Co-reporter:Yang Cui, Mei Zhang, Fu-Sheng DuZi-Chen Li
ACS Macro Letters January 17, 2017 Volume 6(Issue 1) pp:
Publication Date(Web):December 14, 2016
DOI:10.1021/acsmacrolett.6b00833
We report the straightforward synthesis of two types of H2O2-cleavable poly(ester-amide)s (P1 and P2) via the Passerini multicomponent polymerization (P-MCP) of 4-formylbenzeneboronic acid pinacol ester with 1,6-diisocyanohexane and 1,6-hexanedioic acid or a polyethylene glycol (PEG) dicarboxylic acid. The H2O2-cleavable phenylboronic acid ester was integrated into the polymer backbone by the in situ formed benzyl ester bond. GPC and 1H NMR confirmed the complete H2O2-triggered degradation of these polymers in aqueous medium by a mechanism of sequential oxidation of phenylboronic acid ester and self-immolative elimination. Compared with the hydrophobic polymer P1, the PEG-based water-soluble polymer P2 degraded much faster even at a lower H2O2 concentration. Cytocompatible nanoparticles of polymer P1 loaded with fluorescent Nile red were fabricated, and controlled release of Nile red in response to H2O2 was achieved, thus, demonstrating the utility of these polymers as potential H2O2-responsive delivery vehicles.
Co-reporter:Zi-Chen Li;Fang-Yi Qiu;Fu-Sheng Du;Mei Zhang
Macromolecules January 10, 2017 Volume 50(Issue 1) pp:23-34
Publication Date(Web):December 21, 2016
DOI:10.1021/acs.macromol.6b01883
Functional polyesters and poly(carbonate)s (PCs) with controlled and on-demand degradation properties have great advantages for biomedical and pharmaceutical applications. Herein, we report a new kind of aliphatic PC that possesses the feature of oxidation promoted degradation. Two six-membered cyclic carbonates (C1 and C2) containing phenylboronic ester group have been synthesized from serinol (1) and 2-aminomethyl-2-methylpropane-1,3-diol (2), respectively. Both monomers could undergo well-controlled ring-opening polymerization (ROP) catalyzed by an organic base, but the 5,5-disubstituted C2 has the character of equilibrium ROP and a much slower rate than the monosubstituted C1. The copolymerization of C1 or C2 with trimethylene carbonate and its derivative leads to a series of copolymers. Two series of amphiphilic block copolymers (BPC1s and BPC2s) have been prepared from C1 and C2 using poly(ethylene glycol) as the macroinitiator. They are able to form nanoparticles with the diameters less than 150 nm. The H2O2-triggered decomposition of C1, C2, and their corresponding noncyclic model compounds was studied by 1H NMR, showing the consecutive process of oxidation, 1,6-elimination, release of CO2, and intramolecular isomerization or cyclization. The degradation of the block copolymer nanoparticles, investigated by 1H NMR, GPC, laser light scattering (LLS), and Nile Red fluorescence, can also be accelerated drastically by H2O2 following the similar mechanism but is affected by steric hindrance of the polymer chain and heterogeneous microenvironment inside the nanoparticles. The results of 1H NMR and LLS reveal that the nanoparticles of BPC1 and BPC2 exhibited different degradation profiles, with a slightly faster degradation rate for BPC2. Of particular interest, BPC2 nanoparticle is sensitive to as low as 0.02 mM H2O2.
Co-reporter:Shan Su;Fu-Sheng Du;Zi-Chen Li
Organic & Biomolecular Chemistry 2017 vol. 15(Issue 39) pp:8384-8392
Publication Date(Web):2017/10/11
DOI:10.1039/C7OB02188G
Maleamic acid derivatives as weakly acid-sensitive linkers or caging groups have been used widely in smart delivery systems. Here we report on the controlled synthetic methods to mono- and dialkyl substituted maleamic acids and their pH-dependent hydrolysis behaviors. Firstly, we studied the reaction between n-butylamine and citraconic anhydride, and found that the ratio of the two n-butyl citraconamic acid isomers (α and β) could be finely tuned by controlling the reaction temperature and time. Secondly, we investigated the effects of solvent, basic catalyst, and temperature on the reaction of n-butylamine with 2,3-dimethylmaleic anhydride, and optimized the reaction conditions to efficiently synthesize the dimethylmaleamic acids. Finally, we compared the pH-dependent hydrolysis profiles of four OEG-NH2 derived water-soluble maleamic acid derivatives. The results reveal that the number, structure, and position of the substituents on the cis-double bond exhibit a significant effect on the pH-related hydrolysis kinetics and selectivity of the maleamic acid derivatives. Interestingly, for the mono-substituted citraconamic acids (α-/β-isomer), we found that their hydrolyses are accompanied by the isomerization between the two isomers.
