Toward Tertiary Amine-Modulated Acid-Triggered Hydrolysis of Copolymers Containing Pendent Ortho Ester Groups

Abstract

We describe an efficient approach to modulate the hydrolysis of the ortho ester-containing polymers by incorporating different amount of tertiary amino (TA) groups. The block copolymers (NE0–NE3) contain a hydrophilic poly(ethylene glycol) (PEG) segment and hydrophobic chains constituted by random methacrylate copolymers with pendent acid-labile cyclic ortho ester and TA groups and were synthesized by a two-step approach. First, atom transfer radical copolymerization of 2-hydroxyethyl methacrylate and 2-(diethylamino)ethyl methacrylate using mPEG45-Br as a macroinitiator afforded the block copolymer precursors. Then, reaction of the precursors with 2-ethylidene-4-methyl-1,3-dioxolane transformed the pendent hydroxyl groups into cyclic ortho ester groups. The hydrophobic chains are similar in degree of polymerization, but the percent molar content of TA increases from 0% for NE0 to ∼15% for NE3. In phosphate buffer at pH 8.4, all the four amphiphilic block copolymers can self-assemble into stable nanoparticles with a monomodal distribution, which have a similar hydrophilic/hydrophobic balance as revealed by using pyrene and Nile red (NR) as fluorescent probes. Kinetic measurements of the ortho ester hydrolysis in the copolymer nanoparticles were studied at different pH values by 1H NMR spectroscopy, NR fluorescence probe, and light scattering. The results indicated that all the copolymer nanoparticles exhibit the pH-dependent hydrolysis behaviors with the half-life times ranging from hundreds of minutes at pH 5.4 to several days at neutral pH. More importantly, we found that the TA units have an amphoteric effect on the hydrolysis kinetics of the surrounding pendent ortho esters in acidic media. When compared with copolymer nanoparticles of NE0 with no TA unit, the NE1 nanoparticles with a small amount of TA unit hydrolyzed much slower, whereas a faster hydrolysis was observed for the NE3 nanoparticles containing a higher amount of TA unit.