SO' OEN ID *L 20 * N - 08 NormalizedRIResponse/A.U WAL mm - 9 . 99 , N = 30 ASOMO windtudsmated mahannammmmmmmmmmmmmmmmmmmmmmmmmm 16 18 20 Retetion time / min Figure 7A - chex - bottebrush PEG -BASP rrrrrrr . ... NormalizedRIResponse/A.U . errrrrrrrrrr . K . - . * . ** . 18 20 . Retetion time / min . Figure 7B Patent Application Publication Feb . 7 , 2019 Sheet 9 of 16 US 2019 /0038782 A1 chex -bottlebrush m = 9 . 99 , N = 15 m 5 .05 , N = 20 m = 7 .07 , N = 20 m = 5 .05 , N = 30 m = 7 .07 , N = 30 - .www , - , - , - , - , - , - , -m , - , - , - , - , - , - , - , - , - , - , - , - , - , - 9, - , - , -. , - , ,99 - , - , - , - , - , - , - , - , - , - , - N, - , - , - , - , - , - , -= , - , - , - , - , - , - ,30 - , - , WODOWE E 330 335 340 345 350 355 Field Strength /mT Figure 8 Patent Application Publication Feb . 7 , 2019 Sheet 10 of 16 US 2019 /0038782 A1 . » E3 } } ???? ??? h?wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww??wwwwwwwwwwwwwwwww Figure 9A . ? . ?????? : : . : . : . : . : . Figure 9B . Patent Application Publication Feb . 7 , 2019 Sheet 11 of 16 US 2019 /0038782 A1 . * VyyyyyUUUUUUUUUUUUU . 7 . ' . ' . ' . ' . 1 . * * * * * . ' ' . ' ' . ' . ' . 2 . 22 . * . ..