Supporting information. A biocompatible calcium bisphosphonate coordination polymer: towards a metal-linker synergistic therapeutic effect?

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1 Supporting information A biocompatible calcium bisphosphonate coordination polymer: towards a metal-linker synergistic therapeutic effect? Elsa Alvarez, a Alfonso Garcia Marquez, a Thomas Devic, a Nathalie Steunou, a Christian Serre, a Christian Bonhomme, b Christel Gervais, b Isabel Izquierdo-Barba, c d Maria Vallet-Regi, c d Danielle Laurencin, e Francesco Mauri, f and Patricia Horcajada* a a Institut Lavoisier, UMR CNRS 8180, Université de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats- Unis, Versailles cedex, France. Fax: ; Tel: ; patricia.horcajadacortes@uvsq.fr b Laboratoire de Chimie de la Matière Condensée de Paris, Université Pierre et Marie Curie Paris 06 UMR CNRS 7574, Collège de France, 11 Place Marcelin Berthelot, Paris Cedex 05, France c Departamento de Química Inorgánica y Bioinorgánica, Facultad de Farmacia, Universidad Complutense de Madrid Madrid, Spain. d Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. e Institut Charles Gerhardt de Montpellier, UMR 5253, CNRS UM2 UM1 ENSCM, CC 1701 Université de Montpellier 2, Place E. Bataillon, Montpellier cedex 5, France. f Laboratoire de Minéralogie Cristallographie UMR CNRS 7590, Université Pierre et Marie Curie Paris 06, France.

2 Synthesis. BioMIL-4: In a typical synthesis, 1 mmol of the calcium salt (Ca(NO 3 ) 2.4H 2 O, CaCO 3 or Ca(OH) 2 ), and 1 mmol of sodium alendronate were dispersed in 5 ml of water or solvent mixture in presence or not of a 2 M sodium hydroxide solution (1.2 mmol or 0.5 mmol; see Table S1). The reaction mixture was heated in a teflon lined autoclave at different temperatures for 24 hours (see Table S1). Solid was washed with water and dried for further characterizations. Ca[C 4 H 12 NO 7 P 2 ] 2 : 1 mmol of the Ca(NO 3 ) 2.4H 2 O and 0.5 mmol of sodium alendronate were dispersed in 5 ml of water. The reaction mixture was heated in a teflon lined autoclave at different temperatures for 24 hours (see Table S1). After this period of time, the solid obtained was washed with water and dried for further characterizations. Table S1.Synthesis conditions and ratios Precursor Ratio a M : L b a Ratio T ( C) XRD L : B b Figure S12 c BioMIL-4 Ca(NO 3 ) 2.4H 2 O BioMIL a 1 : b Ca(OH) c CaCO d e BioMIL-4 + Ca(NO 3 ) 2.4H 2 O f Ca[C 4 H 12 NO 7 P 2 ] g 2 Ca[C 4 H 12 NO 7 P 2 ] Ca(NO 3 ) 2.4H 2 O 1 : Ca[C 4 H 12 NO 7 P : h a Molar ratio; b M, L and B stand for metal, linker and base (NaOH), respectively; c See XRD patterns in Figure S12. ] 2

3 Table S2. Bond valence calculations, using the bond parameters proposed by Brese et al. 1 These calculations suggest that whereas O1, O2, O4 and O5 are deprotonated, H atoms remain on O7 and partially on O3 and O6. At. 1 At. 2 At. 1-At. 2 distance (Å) υ total Ca1 O1-1+x, y, z O5-1+x, y, z O4-0.5+x, 1.5-y, 1-z O2 x, y, z O4 x, y, z O7 x, y, z O1 P1 x, y, z Ca1 1+x, y, z O2 P1 x, y, z Ca1 x, y, z O3 P1 x, y, z O4 P2 x, y, z Ca1 0.5+x, 1.5-y, 1-z Ca1 x, y, z O5 P2 x, y, z Ca1 1+x, y, z O6 P2 x, y, z O7 C1 x, y, z Ca1 x, y, z Table S3. Hydrogen bond distances and angles. Type Donor (D) Acceptor (A) H A (Å) D A (Å) D-H A ( ) N + H O N1-H1A O (2) N + H O N1-H1B O (2) OH O O7-H O8A (3) - OH O O7-H O8B (2) - OH O - O6-H6 O (9) OH O O8A-H O (4) - OH O O8B-H O (2) - OH O O8A -H O (5) - OH O O8B-H O (2) -