Co-reporter:Mei Zhang, Cheng-Cheng Song, Ran Ji, Zeng-Ying Qiao, Chao Yang, Fang-Yi Qiu, De-Hai Liang, Fu-Sheng Du and Zi-Chen Li
Polymer Chemistry 2016 vol. 7(Issue 7) pp:1494-1504
Publication Date(Web):14 Jan 2016
DOI:10.1039/C5PY01999K
Oxidation stress has been becoming an important target for the development of smart nanomedicines, triggering research interest in oxidation responsive polymers. Herein, we report a new type of temperature/oxidation dual responsive copolymer. They were synthesized by the sequential atom transfer radical copolymerization (ATRP) of N-isopropylacrylamide (NIPAM, M1) and a phenylboronic pinacol ester-containing acrylate (M2) and dialysis against water to remove the pinacol protecting groups. The copolymers with a small amount of phenylboronic acid units (<7%) were soluble in cold neutral phosphate buffer but showed lower critical solution temperatures in the range of 12–31 °C. The thermally induced phase transition profiles depended on both the composition and concentration of the polymers. The cloud points of the copolymers were shifted to higher temperatures upon H2O2 induced oxidation of the phenylboronic acid and the subsequent 1,6-elimination. Using PEG-Cl as the macroinitiator to initiate ATRP of M1 and M2, three block copolymers composed of a PEG block and a temperature/oxidation dual responsive segment were prepared after dialysis in water. These block copolymers had a similar ratio of NIPAM to phenylboronic acid units but different molecular weights. We have studied their thermal self-assembly and H2O2 triggered decomposition by laser light scattering, 1H NMR, and transmission electron microscopy. Upon a fast heating protocol, these block copolymers formed stable micelle-like nanoparticles (at 37 °C) that were capable of encapsulating doxorubicin (DOX) and showed H2O2 triggered release. The naked nanoparticles were cytocompatible, however the DOX-loaded ones exhibited concentration dependent cytotoxicity, in particular to cancer cells.
Co-reporter:An Lv, Yang Cui, Fu-Sheng Du, and Zi-Chen Li
Macromolecules 2016 Volume 49(Issue 22) pp:8449-8458
Publication Date(Web):November 10, 2016
DOI:10.1021/acs.macromol.6b01325
We report the novel synthesis of thermally degradable polyesters through the postpolymerization modification of an unsaturated aliphatic polyester from maleic acid via Michael addition reaction with β-amino mercaptans. A high molecular weight polyester (P0) was synthesized by the acyclic diene metathesis (ADMET) polymerization of a diene monomer, di(10-undecenyl) maleate. Postpolymerization modification of P0 with three β-amino mercaptans (2-aminoethanethiol, l-cysteine methyl ester, and 2-(butylamino)ethanethiol) and 2-mercaptoethanol via the selective and quantitative thiol–Michael addition reaction with the maleate vinylic double bonds afforded four polyesters (P1–P4). All the polyesters were characterized by 1H NMR, GPC, and MALDI-TOF-MS, and their thermal properties were studied by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). The three polymers with pendant amino groups (P1–P3) subjected to thermal-induced degradation in the solid state, the driving force of which is the intramolecular cyclization at elevated temperatures with the formation of six-membered lactam derivatives. Degradation kinetics of P1–P3 in the solid states at different temperatures was studied in detail. It was found that increase of the steric hindrance and decrease of the nucleophilicity of the pendent amino groups could increase the degradation temperatures from 0 °C (P1) to 50 °C (P3). Alternatively, protonation of the amino groups of P1 and P2 with trifluoroacetic acid (TFA) could decrease the nucleophilicity of the primary amino groups, and the polymers P1-Boc and P2-Boc showed enhanced thermal stability up to 80 °C. Degradation of these two polymers via intramolecular cyclization occurred only when TFA was removed at higher temperatures. When the pendant group was a hydroxyl group as in polymer P4, no intramolecular cyclization occurred, and the polymer was thermally stable up 130 °C. Thus, the results highlight the importance of sequence, functional group, and nucleophilicity of the amino groups in determining the intramolecular cyclization and thermal degradation of these polyesters.
Co-reporter:Fang-Yi Qiu, Cheng-Cheng Song, Mei Zhang, Fu-Sheng Du, and Zi-Chen Li
ACS Macro Letters 2015 Volume 4(Issue 11) pp:1220
Publication Date(Web):October 21, 2015
DOI:10.1021/acsmacrolett.5b00533
We report a new type of oxidation-promoted fast-degradable aliphatic poly(carbonate)s (PCs) prepared by the ring-opening polymerization (ROP) of a six-membered cyclic carbonate containing a phenylboronic pinacol ester. The ROP of this monomer catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proceeded rapidly at ambient temperature with a good control over molecular weight and polydispersity at high monomer conversion. The H2O2-induced decomposition of this cyclic monomer and its noncyclic carbonate analogue was first studied by 1H NMR in order to clearly demonstrate the degradation mechanism of the PCs. The results of 1H NMR, GPC, and Nile Red fluorescence measurements revealed that the PC nanoparticles formulated by the o/w emulsion method were stable in neutral buffer, but upon triggering with H2O2, they underwent rapid surface degradation via the consecutive processes of oxidation, 1,6-elimination, release of CO2, and intramolecular cyclization. The degradation rates of the nanoparticles were dependent on the concentration of H2O2, and the nanoparticles were even sensitive to 0.5 mM of H2O2.
