Co-reporter:Yue Sun;Xueqiong Du;Jinlin He;Jian Hu;Mingzu Zhang
Journal of Materials Chemistry B 2017 vol. 5(Issue 20) pp:3771-3782
Publication Date(Web):2017/05/24
DOI:10.1039/C7TB00440K
“Intelligent” crosslinked nanoparticles (NPs) provide great advantages in enhancing drug bioavailability and reducing side effects in anticancer therapeutics. In this study, a novel biodegradable polyphosphoester-based functional copolymer prodrug PTX-(PBYP-g-MPA)-b-PEEP was prepared to construct pH/redox dual-responsive core-crosslinked nanoparticles (DOX/CCL NPs), in which paclitaxel (PTX) was conjugated to the polyphosphoester to form an amphiphilic prodrug and doxorubicin (DOX) was encapsulated inside the prodrug NPs. At first, PTX was used as an initiator to polymerize 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP) and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) by one-pot sequential ring-opening polymerization, yielding a biodegradable polymeric prodrug PTX-PBYP-b-PEEP. Subsequently, a radical-mediated thiol–yne “click” reaction was performed between the alkynyl groups on the PBYP segment and the thiol group of 3-mercaptopropionic acid (MPA) to form a functional carboxyl group at the side chain. The potential positively charged DOX·HCl can be physically encapsulated via electrostatic interaction with the carboxyl group and hydrophobic interaction. Afterwards, the DOX/CCL NPs with cleavable disulfide (S–S) linkages can be formed by partial crosslinking through amidation between the pendant carboxyl groups and cystamine. These NPs possess multifunctional characteristics used for in vitro drug release. Notably, a redox-responsive crosslinker, cystamine dihydrochloride, and synergetic non-covalent interactions not only stabilize the nanoparticles, achieve high DOX-loading capacity of drug loading content (DLC, 14.6%) and drug loading efficiency (DLE, 73.1%), but also endow the DOX/CCL NPs with controlled drug release capacity, which is due to the cleavage of S–S bonds in the presence of 10 mM glutathione (GSH) and weakened electrostatic interaction caused by the protonation of carboxyl groups at a lower pH (5.0). Moreover, these pH/redox dual-responsive DOX/CCL NPs can be steadily internalized by HeLa cells, exhibiting high-efficiency cellular proliferation inhibition. This study presents a promising strategy for controlled intracellular drug release in cancer therapy.
Co-reporter:Zi-xu Gu;Jun Cheng;Ming-zu Zhang;Jin-lin He
Chinese Journal of Polymer Science 2017 Volume 35( Issue 9) pp:1061-1072
Publication Date(Web):05 July 2017
DOI:10.1007/s10118-017-1966-x
Due to the non-crystalline properties of short chain perfluoroalkyl groups, using short chain perfluoroalkyl to stabilize low surface free energy polymers has been a challenging task. In this study, we prepare a series of random copolymers poly(perfluorohexylethyl methacrylate)-co-poly(stearyl acrylate) (P13FMA-co-PSA) and block copolymers poly(perfluorohexylethyl methacrylate)-b-poly(stearyl acrylate) (P13FMA-b-PSA), and systematically investigate the effects of the sequence structure and the content of 13FMA of the fluorinated copolymers on surface free energy and surface reorganization. Static/dynamic contact angle goniometry and water/oil repellency analyses demonstrate that the random polymer P13FMA-co-PSA could not achieve low surface free energy and low surface reorganization at the same time. In contrast, for the block copolymer P13FMA-b-PSA, both low surface free energy and low surface reorganization are acquired simultaneously. The results of X-ray photoelectron spectroscopy (XPS), dynamic contact angle goniometry and differential scanning calorimetry (DSC) reveal the above-mentioned properties. The consecutive 13FMA segments improve the surface fluorine density, while the consecutive SA chains enhance the crystallinity of the SA segments, and further hinder the surface reorganization of the perfluoroalkyl groups. Therefore, P13FMA-b-PSA exhibits a higher utilization efficiency of fluorine atoms and a better structural stability than P13FMA-co-PSA.
