Influence of 2-(diisopropylamino)ethyl methacrylate on acid-triggered hydrolysis of cyclic benzylidene acetals and their importance in efficient drug delivery

Abstract

The ability to tune the degradation rate of a biodegradable polymer, which can achieve precise spatiotemporal control of drug delivery, is of considerable interest for biomedical applications. In this study, a series of amphiphilic copolymers, methoxy poly(ethyleneglycol)-b-poly((2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate)-co-2-(diisopropylamino)ethyl methacrylate) (mPEG-b-P (TTMA-co-DPA), PETD) with different numbers of DPA units, were synthesized by Reversible Addition Fragmentation Chain Transfer (RAFT) copolymerization, in which DPA containing tertiary amines were introduced to adjust the hydrolysis behavior of cyclic benzylidene acetals (CBAs). The molecular structure and the chemical composition of PETD were characterized by 1 H NMR and gel permeation chromatography (GPC). PETD could self-assemble into stable nanoparticles with well-defined spherical morphology and displayed high drug loading capacity with doxorubicin (DOX) as the drug model. The hydrolysis behavior of CBAs in the PETD NPs was investigated by UV/vis spectroscopy under different pH values. Compared with PETD-0 bearing no DPA unit, the hydrolysis rate of PETD-3 with more DPA was faster, while PETD-1 with less DPA hydrolyzed much slower, which indicated that the introduction of DPA had an amphoteric effect on the hydrolysis behavior of CBAs under acidic conditions. In addition, the in vitro release of DOX was also investigated under different pH conditions and the result was in accordance with the hydrolysis result. Furthermore, the results of fluorescence microscopy demonstrated improved internalization of DOX-loaded PETD-3 NPs in HepG-2 cells with rapid DOX release intracellularly, which showed considerable cytotoxicity against HepG-2 cells. † Electronic supplementary information (ESI) available. See

Self-assembled PEG-b-PDPA-b-PGEM copolymer nanoparticles as protein antigen delivery vehicles to dendritic cells: preparation, characterization and cellular uptake

“…N -( tert -Butoxycarbonyl) amino ethyl methacrylate (tBAM) was synthesized as previously described [ 38 ]. The macro chain transfer agent mPEG-CTAm was synthesized by the chemical conjugation between mPEG and S -1-dodecyl- S -(α,α′-dimethyl-α″-acetic acid) trithiocarbonate as described elsewhere [ 39 , 40 ]. Fluorescein isothiocyanate labeled ovalbumin (OVA-FITC) was provided by Beijing Solarbio Science & Technology Co. (Beijing, China).…”

Imidazole‐Mediated Dual Location Disassembly of Acid‐Degradable Intracellular Drug Delivery Block Copolymer Nanoassemblies

“…One approach to achieve this is to incorporate acid‐ionizable groups into the structure of the acid‐cleavable micelle cores. Tertiary dialkylamino groups, such as, dimethylaminoethyl, [ 11 ] diethylaminoethyl, [ 12 ] and diisopropylaminoethyl [ 13 ] groups have been explored as acid‐ionizable groups. In acidic pH lower than their pKa values, these groups can be protonated, which increases the polarity of the hydrophobic cores.…”

Synergistic dual-pH responsive copolymer micelles for pH-dependent drug release

“…18 Despite the advances of good stability at pH 7.4, the existing ketal or acetal-containing polymeric materials can not undergo rapid acid catalyzed hydrolysis in acidic pH ( pH 6-5) unless fully hydrated, which may in some instances reduce the drug delivery efficacy. [19][20][21][22][23] Therefore, it appears to be impossible using a single pH response moiety to construct ideal polymers that are stable both at storage and at pH 7.4, while quickly degrading under mildly acidic conditions. 24 In this study, synergistic dual-pH response poly(ethylene glycol)-b-(poly ε-caprolactone-g-poly((2,2-dimethyl-1,3-dioxolane-4-yl methyl acrylate)-co-2(dimethylamino)ethyl methacrylate), mPEG-b-(PCL-g-P(DA-co-DMAEMA)) was developed by incorporating tertiary amino groups of DMAEMA into pHresponsive ketal groups of DA.…”