Co-reporter:Ran Ji, Jing Cheng, Cheng-Cheng Song, Fu-Sheng Du, De-Hai Liang, and Zi-Chen Li
ACS Macro Letters 2015 Volume 4(Issue 1) pp:65
Publication Date(Web):December 24, 2014
DOI:10.1021/mz5007359
We demonstrate a new type of acid-sensitive amphiphilic polypseudorotaxanes (PPRs) formed via inclusion complexation between Pluronic F127 and the hydrophobic β-cyclodextrin (CD) derivative in alcoholic solvents. The 6-OH ortho ester-substituted hydrophobic β-CD derivative (EMD-CD) was prepared by “click” reaction of β-CD with 2-ethylidene-4-methyl-1,3-dioxalane under mild conditions. The water-insoluble EMD-CD (host) is capable of forming PPRs with F127 (guest) in ethanol or methanol but not in water, which is confirmed by 1H NMR, wide-angle X-ray diffraction, small-angle X-ray scattering, and the time-dependent threading kinetics. Depending on the host/guest ratio, the PPRs self-assembled into sheet-like structure or vesicular nanoparticles with different sizes in water. These PPR assemblies were stable at pH 8.4 but quickly dissociated into biocompatible products in neutral or in acidic buffers due to the hydrolysis of the ortho ester groups. Good biocompatibility, ease of fabrication, and extremely pH-sensitive character make the PPRs promising carriers for anticancer drug delivery. Moreover, the present work provides an alternative method for the preparation of PPRs composed of water-insoluble CD derivatives.
Co-reporter:Fang-Yi Qiu;Mei Zhang;Ran Ji;Fu-Sheng Du;Zi-Chen Li
Macromolecular Rapid Communications 2015 Volume 36( Issue 22) pp:2012-2018
Publication Date(Web):
DOI:10.1002/marc.201500349
Co-reporter:Yao-Zong Wang, Lei Li, Fu-Sheng Du, Zi-Chen Li
Polymer 2015 Volume 68() pp:270-278
Publication Date(Web):26 June 2015
DOI:10.1016/j.polymer.2015.05.032
•Photo-labile polymers are synthesized by Passerini multicomponent polymerization.•These polymers show dual functions, substrate adhesiveness and UV degradation.•The adhesion performance can be tuned by varying the catechol contents.We report a facile synthetic approach to a new type of catechol containing UV dimantlable adhesive. A series of linear polymers containing pendent catechol moieties and main chain o-nitrobenzyl ester groups were synthesized by the Passerini multicomponent polymerization (MCP) of a di-o-nitrobenzaldehyde, 1,6-diisocyanohexane, 3-(3,4-dihydroxyphenyl) propionic acid, and undecanoic acid. The content of the catechol moieties was adjusted by varying the molar ratio of 3-(3,4-dihydroxyphenyl) propionic acid to undecanoic acid. The thermal properties of these polymers were investigated, they are stable up to 250 °C, and the glass transition temperatures (Tg) are in the range of 17–70 °C. Increasing the catechol content will increase the Tg and slightly decrease the thermal stability. The pendent catechol groups and the in situ formed o-nitrobenzyl ester linkages in the polymer main chain endow the polymer with dual functions, substrate adhesiveness and UV degradation. The UV degradation process was monitored by 1H NMR, GPC, UV–Vis and FTIR. Lap shear strength tests revealed that the adhesion performance of these polymers could be tuned by varying the catechol contents. UV irradiation could cleave the polymer chains, thus decreasing the adhesion strength.
Co-reporter:Cheng-Cheng Song, Fu-Sheng Du and Zi-Chen Li
Journal of Materials Chemistry A 2014 vol. 2(Issue 22) pp:3413-3426
Publication Date(Web):04 Mar 2014
DOI:10.1039/C3TB21725F
Reactive oxygen species (ROS) play key roles in many physiological processes, such as cell signaling and host innate immunity. However, when they are overproduced, ROS may damage biomolecules in vivo and cause diseases such as cardiovascular or neurodegenerative diseases, cancer, and so forth. Oxidative stress is usually implicated in various inflammatory tissues, representing an important target for the development of various therapeutic strategies. Therefore, various probes for the in vitro detection of ROS or the in vivo diagnosis of the oxidative stress-relevant diseases have been developed. Oxidation-responsive polymers have also attracted great interest due to their potential applications in biomedical fields. In this feature article, we summarize six types of oxidation-responsive polymers based on different oxidation-responsive motifs. Poly(propylene sulfide)s, selenium-based polymers, aryl oxalate- and phenylboronic ester-containing polymers are discussed in detail, while poly(thioketal)s and proline-containing polymeric scaffolds are briefly introduced.