Co-reporter:Dongling Cao, Jinlin He, Jiaying Xu, Mingzu Zhang, Lin Zhao, Guangxin Duan, Youwen Cao, Ruhong Zhou and Peihong Ni
Polymer Chemistry 2016 vol. 7(Issue 25) pp:4198-4212
Publication Date(Web):23 May 2016
DOI:10.1039/C6PY00701E
Multiple drugs in combinatory therapy can improve the treatment of cancer due to their efficient reduction of multidrug resistance (MDR) of tumor cells. In this paper, we first synthesized a reduction-sensitive dextran-ss-camptothecin (Dex-ss-CPT, or Dex-CPT) prodrug conjugated by a disulfide bond, and a pH-responsive dextran-hyd-doxorubicin (Dex-hyd-DOX, or Dex-DOX) prodrug linked with an acid-cleavable hydrazone group. The chemical structures of the intermediate polymers and polymeric prodrugs have been fully characterized by 1H NMR, FT-IR, UV-Vis and HPLC analyses, respectively. Both prodrugs could self-assemble into uniform particles in aqueous solution. Subsequently, in vitro synergistic drug release of the two prodrugs was studied by methyl thiazolyl tetrazolium (MTT) assay. The reduction of a disulfide linker generates a thiol intermediate that is followed by intramolecular cyclization and the cleavage of the neighboring carbonate bridge, thus releasing native CPT molecules from the Dex-ss-CPT micelles. Similarly, the pH-sensitive hydrazone bond is broken under intracellular acidic conditions and the DOX parent drug is released from the Dex-hyd-DOX micelles. Finally, in vivo pharmacokinetics and biodistribution were investigated via intravenous administration with various formulations to treat 4T1 tumor-bearing mice. Meanwhile, the antitumor activity was also studied. This work demonstrates an effective anti-cancer prodrug design platform, which is expected to be useful for the treatment of various tumors.
Co-reporter:Sen Li, Jinlin He, Mingzu Zhang, Hairong Wang and Peihong Ni
Polymer Chemistry 2016 vol. 7(Issue 9) pp:1773-1781
Publication Date(Web):21 Jan 2016
DOI:10.1039/C5PY02017D
This paper is aimed at comparing the effects of flexible and rigid blocks on the morphologies of multicompartment aggregates self-assembled from two kinds of fluorinated ABC triblock terpolymers, in which polyisobutylene (PIB) with a low glass transition temperature (Tg ∼ −67 °C) and polystyrene (PS) with high Tg (∼100 °C) were selected as the flexible and rigid blocks, respectively. The fluorinated triblock terpolymers (abbreviated as PIB-b-PDMAEMA-b-POFPMA and PS-b-PDMAEMA-b-POFPMA, respectively) with similar relative block lengths were synthesized via consecutive oxyanion-initiated polymerization (OIP) of 2-N,N-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate (OFPMA) using pre-functionalized PIB-O−K+ or PS-O−K+ as the macroinitiators. These terpolymers could self-assemble in aqueous solution since the PDMAEMA block is hydrophilic, PIB and PS blocks are hydrophobic, while the POFPMA block is both hydrophobic and lipophobic. The self-assembly behavior was analyzed by transmission electron microscopy (TEM). It has been demonstrated that PIB-b-PDMAEMA-b-POFPMA with the flexible PIB block could self-assemble into four types of reproducible nanostructures with the increase of polymer concentrations, including multicompartment micelles, fiber-like aggregates, nanotubules and rod-like aggregates. More interestingly, a uniform zig-zag pattern was observed on the surface of these rod-like aggregates after the solution was maintained without stirring for one week. In contrast, for the PS-b-PDMAEMA-b-POFPMA system containing a rigid PS block, the similar morphologies were rarely observed, except for spherical, hamburger and flower-like multicompartment nanostructures. The present work reveals that the flexibility or rigidity of the hydrophobic segment as well as the polymer concentration exerts a big influence on both the self-assembly behavior and formation of diversified morphologies.
