Supporting Information

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1 Supporting Information Fully acid-degradable biocompatible polyacetal microparticles for drug delivery Sergey E. Paramonov, Eric M. Bachelder, Tristan T. Beaudette, Stephany M. Standley, Cameron C. Lee, Jesse Dashe and Jean M.J. Fréchet* Department of Chemistry, University of California, Berkeley, California *. Degradation byproducts In order to show full degradation of the bulk polymer, the three different polymers were incubated with a 95% methanol and 5% concentrated HCl overnight. Size exclusion chromatography (SEC) measurements were performed for the different degraded polymers (Supplementary Figure 1) and the SEC traces were compared to nondegraded polymer 19. After incubating at the acidic conditions the polymers fully degraded into small molecules. The cytotoxicity of degradation products was also measured and the products were found to be non toxic at concentrations up to 1mg/ml (Supplementary Figure 2). SI 1

2 Small molecular weight products < 500 Da 50 MV Polymer 19 Non-degraded Polymer 19 Degraded Polymer 20 Degraded Polymer 21 Degraded Retention Time (min) Supplementary Figure 1. SEC trace of starting polymer 19 and traces of the degradation reaction mixture for each of polymers 19, 20 and % 100% Viability % 80% 60% 40% 20% Polymer 19 0% ug/ml of particles Supplementary Figure 2. Cytotoxicity of degradation products of polymer 19. The products of degradation are non toxic at the measured concentrations of up to 1mg/ml. Effects of cryoprotectants It has been shown (1-4) that cryoprotectants added to nano- or micro-particles help prevent aggregation. Different known cryoprotectants were added to the double emulsion SI 2

3 particles at 10% (wt/vol) before lyophilization. The size and polydispersity (PDI) of the particles were measured by dynamic light scattering (DLS) and the measured values for the three different polymers are shown in Supplementary Table 1-3. In general, in the absence of cryoprotectants, the three different types of microparticles (polymers 19-21) exhibited a tendency to aggregate after lyophilization. Microparticles made from polymer 19 were the most susceptible to aggregation compared to the other two polymers, since three of the additives did not prevent clumping; while microparticles from polymer 21 were the least susceptible to aggregation compared to the other two polymers, since every additive prevented aggregation. Before Washing with TFF 306±7 nm 0.07±8 After Washing with TFF 255±3 nm 0.1±1 After Lyophilization / PVA Macroscopic NA After Lyophilization / Dextran 10,000 MW Macroscopic NA After Lyophilization / Glucose 237±2 nm 0.159±1 After Lyophilization / PEG 3,000 MW 2700±506 nm (Begin to aggregate) 0.223±5 Supplementary Table 1. Polymer 19 particle size average and PDI as measured by DLS. SI 3

4 Before Washing with TFF 343±4 nm 0.09±2 After Washing with TFF 251±3 nm 0.10±2 After Lyophilization / PVA Macroscopic NA After Lyophilization / Dextran 10,000 MW 4740±957 nm (Begin to aggregate) 0.253±7 After Lyophilization / Glucose 241±2 nm 0.126±2 After Lyophilization / PEG 3,000 MW 324±7 nm 0.155±1 Supplementary Table 2. Polymer 20 particle size average and PDI as measured by DLS. Before Washing with TFF 481±14 nm 0.147±3 After Washing with TFF 374±14 nm 0.205±5 After Lyophilization / PVA 365±7 nm 0.263±2 After Lyophilization / Dextran 10,000 MW 611±138 nm 0.709±5 After Lyophilization / Glucose 295±1 nm 0.175±2 After Lyophilization / PEG 3,000 MW 653±39 nm 0.552±3 Supplementary Table 3. Polymer 21 particle size average and PDI as measured by DLS. SI 4

5 References (1) Bozdag, S., Dillen, K., Vandervoort, J., and Ludwig, A. (2005) The effect of freeze-drying with different cryoprotectants and gamma-irradiation sterilization on the characteristics of ciprofloxacin HCl-loaded poly(d,l-lactide-glycolide) nanoparticles. J Pharm Pharmacol 57, (2) Hirsjarvi, S., Peltonen, L., Kainu, L., and Hirvonen, J. (2006) Freeze-drying of low molecular weight poly(l-lactic acid) nanoparticles: effect of cryo- and lyoprotectants. J Nanosci Nanotechnol 6, (3) Rizkalla, N., Range, C., Lacasse, F. X., and Hildgen, P. (2006) Effect of various formulation parameters on the properties of polymeric nanoparticles prepared by multiple emulsion method. J Microencapsul 23, (4) Shahgaldian, P., Gualbert, J., Aissa, K., and Coleman, A. W. (2003) A study of the freeze-drying conditions of calixarene based solid lipid nanoparticles. Eur J Pharm Biopharm 55, SI 5