Co-reporter:An Lv, Zi-Long Li, Fu-Sheng Du, and Zi-Chen Li
Macromolecules 2014 Volume 47(Issue 22) pp:7707-7716
Publication Date(Web):November 14, 2014
DOI:10.1021/ma5020066
We report a facile strategy for the synthesis, functionalization, and controlled degradation of high molecular weight polyesters based on itaconic acid (IA) and 10-undecenol. A diene monomer, di(10-undecenyl) itaconate (DUI), was synthesized from IA and 10-undecenol by esterification reaction. The acyclic diene metathesis (ADMET) polymerization of DUI was conducted with Grubbs first-generation catalyst (G-I) to afford high molecular weight polyesters (PEIA: P1 and P2). Modification of P1 with three mercaptans (3-mercapto-1,2-propanediol (MP), benzyl mercaptan (BM), and dodecyl mercaptan (DM)) and piperidine (PI) via Michael addition reaction with the itaconate vinyl groups was performed. Quantitative postpolymerization modifications with no degradation of the polyesters were achieved for all the three mercaptans and PI as revealed by NMR and GPC characterizations. One-pot sequential modification of P1 with MP and PI was also successfully conducted. Thermal properties of the modified polyesters were studied by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). All the modified polyesters are semicrystalline with variable glass transition and melting temperatures which are affected by the modified side groups. Based on a detailed model reaction study, controlled modification of the itaconate vinyl groups with primary amines (sec-butylamine and 3-pentanamine) without intramolecular cyclization was achieved. Thus, sec-butylamine was used to modify P1 to generate a secondary amine functionalized polyester (P1-BA/DM) which was stable at low temperature but undergone self-degradation in solid or solution via intramolecular cyclization with the formation of a five-membered lactam at elevated temperatures. This is a new kind of self-degradable polyester with controllable degradation rates.
Co-reporter:Ran Ji, Jing Cheng, Ting Yang, Cheng−Cheng Song, Lei Li, Fu-Sheng Du, and Zi-Chen Li
Biomacromolecules 2014 Volume 15(Issue 10) pp:
Publication Date(Web):August 21, 2014
DOI:10.1021/bm500711c
We report a new type of pH-sensitive supramolecular aggregates which possess a programmable character of sequential dePEGylation and degradation. As a platform of designing and building multifunctional supramolecular nanoparticles, a family of 6-OH ortho ester-modified β-cyclodextrin (β-CD) derivatives have been synthesized via the facile reaction between β-CD and cyclic ketene acetals with different alkyl lengths. These asymmetric acid-labile β-CD derivatives formed amphiphilic supramolecules with adamantane-modified PEG through host–guest interaction in polar solvents such as ethanol. The supramolecules can self-assemble in water to form acid-labile supramolecular aggregates. The results of TEM and light scattering measurements demonstrate that the size and morphology of the aggregates are influenced by the alkyl or PEG length and the host–guest feed ratio. By carefully balancing the alkyl and PEG lengths and adjusting the host–guest ratio, well-dispersed vesicles (50–100 nm) or sphere-like nanoparticles (200–500 nm) were obtained. Zeta potential measurements reveal that these supramolecular aggregates are capable of being surface-functionalized via dynamic host–guest interaction. The supramolecular aggregates were stable at pH 8.4 for at least 12 h as proven by the 1H NMR and LLS measurements. However, rapid dePEGylation occurred at pH 7.4 due to the hydrolysis of the ortho ester linkages locating at the interface, which resulted in aggregation of the dePEGylated hydrophobic inner cores. Upon further decreasing the pH to 6.4, the hydrophobic cores were further degraded due to the acid-accelerated hydrolysis of the ortho esters. The incubation stability of the acid-labile supramolecular aggregates in neutral buffer could be improved by incorporating hydrophobic poly(ε-caprolactone) into the core of the aggregates.
Co-reporter:Cheng-Cheng Song, Ran Ji, Fu-Sheng Du, De-Hai Liang, and Zi-Chen Li
ACS Macro Letters 2013 Volume 2(Issue 3) pp:273
Publication Date(Web):March 8, 2013
DOI:10.1021/mz4000392
We report a versatile method to tune the hydrolysis of the ortho ester-containing block copolymers by covalently incorporating oxidation-sensitive phenylboronic ester units. A series of block copolymers which contain a polyethylene glycol (PEG) block and a hydrophobic segment composed of different amounts of pendent ortho ester and phenylboronic ester groups were synthesized. These copolymers can self-assemble into narrowly dispersed micelle-like nanoparticles in phosphate buffer. The kinetics of phenylboronic ester oxidation and ortho ester hydrolysis in the nanoparticles were studied at different pH and H2O2 concentration. The results indicated that the phenylboronic ester oxidation rate was faster than the ortho ester hydrolysis rate at neutral pH, and both processes were accelerated with increasing H2O2 concentration. Nanoparticles which are extremely sensitive to the biorelevant concentration of H2O2 (50 μM) at pH 7.4 were obtained, suggesting great promise for inflammation-specific drug delivery.
Co-reporter:Zeng-Ying Qiao, Jing Cheng, Ran Ji, Fu-Sheng Du, De-Hai Liang, Shou-Ping Ji and Zi-Chen Li
RSC Advances 2013 vol. 3(Issue 46) pp:24345-24353
Publication Date(Web):07 Oct 2013
DOI:10.1039/C3RA42824A
A family of amphiphilic block copolymers with pendent ortho ester groups were synthesized by modifying the double hydrophilic block copolymer PEO114-b-PVA240 with 2-ethylidene-4-methyl-1,3-dioxolane (EMD) under mild conditions (30 °C). The degree of modification (DM) of the ortho ester groups can be tuned by simply varying the feed ratio of EMD to the hydroxyl groups in the PVA block. These block copolymers are stable in an anhydrous environment. Laser light scattering (LLS) and transmission electron microscopy (TEM) measurements revealed that in weakly basic aqueous buffer, these amphiphilic block copolymers self-assembled into aggregates with different size and morphology, ranging from solid-like spherical nanoparticles to polymersomes as the DM increased. The acid-triggered dissociation behaviour of the aggregates were studied by LLS, nile red (NR) fluorescence and TEM. The copolymer aggregates dissociated faster in a buffer with the lower pH; the dissociation rate of the aggregates became faster for the copolymers with lower DM. The polymersomes can load both hydrophilic biomacromolecules like lysozyme and hydrophobic anticancer drug doxorubicin (DOX). The drug-loaded polymersomes were stable in neutral phosphate buffer for at least 6 h with a payload leakage of less than 25% in 12 h at 37 °C; however, significant acid-triggered payload release was accomplished even at a mildly acidic pH (6.0). Finally, the DOX-loaded polymersomes exhibited a concentration-dependent toxicity to MCF-7 and HeLa cells while the copolymers themselves are non-toxic.
