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1 Electronic Supplementry Mteril (ESI) for ChemComm. This journl is The Royl Society of Chemistry 216 Electronic Supplementry Informtion (ESI) noscle Covlent Orgnic Frmeworks s Smrt Crriers for Drug Delivery Linyi Bi, Soo Zeng Fion Phu, Wei Qi Lim, Avijit Jn, Zhong Luo, Huijun Phoee Thm, Lingzhi Zho, Qing Go, Ynli Zho*,, Division of Chemistry nd Biologicl Chemistry, School of Physicl nd Mthemticl Sciences, nyng Technologicl University, 21 nyng Link, Singpore E- mil: zhoynli@ntu.edu.sg School of Mterils Science nd Engineering, nyng Technologicl University, 5 nyng Avenue, Singpore S1

2 1. Mterils nd instruments All regents nd chemicls were purchsed commercilly nd used without further purifictions unless otherwise stted. Specilly, nhydrous 1,4-dioxne, nhydrous mesitylene, nhydrous THF nd 4,4'-iphenyldimine were purchsed from Sigm-Aldrich. Rections were monitored y TLC nd visulized y dul short wve/long wve UV lmp. Column flsh chromtogrphy ws performed using 23-4 mesh silic gel. 1.1 MR MR spectr were recorded y Bruker BBFO-4 spectrometer with CDCl 3 s solvent. Chemicl shifts for 1 H MR were reported s δ, prts per million, reltive to the signl of CDCl 3 t 7.26 ppm. Chemicl shifts for 13 C MR were reported s δ, prts per million, reltive to the centerline signl of the CDCl 3 triplet t 77. ppm. Proton nd cron ssignments were estlished using spectrl dt of similr compounds. The revitions s, r. s, d, dd, r. d, ddd, t, q, r. q, m, nd r. m stnd for the resonnce multiplicity singlet, rod singlet, doulet, doulet of doulets, rod doulet, doulet of doulet of doulets, triplet, qurtet, rod qurtet, multiplet nd rod multiplet, respectively. 1.2 Thermogrvimetric nlysis (TGA) nd Fourier trnsform infrred (FT-IR) TGA ws performed on TGA 5 thermo grvimetric nlyzer y heting the smples t 2 ºC min -1 to 1 ºC in nitrogen tmosphere (6 ml/min). FTIR spectr (KBr, Aldrich) were mesured with SHIMADZU IR Prestige-21 spectrometer. Smples were pcked firmly to otin trnsprent films. 1.3 PXRD mesurement PXRD studies were performed on SHIMADZU XRD-6 Lx diffrctometer using Cu-K rdition t 4 kv nd 3 ma with scnning rte of 2 o s -1 (2θ) t room temperture. 1.4 UV sorption nd fluorescence spectr Asorption spectr were recorded on UV-36 UV vis IR spectrophotometer (Shimdzu), while emission spectr were recorded on RF-531 PC spectrofluorophotometer (Shimdzu) with cm pth length cell. 1.5 TEM mesurements Trnsmission electron microscopy (TEM) imges were mesured on JEM-14 (JEOL) operted t 1-12 kv. 2. Experimentl detils 2.1 Synthesis of S1,S2 4,4'-Biphenyldimine (83 mg,.3 mmol) nd 1,3,5-triformylenzene (48 mg, mmol) were weighed into 25 ml Schlenk storge tue (SynthwreTM, OD28 x L12mm, high vccum vlve size -8mm, with PTFE o-ring & wiper), dissolved in mixed solvent (3 ml, 1,4-dioxne:mesitylene = 1:1) nd sonicted for 1 min. After tht, queous HOAc (.3 ml, 6 mol/l) ws dded to the mixture. The tue ws degssed y three freeze-pump-thw cycles. Finlly, the tue ws seled off, heted t 12 ºC in n oven t the sme time, nd left undistured for 72 h. The precipittes S2