Co-reporter:Jian Hu, Mingzu Zhang, Jinlin He and Peihong Ni
RSC Advances 2016 vol. 6(Issue 47) pp:40858-40868
Publication Date(Web):11 Apr 2016
DOI:10.1039/C6RA07420K
We recently reported a precise modular synthesis technique and structure–property study, in which a series of acid-cleavable star-block copolymers containing poly(ethylene glycol) monomethyl ether (mPEG) and poly(ε-caprolactone) (PCL) blocks linked with acid-cleavable acetal groups, abbreviated as (mPEG-a-PCL-a-)3, were prepared and characterized. In this paper, we focus on developing the acid-cleavable star-block copolymer into an injectable hydrogel that is based on inclusion complexes between (mPEG-a-PCL-a-)3 and α-cyclodextrin (α-CD). The gelation times for the hydrogels were tested by a vial-tilting method, and the results indicated that these gels have a fast gelation process. Wide angle X-ray diffraction (WAXD) and differential scanning calorimetry (DSC) analyses were utilized to study the formation of necklace-like crystalline inclusion complexes between PEG-containing polymers and α-CD. Scanning electron microscopy (SEM) observation results showed that these lyophilized hydrogels with different components mainly exhibited a porous spongelike structure. Good structure recovery properties of the supramolecular hydrogels, which were identified by rheological tests, indicate that these hydrogels have great potential application in the area of injectable hydrogels. These supramolecular hydrogels show flowable characters under a large stress, and the hydrogel systems exhibit unique structure-related reversible gel–sol transition properties at a certain stress. After removal of the high shear stress, the network structures of the sol solutions started being restored immediately. Furthermore, these hydrogels are essentially elastic in response to small stresses over a frequency range that covers everyday activities such as walking and running. Doxorubicin hydrochloride (DOX·HCl), as a model drug, was encapsulated into the hydrogels, and was then released from the drug-loaded hydrogels because the acetal groups possess pH-triggered fracture behavior. It is expected that this kind of injectable hydrogel has promising applications in the treatment of joint disease.
Co-reporter:Zixu Gu, Mingzu Zhang, Jinlin He, Peihong Ni
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2016 Volume 502() pp:159-167
Publication Date(Web):5 August 2016
DOI:10.1016/j.colsurfa.2016.05.016
•The relationship between the comonomer structures of fluorinated copolymers and surface free energy, as well as surface reorganization behaviors.•Poly(perfluorohexylethyl methacrylate)-co-poly[n-alkyl (H ormethyl)acrylate], abbreviated as P13FMA-co-P(AnA) or P13FMA-co-P(AnMA), n = 1, 2, 4, 8, 12, 16, and 18.•The surface free energy of copolymers was influenced not by the side-chain length of comonomers, but by the group (H or CH3) at α-position of comonomer.•The surface reorganization is directly correlated with the copolymer Tg or Tm.In this work, we report on surface energy and surface reorganization behaviors of a series of fluorinated copolymers poly(perfluorohexylethyl methacrylate)-co-poly[n-alkyl (H or methyl)acrylate], abbreviated as P13FMA-co-P(AnA) or P13FMA-co-P(AnMA), as a function of the lengths of non-fluoroalkyl group in the pendent groups of the comonomers and the presence of hydrogen (H) or methyl (CH3) in the α-position of comonomers. Although the different copolymers that were derived from various comonomers formed different fluorine-enriched concentrations on the gas-solid interface, the increasing chain lengths of the alkyls have less impact the surface energy of the fluorinated copolymers. The methyl at the α-position of methacrylate monomer results in the significant increase of surface energy. The dynamic contact angle measurements show that the surface reorganization of the fluorinated chains are directly associated with the Tg or Tm of these copolymers. For P13FMA-co-P(AnMA) system, it has higher Tg and lower surface reorganization. However, when the carbon numbers (n) of the alkyl in comonomers are larger than 12, P13FMA-co-P(AnA) shows higher Tm and smaller hysteresis contact angle, as well as more stable low surface energy, compared to those of P13FMA-co-P(AnMA).Two types of fluorinated copolymers based on 13FMA and n-alkyl (meth)acrylate with different alkyl groups have been synthesized. This paper focuses on the effects of the group (H or CH3) at α-position and the side-chain lengths of (meth)acrylate on surface free energy and surface reorganization behaviors of the copolymer films, and will provide a theoretical basis for comonomer selection.