Co-reporter:Cheng-Cheng Song, Cui-Cui Su, Jing Cheng, Fu-Sheng Du, De-Hai Liang, and Zi-Chen Li
Macromolecules 2013 Volume 46(Issue 3) pp:1093-1100
Publication Date(Web):February 1, 2013
DOI:10.1021/ma301964n
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.
Co-reporter:Zeng-Ying Qiao, Ran Ji, Xiao-Nan Huang, Fu-Sheng Du, Rui Zhang, De-Hai Liang, and Zi-Chen Li
Biomacromolecules 2013 Volume 14(Issue 5) pp:
Publication Date(Web):April 9, 2013
DOI:10.1021/bm400180n
A series of well-defined thermoresponsive diblock copolymers (PEO45-b-PtNEAn, n = 22, 44, 63, 91, 172) were prepared by the atom transfer radical polymerization of trans-N-(2-ethoxy-1,3-dioxan-5-yl) acrylamide (tNEA) using a poly(ethylene oxide) (PEO45) macroinitiator. All copolymers are water-soluble at low temperature, but upon quickly heating to 37 °C, laser light scattering (LLS) and transmission electron microscopy (TEM) characterizations indicate that these copolymers self-assemble into aggregates with different morphologies depending on the chain length of PtNEA and the polymer concentration; the morphologies gradually evolved from spherical solid nanoparticles to a polymersome as the degree of polymerization (“n”) of PtNEA block increased from 22 to 172, with the formation of clusters with rod-like structure at the intermediate PtNEA length. Both the spherical nanoparticle and the polymersome are stable at physiological pH but susceptible to the mildly acidic medium. Acid-triggered hydrolysis behaviors of the aggregates were investigated by LLS, Nile red fluorescence, TEM, and 1H NMR spectroscopy. The results revealed that the spherical nanoparticles formed from PEO45-b-PtNEA44 dissociated faster than the polymersomes of PEO45-b-PtNEA172, and both aggregates showed an enhanced hydrolysis under acidic conditions. Both the spherical nanoparticle and polymersome are able to efficiently load the hydrophobic doxorubicin (DOX), and water-soluble fluorescein isothiocyanate-lysozyme (FITC-Lys) can be conveniently encapsulated into the polymersome without using any organic solvent. Moreover, FITC-Lys and DOX could be coloaded in the polymersome. The drugs loaded either in the polymersome or in the spherical nanoparticle could be released by acid triggering. Finally, the DOX-loaded assemblies display concentration-dependent cytotoxicity to HepG2 cells, while the copolymers themselves are nontoxic.
Co-reporter:Cheng-Cheng Song, Ran Ji, Fu-Sheng Du, and Zi-Chen Li
Macromolecules 2013 Volume 46(Issue 21) pp:8416-8425
Publication Date(Web):October 18, 2013
DOI:10.1021/ma401656t
We report the synthesis of a new type of amphiphilic poly(amino ester)s which can be completely degraded in aqueous media via H2O2 oxidation. The polymers were prepared by the controlled Michael-type addition polymerization of a phenylboronic pinacol ester-containing diacrylate and N-aminoethylpiperazine, followed by postmodification with mPEG5K-succinimide ester. Upon oxidation, the side chain phenylboronic esters will be transformed into phenol groups which can trigger the sequential self-immolative process to degrade the polymer main chain. Meanwhile, the amino groups on the polymer main chain are capable of trapping the highly active quinone methides generated in situ during the oxidative degradation of the polymers. Based on the detailed oxidation kinetics and products of several model compounds, the H2O2-triggered degradation of nanoparticles of these copolymers was investigated by NMR spectroscopy, GPC, and Nile red fluorescence probe. The results demonstrate that the poly(amino ester) backbones were completely degraded by H2O2, resulting in the dissociation of nanoparticles. Oxidative degradation rates of the nanoparticles could be accelerated by increasing the concentration of H2O2, the PEGylation degree, or the pH of the buffer. Interestingly, the in situ formed quinone methides could be captured by secondary amines due to their higher nucleophilicity than H2O. Of potential importance, these amphiphilic oxidation-responsive copolymers are sensitive to stimulation of 200 μM H2O2; therefore, they may find application in the field of intelligent drug/gene delivery systems.