3 were isolted y centrifugtion, wshed with nhydrous THF for 3 times, nd dried t 12 ºC under vcuum for 24 h, to give yellow powder with up to 9 % isoltion yields. The synthetic procedure is shown elow. OHC CHO + CHO 3M HOAc, Dioxne/mesitylene 12 o C, ~72h 1.9 nm H 2 H Synthesis of S1,S2 2,4,6-Tris(4-minophenyl)-1,3,5-trizine (1) nd 1,3,5-triformylenzene (2) were synthesized ccording to the reported procedures. S3 The 1 H MR nd 13 C MR spectr mtched well with those reported ones. Then, compounds 1 (7 mg, mmol) nd 2 (48 mg, mmol) were plced in 25 ml Schlenk storge tue, which were dissolved in mixture solvent (1 ml, 1,4- dioxne : mesitylene = 1:1, v:v), nd sonicted for 1 min. After tht, queous HOAc (.75 ml, 6M) ws dded, nd the mixture ws degssed y three freeze-pump-thw cycles. Finlly, the tue ws seled, heted t 12 o C in n oven, nd left undistured for 72 h. The precipitte ws collected through centrifugtion, which ws wshed with nhydrous THF for 3 times, nd then dried t 15 C under vcuum for 24 h. A yellow powder ws otined in 9% isoltion yield. The synthetic procedure is shown elow. H 2 C H 2 COOH 1) Ac 2 O, -25 o C 2) ClSO 3 H, o C, 24 h 3) 12M HCl, reflux, 3h 4) 2% OH 1) MeOH, conc. H 2 SO 4, reflux, 12h 2)LiAlH 4 /THF, o C, 2, 12h H 2 H 2 1 CHO 6M HOAc Dioxne/mesitylene 12 o C, 3 dys HOOC COOH 3) PCC, Celite/DCM, ether OHC CHO Theoreticl clcultions Density functionl theory clcultions were performed with the Gussin 9 progrm S4 using the B3LYP functionl. All-electron doule-ξ vlence sis sets with polriztion functions 6-31G* were used for ll toms. Geometry optimiztions were performed with full relxtion of ll toms in gs phse without solvent effects. S3

4 3. Structurl modeling S4 3.1 Tle S1. Simulted dt of Spce group Clculted unit cell P6/M (o.175) == Å, c= Å; α=β=9, γ=12 tom x y z C C C C C C C C C H H H H H H () () Figure S1. () Crystl lttice of the unit cell simulted in n eclipsed rrngement (top view in AB plne) for ; () Pcking structure of 9 unit cells simulted in n eclipsed rrngement (top view in AB plne). S4

5 3.2 Tle S2. Simulted dt of Spce group P-6 (o.174) Clculted unit cell == Å, c=3.497 Å; α=β=9, γ=12 tom x y z C C C H C H C C H C H C C H C () () Figure S2. () Crystl lttice of the unit cell simulted in n eclipsed rrngement (top view in AB plne) for ; () Pcking structure of 9 unit cells simulted in n eclipsed rrngement (top view in AB plne). S5

6 4. Physicl properties (1) (11) (2) (21) (1) (degree) Figure S3. Theoreticl clcultion nd prcticl PXRD of : () pcking structure simulted in n eclipsed rrngement (top view in AB plne); () experimentl PXRD pttern of (lck curve), simulted PXRD pttern for eclipsed structure (red curve), nd simulted PXRD pttern for stggered structure (lue curve). (11) (2) (1) Thet / degree Figure S4. Theoreticl clcultion nd prcticl PXRD of : () pcking structure simulted in n eclipsed (upper) nd stggered structure (down); () experimentl PXRD pttern of (red curve), nd simulted ptterns of eclipsed (lue curve) nd stggered (pink curve) structures. S6

7 STP(V /cm 3 g -1 ) c P/P 1 / [ W((P /P) - 1) ] d ,r= ,r= Reltive pressure (P/P ) 1.1 nm 1.4 nm Pore Width (A) Pore Width (A) Figure S5. () 2 dsorption isotherms nd () BET results of the COFs; (c,d) Pore-size distriution plots of two COFs clculted from experimentl 2 dsorption isotherms using the nonlocl density functionl theory (LDFT). 5. T-plot method Low-pressure gs sorption mesurements were performed y using Quntchrome Instruments Autosor-iQ (Boynton Bech, Florid USA) with the extr-high pure gses. The s-synthesized COFs were immersed in CH 2 Cl 2 (3 ml) for 3 dys, during which CH 2 Cl 2 ws replced for three times. Then, the smples were moved into smple cell nd dried under vcuum t 6 C y using the out gsser function for 8 h efore the mesurements. Tle S3. T-plot method for microporous nd mesoporous volumes. [] Totl pore volume (cc/g) [] Micropore volume (cc/g) [c] Mesopore volume (cc/g) [] Micropore re (m 2 /g) [] Externl surfce re (m 2 /g) The dt ws determined y 2 dsorption/desorption isotherms t 77K: [] clculted y the point of the highest dsorption; [] determined y the t-plot method, where the contriution points re from in P/P ; [c] otined y the difference etween the totl pore volume nd micropore volume. S7