Co-reporter:Qingqing Zhang, Jinlin He, Mingzu Zhang and Peihong Ni
Journal of Materials Chemistry A 2015 vol. 3(Issue 24) pp:4922-4932
Publication Date(Web):14 May 2015
DOI:10.1039/C5TB00623F
A new kind of reduction-cleavable polymer-camptothecin (CPT) prodrug has been developed, in which the polymer backbone consists of a biodegradable diblock polyphosphoester (PBYP-b-PEEP), and a modified CPT is linked onto the pendant alkynes of PBYP via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to yield the polymeric prodrug, abbreviated as (PBYP-g-ss-CPT)-b-PEEP. The resulting prodrug could self-assemble into uniform prodrug micelles in aqueous solution. Since the releasable disulfide carbonate between the CPT and the polyphosphoester would be disrupted under an intracellular reducing environment, the disassociation of prodrug micelles could result in a rapid release of the CPT parent drug. The chemical structures of the intermediate polymers and a polymeric prodrug have been fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The self-assembly behavior of the prodrug was investigated by the fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The DLS results indicated that these prodrug micelles were relatively stable in neutral pH media, but could be degraded under the reductive conditions. The in vitro drug release studies showed that the CPT release from prodrug micelles was proceeded in a glutathione (GSH)-dependent manner. A methyl thiazolyl tetrazolium (MTT) assay demonstrated that the prodrug micelles could efficiently inhibit the proliferation of HepG2 cells. In addition, the intracellular uptake of prodrug micelles could efficiently release CPT into HepG2 cells, which was observed using a live cell imaging system. All these results indicated that this GSH-responsive polymeric prodrug has high potential for reduction-triggered cancer chemotherapy.
Co-reporter:Kai Ren, Mingzu Zhang, Jinlin He, Yixian Wu, and Peihong Ni
ACS Applied Materials & Interfaces 2015 Volume 7(Issue 21) pp:11263
Publication Date(Web):May 8, 2015
DOI:10.1021/acsami.5b01410
To develop a novel biodegradable and quite adhesive coating material for fabricating a paclitaxel (PTX)-containing eluting stent, herein, we report two kinds of drug eluting stent (DES) materials. One of them is a prodrug, PTX end-capped poly(lactic acid)-b-polyisobutylene (PTX-PLA-b-PIB) diblock copolymer, which possesses favorable biodegradability and biocompatibility. The other is a mixture of PIB-b-PLA diblock copolymer and PTX. PIB-b-PLA was synthesized via the ring-opening polymerization (ROP) using hydroxyl-terminated polyisobutylene (PIB-OH) as the initiator, while the PTX-PLA-b-PIB prodrug was prepared through a combination of ROP and Cu(I)-catalyzed azide–alkyne cycloaddition “click” reaction. The chemical structures and compositions as well as the molecular weights and molecular weight distributions of these copolymers have been fully characterized by 1H nuclear magnetic resonance, Fourier transform infrared, and gel permeation chromatography measurements. The thermal degradation behavior and glass transition temperature (Tg) of the copolymers were studied by thermogravimetric analysis and differential scanning calorimetry, respectively. The solutions of PTX-PLA-b-PIB and the PIB-b-PLA/PTX mixture were separately coated onto the bare metal stents to form the PTX-containing DES. Subsequently, the surface structures and morphologies of the bare stent and DES were studied by atomic force microscopy and scanning electron microscopy, respectively. The in vitro release of PTX from these stents was conducted in a buffer medium (PBS 7.4) at 37 °C. The results showed that the coating formed by a blend of PTX-PLA-b-PIB, PIB-b-PLA, and PTX yielded a release that was better sustained than those of the individual PTX-PLA-b-PIB prodrug or PIB-b-PLA/PTX mixture. MTT assays demonstrated that the stent coated with PTX-PLA-b-PIB displayed a cytotoxicity lower than that of the PIB-b-PLA/PTX mixed layer, and the biocompatibility of coatings can be effectively improved by the prodrug.Keywords: biodegradability; drug delivery; drug eluting stent; paclitaxel; prodrug;
Co-reporter:Fei Li, Jinlin He, Mingzu Zhang and Peihong Ni
Polymer Chemistry 2015 vol. 6(Issue 28) pp:5009-5014
Publication Date(Web):03 Jun 2015
DOI:10.1039/C5PY00620A
An acid-labile and PEGylated polyphosphoester-doxorubicin prodrug (PBYP-g-PEG-g-DOX) was prepared via a combination of ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” chemistry. The resulting multifunctional prodrug was then used to interact with α-cyclodextrin (α-CD) to fabricate a novel supramolecular hydrogel based on inclusion complexation.