Co-reporter:Jing Cheng, Ran Ji, Shi-Juan Gao, Fu-Sheng Du, and Zi-Chen Li
Biomacromolecules 2012 Volume 13(Issue 1) pp:
Publication Date(Web):December 16, 2011
DOI:10.1021/bm201410c
This work presents a facile approach for preparation of acid-labile and biocompatible polymers with pendent cyclic ortho esters, which is based on the efficient and mild reactions between cyclic ketene acetal (CKA) and hydroxyl groups. Three CKAs, 2-ethylidene-1,3-dioxane (EDO), 2-ethylidene-1,3-dioxolane (EDL), and 2-ethylidene-4- methyl-1,3-dioxolane (EMD) were prepared from the corresponding cyclic vinyl acetals by catalytic isomerization of the double bond. The reaction of CKAs with different alcohols and diols was examined using trace of p-toluenesulfonic acid as a catalyst. For the monohydroxyl alcohols, cyclic ortho esters were formed by simple addition of the hydroxyl group toward CKAs with ethanol showing a much greater reactivity than iso-propanol. When 1,2- or 1,3-diols were used to react with the CKAs, we observed the isomerized cyclic ortho esters besides the simple addition products. Biocompatible polyols, that is, poly(2-hydroxyethyl acrylate) (PHEA) and poly(vinyl alcohol) (PVA) were then modified with CKAs, and the degree of substitution of the pendent ortho esters can be easily tuned by changing feed ratio. Both the small molecule ortho esters and the CKA-modified polymers demonstrate the pH-dependent hydrolysis profiles, which depend also on the chemical structure of the ortho esters as well as the polymer hydrophobicity.
Co-reporter:Rui Zhang;Yang Wang;Fu-Sheng Du;Ying-Li Wang;Ying-Xia Tan;Shou-Ping Ji;Zi-Chen Li
Macromolecular Bioscience 2011 Volume 11( Issue 10) pp:1393-1406
Publication Date(Web):
DOI:10.1002/mabi.201100094
Co-reporter:Yang Wang, Rui Zhang, Ning Xu, Fu-Sheng Du, Ying-Li Wang, Ying-Xia Tan, Shou-Ping Ji, De-Hai Liang, and Zi-Chen Li
Biomacromolecules 2011 Volume 12(Issue 1) pp:
Publication Date(Web):December 2, 2010
DOI:10.1021/bm101005j
Linear reduction-degradable cationic polymers with different secondary amine densities (S2 and S3) and their nonreducible counterparts (C2 and C3) were synthesized by Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC) step-growth polymerization of the dialkyne-oligoamine monomers and the diazide monomers. These polymers were studied with a goal of developing a set of new gene carriers. The buffering capacity and DNA binding ability of these polymers were evaluated by acid−base titration, gel retardation, and ethidium bromide (EB) exclusion assay. The polymers with lower amine density exhibit a weaker DNA-binding ability but a stronger buffering capacity in the range of pH 5.1 and 7.4. Particle size and zeta-potential measurements demonstrate that the polymers with higher amine density condense pDNA to form polyplexes with smaller sizes, while the disulfide bond in the backbone shows a negative effect on the condensing capability of the polymers, resulting in the formation of polyplexes with large size and nearly neutral surface. The reduction-sensitive polyplexes formed by polymer S2 or S3 can be disrupted by dithiothreitol (DTT) to release free DNA, which has been proven by the combination of gel retardation, EB exclusion assay, particles sizing, and zeta potential measurements. Cell viability measurements by MTT assay demonstrate that the reduction-degradable polymers (S2 and S3) have little cytotoxicity while the nonreducible polymers (C2 and C3) show obvious cytotoxicity, in particular, at high N/P ratios. In vitro transfection efficiencies of these polymers were evaluated using EGFP and luciferase plasmids as the reporter genes. Polymers S3 and S2 show much higher efficiencies than the nonreducible polymers C3 and C2 in the absence of 10% serum; unexpectedly, the lowest transfection efficiency has been observed for polymer S3 in the presence of serum.
Co-reporter:Zeng-Ying Qiao, Fu-Sheng Du, Rui Zhang, De-Hai Liang and Zi-Chen Li
Macromolecules 2010 Volume 43(Issue 15) pp:6485-6494
Publication Date(Web):July 16, 2010
DOI:10.1021/ma101090g
Two acrylate monomers with six-member cyclic ortho ester groups, i.e., 2-(1,3-dioxan-2-yloxy)ethyl acrylate (DEA) and 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), were synthesized. These two monomers were copolymerized with an oligo(ethylene glycol) acrylate (OEGA) under atom transfer radical polymerization conditions to afford two series of thermoresponsive copolymers, poly(DEA-co-OEGA)s and poly(DMDEA-co-OEGA)s. All the copolymers were soluble in water to form transparent solutions at low temperature, however, some of them exhibited association behaviors below the cloud point (CP) as evidenced by 1H NMR, dynamic light scattering (DLS) and fluorescence method. The aggregation tendency of the copolymers depends on their composition as well as the structure of the ortho ester units. With a similar composition, poly(DMDEA-co-OEGA) showed a stronger aggregation tendency than poly(DEA-co-OEGA). In addition, increasing molar content of the ortho ester units in a copolymer promoted its aggregation in water. Thermally induced phase transitions of these copolymers were studied by various methods including turbidimetry, temperature-dependent 1H NMR, DLS, and microscopy. The results indicate that CP of the copolymers increased with increasing the content of OEGA units, but the changing behaviors of CP were rather different for two types of copolymers, which can be ascribed to the difference in hydrophobicity of the ortho ester units. Little hysteresis was observed for the copolymers with more OEGA units while those with more ortho ester units showed significant hysteresis probably due to the hydrophobic character of the ortho ester. The formation of coacervate droplets above CP reveals that the copolymers underwent a liquid−liquid phase separation upon heating. pH-dependent hydrolyses of the copolymers were studied by turbidimetry and 1H NMR methods. The hydrolysis rate depends greatly on pH and the hydrophilic/hydrophobic balance of the copolymers: lower pH and more hydrophilic character resulted in a faster hydrolysis rate. Finally, this type of acid-labile thermoresponsive copolymers and the acid-catalyzed hydrolysis products have low cytotoxicity.