8 6. Drug loding nd relese F O H HS O Me Me COOH H O HOOC Me 5-fluorourcil (5-FU) Cptopril Iuprofen (IBU) Three drugs, i.e., 5-fluorourcil (5-FU), cptopril nd iuprofen (IBU) were used for drug loding nd relese studies (their chemicl structures re shown ove). The drug ws loded y immersing solvent-free COF smples in hexne solution of drug with certin concentrtion. A typicl procedure for loding drug in COFs ws s follows: COF (5 mg) ws suspended in hexne solution of drug (5 ml,.1 M) under stirring for 6h, while preventing evportion of hexne y covering with cp. The drug-loded smple ws seprted from solution y vcuum filtrtion, wshed with hexne, nd dried t room temperture. A typicl procedure for relesing drug from drug-loded COF ws s follows: the drug-loded COF (1 mg) ws plced in vil nd dipped in 2 ml of phosphte uffered sline (PBS, ph = 7.4, stndrd uffer solution from Sigm) t 37 C. At predetermined time intervls, the dissolution medium ws replced with 2 ml of fresh PBS, nd the withdrwn medium ws used to determine the drug concentrtion. The drug concentrtion ws nlyzed y UV-Vis spectrophotometry with the help of clirtion curve. The relese study ws continued until no drug ws detectle in the withdrwn PBS. Figure S6. TEM imges of the two COFs in PBS solution with it DMSO s n dditive: () PI- 3-COF nd (). S8

9 Cptopril@ 5-FU@ IBU@ FU@ Cptopril@ IBU@ Wvenumer (cm) Wvenumer (cm) Figure S7. (,) FTIR spectr of two COFs (lck curve) nd drug loded COFs: 5-FU (lue curve), cptopril (red curve), nd IBU (green curve). Weight Percent (1%) 5-FU@ Cptopril@ IBU@ Weight Percent (1%) 5-FU@ Cptopril@ IBU@ Temperture (degree) Temperture (degree) Figure S8. (,) TGA curves of two COFs (lck curve) nd drug loded COFs: 5-FU (red curve), cptopril (lue curve), nd IBU (pink curve). STP(V /cm 3 g -1 ) FU@ Cptopril@ IBU@ STP(V /cm 3 g -1 ) FU@ Cptopril@ IBU@ P/P P/P Figure S9. (,) 2 dsorption isotherms of two COFs (lck curve) nd drug loded COFs: 5-FU (lue curve), cptopril (pink curve), nd IBU (red curve) t 77 K. S9

10 FU@ Cptopril@ IBU@ thet (degree) thet (degree) 5-FU@ Cptopril@ IBU@ Figure S1. (,) PXRD ptterns of drug loded COFs: 5-FU (lck curve), cptopril (red curve), nd IBU (lue curve) FU@ Cptopril@ IBU@ Binding Energy (ev) FU@ Cptopril@ IBU@ Binding Energy (ev) Figure S11. (,) XPS spectr of two COFs (lck curve) nd drug loded COFs: 5-FU (lue curve), cptopril (red curve), nd IBU (green curve). S1

11 Cell Viliity (1%) 5-FU Cptopril IBU Cell Viliity (1%) 5-FU Cptopril IBU c Drugs t different concentrtion (*8 ug/ml) Cell Viliity (1%) d Cell Viliity (1%) Drugs t different concentrtion (*15 ug/ml) Concentrtion (*5 ug/ml) 5-FU Cptopril IBU COF t 1 ug/ml Figure S12. (,) In vitro cell cytotoxicity of three drugs incuted for 24 h, respectively. x xis represents the concentrtions of drugs. The corresponding concentrtions re, 8 g,16 g, 24 g nd 32 g for (), nd, 15 g, 3 g, 45 g nd 6 g for (); (c) In vitro cell cytotoxicity of two COFs nd their concentrtion rnge ws 5~2 mg/ml; (d) In vitro cell cytotoxicity of drug loded COFs ginst MCF-7 cells t 1 g/ml for 24 h. The concentrtion of loded drugs depends on the COF loding cpcity, i.e., 16% nd 3% for nd, respectively. S11