4 Electronic Supplementary Material (ESI) for CrystEngComm Figure S1. SEM images of the single crystal of BioMIL-4 (left) and Ca[C 4 H 12 NO 7 P 2 ] 2 (right) θ ( ) Figure S2. Experimental (top) and calculated (botom )XRPD patterns of BioMIL-4. 80

5 Mass Loss (%) Temperature (ºC) Mass Loss (%) Temperature (ºC) Figure S3.TGA of BioMIL-4 (left) and Ca[C 4 H 12 NO 7 P 2 ] 2 (right). Figure S4. Structure of Ca[C 4 H 12 NO 7 P 2 ] 2.

6 Solid State NMR Figure S5. 1 H MAS NMR spectrum of BioMIL-4 (ν 0 = MHz, ν rot =30 khz). Figure S6. 1 H MAS NMR spectrum of Ca[C 4 H 12 NO 7 P 2 ] 2. (ν 0 = MHz, ν rot =30 khz).

7 δ iso (ppm) C Q (MHz) η Ca C C C C P P H1A 4.2 H1B 8.9 H1C 7.8 H2A 1.2 H2B 1.1 H3A 0.4 H3B 2.1 H4A 2.9 H4B 1.7 H H7 3.4 H8 7.3 H9 5.2 Figure S7. Calculated NMR parameters of BioMIL-4.

8 δ iso (ppm) C Q (MHz) η Ca C C C C P P H H H H H H H H H H H H Figure S8. Calculated NMR parameters of Ca[C 4 H 12 NO 7 P 2 ] 2.

9 Ca chemical shift (ppm) Figure S9. On the top: 43 Ca MAS NMR spectrum of BioMIL-4 recorded at 14.1 T (see main text for experimental details). On the bottom: Simulation of the 43 Ca MAS NMR spectrum of BioMIL-4 assuming one calcium site C q 3.8 MHz, η ~0.5, δ iso ~35 ppm (l 0 ) Figure S10. Refocused 1 H- 31 P CP MAS-J-INADEQUATE experiments for Bio-MIL-4. The efficiency of the INADEQUATE transfer is evaluated vs the integer l 0 (the characteristic delay ν in the INADEQUATE sequence is synchronized with the MAS rotor frequency, v rot, through ν = l 0.( ν rot ) -1 ). rot = 14 khz, number of scans: 32, relaxation delay: 2 s.

10 a) Alendronate b) Alendronate BioMIL-4 BioMIL-4 Ca[C 4 H 12 NO 7 P 2 ] 2 Ca[C 4 H 12 NO 7 P 2 ] Wavenumber (cm -1 ) Wavenumber (cm -1 ) Figure S11. IR spectra of sodium alendronate, BioMIL-4 and Ca[C 4 H 12 NO 7 P 2 ] 2. a) Full range; b) cm -1 region. BioMIL-4 a b c c e f g Ca[C 4 H 12 NO 7 P 2 ] 2 h θ ( ) Figure S12. XRD patterns of BioMIL-4 and/or Ca[C 4 H 12 NO 7 P 2 ] 2 under different conditions (see terminology in Table S1).

11 3,0 Calcium 9,0 ph Calcium variation (mm) 2,9 2,8 2,7 2,6 2, Time (h) Initial concentration ph 8,5 8,0 7,5 7,0 6,5 6,0 5,5 5,0 4,5 4, Time (h) Figure S13. Calcium concentration and ph of the SBF in contact with the BioMIL-4. 0h 24h 3d 7d 15d Figure S14. IR spectra of the BioMIL-4 in contact with the SBF.

12 0 d Atomic % P=21.36 Ca = 8.37 O = d P=23.31 Ca = 9.21 O = d P=23.31 Ca = 9.64 O = d P=23.11 Ca = 9.56 O =67.33 Figure S15. EDX-SEM the BioMIL-4 in contact with the SBF. 50 d BioMIL-4 Ca[C 4 H 12 NO 7 P 2 ] 2 50 d 10 d 0 d ( ) 2 θ d 0 d ( ) 2θ Figure S16. XRD patterns of BioMIL-4 and Ca[C 4 H 12 NO 7 P 2 ] 2 dispersed in PBS.

13 References 1 Brese, N. E.; O'Keeffe, M., Acta. Cryst. 1991, B47,