Co-reporter:Xiaonan Huang, Fusheng Du, Jing Cheng, Yongquan Dong, Dehai Liang, Shouping Ji, Shrong-Shi Lin and Zichen Li
Macromolecules 2009 Volume 42(Issue 3) pp:783-790
Publication Date(Web):January 16, 2009
DOI:10.1021/ma802138r
An orthoester-containing monomer, trans-N-(2-ethoxy-1,3-dioxan-5-yl)acrylamide (tNEA), was synthesized. Atom transfer radical polymerization of tNEA using a poly(ethylene glycol) (PEG) macroinitiator afforded three acid-labile thermoresponsive block copolymers: PEG-b-PtNEA27, PEG-b-PtNEA56, and PEG-b-PtNEA73. These block copolymers are water-soluble at low temperatures (<13 °C). Thermally induced phase transition behaviors, including the critical aggregation temperatures (CATs), of these polymers were investigated by light scattering and 1H NMR. The results indicated that the longer the PtNEA chain length, the lower the CAT. Upon heating above the CATs, all the three polymers underwent a phase transition and formed polymeric micelles or micelle-like nanoparticles with PEG as the shell and PtNEA block as the core. Both the sizes and morphologies of the micelles were found to be affected by the heating rate and the salt concentration in the buffers. The micelles, formed through a fast heating procedure in the buffer with a relatively high salt concentration, have a smaller size and a more compacted structure. pH-dependent destabilization of the polymeric micelles prepared from PEG-b-PtNEA73 was studied by using light scattering and Nile Red fluorescence. The results demonstrated that hydrophobic Nile Red could be loaded in the micelles that were stable at pH 7.4, but destabilized in mildly acidic media. The dissociation of the micelles and the subsequent release of Nile Red were induced by the acid-triggered hydrolysis of the orthoester groups, which was proved by the 1H NMR spectra.
Co-reporter:Ning Xu;Rui Wang;Fu-Sheng Du;Zi-Chen Li
Journal of Polymer Science Part A: Polymer Chemistry 2009 Volume 47( Issue 14) pp:3583-3594
Publication Date(Web):
DOI:10.1002/pola.23443
Abstract
Amphiphilic, biodegradable block glycopolymers based on poly(ε-caprolactone) (PCL) with various pendent saccharides were synthesized by combination of ring-opening polymerization (ROP) and “click” chemistry. PCL macroinitiators obtained by ROP of ε-caprolactone were used to initiate the ROP of 2-bromo-ε-caprolactone (BrCL) to get diblock copolymers, PCL-b-PBrCL. Reaction of the block copolymers with sodium azide converted the bromine groups in the PBrCL block to azide groups. In the final step, click chemistry of alkynyl saccharides with the pendent azide groups of PCL-b-PBrCL led to the formation of the amphiphilic block glycopolymers. These copolymers were characterized by 1H NMR spectroscopy and gel permeation chromatography. The self-assembly behavior of the amphiphilic block copolymers was investigated using transmission electron microscopy and atomic force microscope, spherical aggregates with saccharide groups on the surface were observed, and the aggregates could bind reversibly with Concanavalin A. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3583–3594, 2009
Co-reporter:Xiao-Nan Huang;Fu-Sheng Du;Bo Zhang;Jing-Yi Zhao ;Zi-Chen Li
Journal of Polymer Science Part A: Polymer Chemistry 2008 Volume 46( Issue 13) pp:4332-4343
Publication Date(Web):
DOI:10.1002/pola.22751
Abstract
Acid-labile, thermoresponsive polymers with pendant six-membered cyclic acetal groups were prepared by radical polymerization of two monomers, N-(2,2-dimethyl-1,3-dioxan-5-yl) methacrylamide (NDMM) and N-(2,2-dimethyl-1,3-dioxan-5-yl) acrylamide (NDMA). The aqueous solution properties of the polymers, PNDMM and PNDMA, were studied by turbidimetry, 1H NMR, fluorescence, and DSC measurements. It is found that both polymers show sensitive and reversible phase transitions with distinct lower critical solution temperatures (LCST). Below their LCSTs, there are still some polymer aggregates as evidenced by measurements of pyrene excitation spectra and urea effects on the cloud points (CP) of polymers. The salting effect of six inorganic sodium salts on the phase transition behavior of PNDMM was investigated by turbidimetric approach. The salting-out to salting-in effect is in the order of SO42− > F− > Cl− > Br− > I− > SCN−, following the Hofmeister's series. pH-dependent hydrolysis of PNDMM and PNDMA was studied by turbidimetric and 1H NMR methods. They are both pH-sensitive and their hydrolysis rates significantly increase with decreasing pH value. The CP of PNDMM gradually increases with the acid-triggered hydrolysis of the acetal groups and the hydrolyzed polymer with ∼ 30% hydrolysis degree does not show thermally induced phase transition. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4332–4343, 2008
Co-reporter:Xiaonan Huang, Fusheng Du, Dehai Liang, Shrong-Shi Lin and Zichen Li
Macromolecules 2008 Volume 41(Issue 14) pp:5433-5440