Co-reporter:Hairong Wang, Jinlin He, Dongling Cao, Mingzu Zhang, Fei Li, Kam Chiu Tam and Peihong Ni
Polymer Chemistry 2015 vol. 6(Issue 26) pp:4809-4818
Publication Date(Web):27 May 2015
DOI:10.1039/C5PY00569H
In this study, three PEGylated doxorubicin (DOX) prodrugs with acid-labile acetal and carbamate linkages have been prepared via the combination of Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkyne and azide (CuAAC) “click” reaction and ammonolysis reaction. The chemical structures of the prodrugs and the drug contents were characterized by 1H NMR, FT-IR and HPLC analyses. To avoid some side effects caused by the acidic degradation products from conventional hydrophobic polymers, DOX was directly linked to the PEG chain. These prodrugs could self-assemble into micelles in aqueous solution with DOX as the core and PEG chains as the corona. The dissociation of prodrug micelles was confirmed by monitoring the size change as a function of time through DLS analysis. Compared with free DOX, the pH-triggered DOX release of prodrugs exhibited a well-controlled and faster release behavior at pH 5.0 than at pH 7.4. In vitro cytotoxicity tests against HeLa cells by MTT assay demonstrated that these prodrugs displayed the desirable antitumor activity. The intracellular drug release was observed by a live cell imaging system at different DOX dosages. This work provides a strategy for the preparation of a new type of pH-cleavable and water-soluble antitumor prodrug for cancer chemotherapy.
Co-reporter:Hairong Wang, Jinlin He, Mingzu Zhang, Kam Chiu Tam and Peihong Ni
Polymer Chemistry 2015 vol. 6(Issue 23) pp:4206-4209
Publication Date(Web):17 Apr 2015
DOI:10.1039/C5PY00466G
Poly(ethyl ethylene phosphate) (PEEP) modified cellulose nanocrystals (CNCs) (CNC-g-PEEP) were synthesized through a “grafting onto” process, in which a combination of ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “click” chemistry was utilized. The resulting suspension of negatively-charged CNC-g-PEEP nanocrystals could be used to encapsulate doxorubicin (DOX) by electrostatic interactions and release the drug in the tumor cell environment.
Co-reporter:Jian Hu, Jinlin He, Dongling Cao, Mingzu Zhang and Peihong Ni
Polymer Chemistry 2015 vol. 6(Issue 17) pp:3205-3216
Publication Date(Web):03 Mar 2015
DOI:10.1039/C5PY00023H
To prevent the disassembly of drug-loaded micelles under the high dilution conditions of the bloodstream, one of the efficient methods is to achieve the cross-linkage inside the micellar core. In this study, we have developed a kind of novel folate-conjugated core cross-linked polyphosphoester micelle with acid-cleavable acetal groups (ACCL-FA). These polyphosphoester-based cross-linked micelles possessed a much smaller size and enhanced stability compared to the uncross-linked (UCL) counterpart, and also showed good biodegradability and low cytotoxicity. The in vitro release studies revealed that the doxorubicin (DOX)-loaded ACCL micelles showed excellent stability with minimal drug release under neutral conditions, and displayed fast micellar dissociation and drug release in the presence of acid or phosphodiesterase I (PDE I). Moreover, with the comparison of the in vitro antitumor activity for free DOX, the DOX-loaded ACCL micelles, the DOX-loaded ACCL-FA micelles and the DOX-loaded folate-conjugated acid-insensitive cross-linked (CCL-FA) micelles, it could be found that the DOX-loaded ACCL-FA micelles exhibited higher inhibition of the proliferation of KB cells. In addition, these FA-decorated ACCL micelles showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated core cross-linked biodegradable micelles are highly promising for targeted cancer chemotherapy.
