Thermo, pH and reduction responsive coaggregates comprising AB₂C₂ star terpolymers for multi-triggered release of doxorubicin

Abstract

Novel 5-arm PEG(PCL) 2 (PNIPAM) 2 (S1) and PEG(PCL) 2 (PAA) 2 (S3) star terpolymers were synthesized, and their aggregates formed by a single star or mixed stars were efficiently used for loading and release of doxorubicin upon dual and triple stimuli. The star terpolymers had two disulfide moieties and poly(ethylene glycol) (PEG, A), poly(3-caprolactone) (PCL, B), poly(N-isopropylacrylamide) (PNIPAM, C 1 ), poly(tert-butyl acrylate) (PtBA, C 2 ), and poly(acrylic acid) (PAA, C 3 ) segments. Terminal diazide functionalized PEG (PEG-(N 3 ) 2 ) and alkyne-mid-functionalized PCL-b-PNIPAM and PCL-b-PtBA diblock copolymers were subjected to an azide-alkyne cycloaddition reaction to generate AB 2 C 2 (C ¼ C 1 and C 2 ) stars followed by selective hydrolysis to obtain a PEG(PCL) 2 (PAA) 2 star. Polymeric micelles were prepared by self-assembly of a single star in aqueous solution, and coaggregates were obtained by coassembly of S1 and S3 mixtures. Various polymeric aggregates had great potential as controlled delivery vehicles due to their reasonable drug loading efficiency and stimuli-adjustable drug release properties. As compared with dually sensitive micelles formed from a single star, triply stimuli-responsive coaggregates may be more promising as controlled delivery vehicles since the drug release properties can be potentially adjusted by various external stimuli and composition of star mixtures.

Synthesis of multifunctional ABC stars with a reduction-labile arm by consecutive ROP, RAFT and ATRP processes

“…Diphenyl phosphate (DPP, 99%), N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA, 99%), 2,2-bis (hydroxylmethyl)propionic acid (98%), and 2,2-dimethoxypropane (98%) were used as received. 2-((2-((2,2-Dihydroxymethyl)propionyloxy)ethyl)disulfanyl)ethyl 4-cyano-4-(phenylcarbonothioylthio)pentanoate (DCP) [40] and 2-(2-cyanopropyl) dithiobenzoate (CPDB) [47] were synthesized according to literature procedures. Toluene and dioxane were distilled over sodium and benzophenone.…”

“…As well-documented, the disulfide linkage can be efficiently cleaved in the presence of reducing agents such as Bu 3 P and glutathione, which has been widely used to enhance the functions and multipurpose applications [40][41][42][43][44][45][46]. In this study, PCL-PNIPAM-PtBA star was chosen as a model sample to understand the degree of cleavage since the cleaved PNIPAM (hydrophilic) and PCL-b-PtBA (hydrophobic) had quite different solubility.…”

“…To this end, a selective esterification between 2-((2-((2,2-dihydroxymethyl)propionyloxy)ethyl) disulfanyl)ethyl 4-cyano-4-(phenylcarbonothioylthio)pentanoate (DCP) [40] and 2-bromoisobutyric acid was performed to afford HBCP (Scheme S1, Supporting Information online). The chemical structure of HBCP was confirmed by 1 H and 13 C NMR ( Figure S1, Supporting Information online), IR ( Figure S2) ppm (C(CH 3 ) 2 Br) in 13 C NMR spectrum.…”

“…Star copolymers and their precursors were characterized by 1 H nuclear magnetic resonance ( 1 H NMR) and gel permeation chromatography (GPC), and the reduction-triggered topological transformation was preliminarily investigated. The success of this study further paves a versatile way to generate reduction-labile ABC stars with rich chemical compositions and adjustable macromolecular parameters, and the resultant stars may have a great potential in multi-stimuli responsive smart materials towards biomedical applications [40][41][42][43][44][45][46].…”

“…The potential reasons lie in the difficulty in preparing heterotrifunctional core agents and finding suitable polymerization methods which are concurrent or compatible with each other. For arm-first and combinatorial methods, steric hindrance may become pronounced especially when the chain length is long enough, and fractional precipitation or a second coupling reaction using insoluble surface-functionalized solid substrates [40] is necessary to remove lowercomposition fractions from the crude products if the linking reaction cannot perform in quantitative efficiency or the reactive polymers are not added according to rigorously equimolar feed ratio. At present, it is timely to further explore facile synthetic routes to construct functional star terpolymers.…”