Publication Date(Web):June 21, 2008
DOI:10.1021/ma800783v
Two acid-labile, thermoresponsive poly(methacrylamide)s with the pendant cyclic orthoester moieties of trans and cis configurations, PtNEM and PcNEM, were synthesized via free radical polymerization of the corresponding trans and cis isomers of N-(2-ethoxy-1,3-dioxan-5-yl)methacrylamide (NEM). The thermally induced phase transition/separation behaviors of both polymers as well as the aqueous solution properties below and above their phase transition temperatures were investigated by means of turbidimetry, DSC, 1H NMR, microscopy, fluorescence probe, and dynamic light scattering. Both PtNEM and PcNEM showed aggregation behaviors below their respective LCSTs, and the former formed more hydrophobic microdomains which had greater capability to solvate pyrene molecules compared with PcNEM. These two polymers exhibited thermally induced sensitive and reversible phase transitions in aqueous solution. PtNEM showed a little lower cloud point but much greater phase transition enthalpy compared to PcNEM. The results of DSC, 1H NMR, and microscopy measurements revealed that PcNEM exhibited a liquid−liquid phase separation while PtNEM likely underwent a liquid−solid transition. Furthermore, the pH-dependent hydrolyses of both polymers were studied by the 1H NMR and turbidimetric approaches. The results indicated that both PtNEM and PcNEM showed acid-triggered hydrolysis behaviors, and the hydrolysis products were affected by the configurations of the pendant cyclic groups. On the basis of these results, we can conclude that the stereochemical structures of the pendant cyclic orthoester groups in these poly(methacrylamide)s greatly affect their aqueous solution properties as well as their hydrolysis behaviors.
Co-reporter:Song Lin, Fusheng Du, Yang Wang, Shouping Ji, Dehai Liang, Lei Yu and Zichen Li
Biomacromolecules 2008 Volume 9(Issue 1) pp:
Publication Date(Web):December 19, 2007
DOI:10.1021/bm7008747
Intelligent gene delivery systems based on physiologically triggered reversible shielding technology have evinced enormous interest due to their potential in vivo applications. In the present work, an acid-labile block copolymer consisting of poly(ethylene glycol) and poly(2-(dimethylamino)ethyl methacrylate) segments connected through a cyclic ortho ester linkage (PEG-a-PDMAEMA) was synthesized by atom transfer radical polymerization of DMAEMA using a PEG macroinitiator with an acid-cleavable end group. PEG-a-PDMAEMA condensed with plasmid DNA formed polyplex nanoparticles with an acid-triggered reversible PEG shield. The pH-dependent shielding/deshielding effect of PEG chains on the polyplex particles were evaluated by ζ potential and size measurements. At pH 7.4, polyplexes generated from PEG-a-PDMAEMA exhibited smaller particle size, lower surface charge, reduced interaction with erythrocytes, and less cytotoxicity compared to PDMAEMA-derived polyplexes. At pH 5.0, ζ potential of polyplexes formed from PEG-a-PDMAEMA increased, leveled up after 2 h of incubation and gradual aggregation occurred in the presence of bovine serum albumin (BSA). In contrast, the stably shielded polyplexes formed by DNA and an acid-stable block copolymer, PEG-b-PDMAEMA, did not change in size and ζ potential in 6 h. In vitro transfection efficiency of the acid-labile copolymer greatly increased after 6 h incubation at pH 5.0, approaching the same level of PDMAEMA, whereas there was only slight increase in efficiency for the stable copolymer, PEG-b-PDMAEMA.
Co-reporter:Cheng-Cheng Song, Fu-Sheng Du and Zi-Chen Li
Journal of Materials Chemistry A 2014 - vol. 2(Issue 22) pp:NaN3426-3426
Publication Date(Web):2014/03/04
DOI:10.1039/C3TB21725F
Reactive oxygen species (ROS) play key roles in many physiological processes, such as cell signaling and host innate immunity. However, when they are overproduced, ROS may damage biomolecules in vivo and cause diseases such as cardiovascular or neurodegenerative diseases, cancer, and so forth. Oxidative stress is usually implicated in various inflammatory tissues, representing an important target for the development of various therapeutic strategies. Therefore, various probes for the in vitro detection of ROS or the in vivo diagnosis of the oxidative stress-relevant diseases have been developed. Oxidation-responsive polymers have also attracted great interest due to their potential applications in biomedical fields. In this feature article, we summarize six types of oxidation-responsive polymers based on different oxidation-responsive motifs. Poly(propylene sulfide)s, selenium-based polymers, aryl oxalate- and phenylboronic ester-containing polymers are discussed in detail, while poly(thioketal)s and proline-containing polymeric scaffolds are briefly introduced.
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