Co-reporter:Jian Hu, Jinlin He, Mingzu Zhang and Peihong Ni
Polymer Chemistry 2015 vol. 6(Issue 9) pp:1553-1566
Publication Date(Web):02 Dec 2014
DOI:10.1039/C4PY01391C
A series of well-defined three-armed star-block copolymers containing poly(ethylene glycol) monomethyl ether (mPEG) and poly(ε-caprolactone) (PCL) blocks linked with acid-cleavable acetal groups, designated as (mPEG-acetal-PCL-acetal-)3 or (mPEG-a-PCL-a-)3, have been prepared via a “coupling-onto” method based on ring-opening polymerization (ROP) and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) “Click” chemistry. The chemical compositions and structures, as well as the molecular weights and molecular weight distributions (PDIs) of these copolymers have been fully characterized by 1H NMR, FT-IR, and GPC measurements. Differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) analyses demonstrated that the thermal behaviors of the star-block copolymers strongly depended on the relative lengths of PEG and PCL blocks in the arms. The self-assembly behaviors of these amphiphilic star-block copolymers were investigated by a fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The results showed that they could self-assemble into spherical micelles at low concentrations and mainly formed short rod-like micelles at high concentrations. Moreover, the acid-cleavable properties of these star-block copolymers were systematically studied by 1H NMR, GPC, and DLS measurements, and the results indicated that they were relatively stable in neutral pH media, but could be degraded under acidic conditions. The in vitro DOX release studies showed that DOX was released from drug-loaded micelles in a pH-sensitive manner. MTT assays demonstrated that these star-block copolymers possess low cytotoxicity against L929 cells and HeLa cells, and the DOX-loaded micelles exhibit a higher inhibition of the proliferation of HeLa cells in comparison with free DOX. Moreover, the results from the live cell imaging system and flow cytometry analysis revealed that these polymeric micelles could efficiently deliver and release DOX into the nuclei of HeLa cells. These pH-triggered shell-sheddable micelles are highly promising for the efficient intracellular delivery of hydrophobic anti-cancer drugs.
Co-reporter:Fei Li, Jinlin He, Mingzu Zhang, Kam Chiu Tam and Peihong Ni
RSC Advances 2015 vol. 5(Issue 67) pp:54658-54666
Publication Date(Web):10 Jun 2015
DOI:10.1039/C5RA06156C
Supramolecular hydrogels, which are held together by noncovalent bonds and show responses to external stimuli, are of great interest in therapeutic delivery and tissue engineering as the injectable depot systems. To obtain a supramolecular hydrogel with multifunctions, such as low cytotoxicity, injectability and stimuli-triggered drug release, we herein report on the synthesis and characterization of a supramolecular hydrogel, which was formed by host–guest interaction between α-cyclodextrin (α-CD) and a PEGylated doxorubicin prodrug linked with an acid-cleavable hydrazone group (mPEG-Hyd-DOX). The polymeric prodrug displayed lower cytotoxicity than the free DOX. The host–guest interaction was demonstrated by X-ray diffraction (XRD) analysis. The structures and morphologies of the supramolecular hydrogels were systematically investigated by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). The sol–gel transition process was monitored by dynamic and steady rheological analysis. The hydrogels could be degraded in the acidic environment of tumor cells and achieved the controlled delivery of DOX. The results of the pH-responsive property, in vitro cytotoxicity and drug release revealed that the supramolecular hydrogels can be used as a potential injectable matrix for the encapsulation and controlled release of anticancer drugs. This study provides an alternative for the construction of dual- or multi-drug delivery systems.