12 Cell Viliity (1%) 5-FU Cptopril IBU Cell Viliity (1%) 5-FU Cptopril IBU c Cell Viliity (1%) Drugs t different concentrtion (*8 ug/ml) Concentrtion (*5 ug/ml) d Cell Viliity (1%) Drugs t different concentrtion (*15 ug/ml) 5-FU Cptopril IBU COF t 1 ug/ml Figure S13. (,) In vitro cell cytotoxicity of three drugs incuted for 48 h, respectively. x xis represents the concentrtions of drugs. The corresponding concentrtions re, 8 g,16 g, 24 g nd 32 g for (), nd, 15 g, 3 g, 45 g nd 6 g for (); (c) In vitro cell cytotoxicity of two COFs nd their concentrtion rnge ws 5~2 mg/ml; (d) In vitro cell cytotoxicity of drug loded COFs ginst MCF-7 cells t 1 g/ml for 48 h. The concentrtion of loded drugs depends on the COF loding cpcity, i.e., 16% nd 3% for nd, respectively. c 1mmol/ml 2mmol/ml 3mmol/ml 4mmol/ml 5mmol/ml 5-FU Wvelength (nm) 1mmol/ml 2mmol/ml 3mmol/ml 4mmol/ml 5mmol/ml Cptopril Wvelength (nm) 1mmol/ml 2mmol/ml 3mmol/ml 4mmol/ml 5mmol/ml IBU Wvelength (nm) Figure S14. UV vis spectr of three drugs in PBS: () 5-FU, () cptopril nd (c) IBU (green curve), where the tests were performed upon the concentrtion chnge from 1 mm/ml to 5 mm/ml. S12

13 Relese Rte (1%) Relese Rte (1%) Time (dys) Time (dys) Figure S15. Relese profiles of drug loded () nd () : 5-FU (lue curve), cptopril (green curve) nd IBU (red curve). 7. References (S1) Q. Go, L. Bi, Y. Zeng, P. Wng, X. Zhng, R. Zou nd Y. Zho, Chem. Eur. J., 215, 21, (S2) Q. Go, L. Bi, X. Zhng, P. Wng, P. Li, Y. Zeng, R. Zou nd Y. Zho, Chin. J. Chem., 215, 33, (S3) () G. Gttuso, G. Grsso,. Mrino, A. otti, A. Ppplrdo, S. Ppplrdo, M. F. Prisi, Eur. J. Org. Chem. 211, ; () P. Pndey, A. P. Ktsoulidis, I. Eryzici, Y. Wu, M.G. Kntzidis, S.T.guyen. Chem. Mter. 21, 22, (S4) M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseri, M. A. Ro, J. R. Cheesemn, G. Sclmni, V. Brone, B. Mennucci, G. A. Petersson, H. ktsuji, M. Cricto, X. Li, H. P. Hrtchin, A. F. Izmylov, J. Bloino, G. Zheng, J. L. Sonnenerg, M. Hd, M. Ehr, K. Toyot, R. Fukud, J. Hsegw, M. Ishid, T. kjim, Y. Hond, O. Kito, H. ki, T. Vreven, J. A., Jr. Montgomery, J. E. Perlt, F. Ogliro, M. Berprk, J. J. Heyd, E. Brothers, K.. Kudin, V.. Stroverov, R. Koyshi, J. ormnd, K. Rghvchri, A. Rendell, J. C. Burnt, S. S. Iyengr, J. Tomsi, M. Cossi,. Reg, J. M. Millm, M. Klene, J. E. Knox, J. B. Cross, V. Bkken, C. Admo, J. Jrmillo, R. Gomperts, R. E. Strtmnn, O. Yzyev, A. J. Austin, R. Cmmi, C. Pomelli, J. W. Ochterski, R. L. Mrtin, K. Morokum, V. G. Zkrzewski, G. A. Voth, P. Slvdor, J. J. Dnnenerg, S. Dpprich, A. D. Dniels, Ö. Frks, J. B. Foresmn, J. V. Ortiz, J. Cioslowski nd D. J. Fox, Gussin 9, Revision A.2, Gussin, Inc., Wllingford CT, 29. S13