Co-reporter:Ying Hao, Jinlin He, Sen Li, Jian Liu, Mingzu Zhang and Peihong Ni
Journal of Materials Chemistry A 2014 vol. 2(Issue 27) pp:4237-4249
Publication Date(Web):15 Apr 2014
DOI:10.1039/C4TB00334A
An emerging strategy for synergistic gene and drug therapy is establishing a new paradigm for the synthesis of diversified and functional block copolymers with applications ranging from gene and drug delivery to fluorescence detection. In this paper, we report on a novel amphiphilic block copolymer containing a fluorescent coumarin derivative (CE), an acid-cleavable (acetal group, -a-) linkage between hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) and poly[poly(ethylene glycol)methyl ether methacrylate] (PPEGMA) blocks, abbreviated as CE-PCL-a-(PDMAEMA-co-PPEGMA), which was synthesized by a combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP) and CuAAC “click” reaction. The chemical composition and structures of these copolymers were fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The micelles self-assembled from these block copolymers could simultaneously encapsulate anti-cancer drug doxorubicin (DOX) and DNA to form a micelleplex with the hydrophilic brush-type PPEGMA on the surface, and the loaded cargoes could be released after the acetal linkage was cleaved under intracellular acidic conditions. Subsequently, the formed micelles as the drug and gene co-delivery vectors were investigated by employing gel retardation assay, zeta potential, dynamic light scattering (DLS), and transmission electron microscopy (TEM). A fluorescence spectrometer was further used to evaluate the fluorescence of polymers. Finally, in vitro drug release, cytotoxicity and transfection were also studied. All these results indicated that this acid-cleavable and fluorescent block copolymer would hold significant potential as a combined drug and DNA carrier.
Co-reporter:Yang Zhang, Jinlin He, Dongling Cao, Mingzu Zhang and Peihong Ni
Polymer Chemistry 2014 vol. 5(Issue 17) pp:5124-5138
Publication Date(Web):16 May 2014
DOI:10.1039/C4PY00538D
Novel galactosamine (Gal)-modified polymeric micelles which were responsive to both reduction (via the disulfide group, -ss-) and pH (acetal group, -a-) were constructed from poly(ethylethylene phosphate)-a-poly(ε-caprolactone)-ss-poly[2-(dimethylamino)ethyl methacrylate] (Gal-PEEP-a-PCL-ss-PDMAEMA) terpolymers in order to develop a multifunctional bioreducible system for the targeted co-delivery of anticancer drugs and DNA. These multifunctional terpolymers were synthesized via a combination of ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction. The chemical structures, chemical compositions, the molecular weights and molecular weight distributions of these terpolymers have been fully characterized, and their self-assembly behavior was studied in detail. The interaction between the terpolymers and DNA was studied by an agarose gel retardation assay. The physical properties of the resulting polyplexes were further determined by zeta potential, dynamic light scattering (DLS) and TEM analyses. The micelles containing the acetal and disulfide groups could be dissociated in an intracellular environment. The reduction- and pH-triggered release of doxorubicin (DOX) from DOX-loaded micelles showed that the release of DOX was accelerated at pH 5.0 and pH 7.4 with 10 mM cytoplasmic glutathione (GSH), and that the release rate was further enhanced at pH 5.0 with 10 mM GSH. A methyl thiazolyl tetrazolium (MTT) assay indicated that the blank micelles displayed relatively low cytotoxicity towards HeLa and HepG2 cells. Although the DOX-loaded micelles could efficiently prohibit the growth of both cell types, they exhibited much higher cytotoxicity towards HepG2 cells than HeLa cells. In addition, the intracellular uptake and transfection of Gal-PEEP-a-PCL-ss-PDMAEMA/DNA/DOX polyplexes into HepG2 cells was more efficient than that into HeLa cells, as revealed by a live cell imaging system, owing to specific ligand–receptor interactions between Gal and asialoglycoprotein receptors overexpressed on the surface of HepG2 cells. These results provide a facile strategy for the preparation of multifunctional biodegradable polymeric micelles that may act as a promising platform for the targeted intracellular co-delivery of hydrophobic drugs and nucleic acids.
Co-reporter:Yunfeng Tao, Jinlin He, Mingzu Zhang, Ying Hao, Jian Liu and Peihong Ni
Polymer Chemistry 2014 vol. 5(Issue 10) pp:3443-3452
Publication Date(Web):04 Feb 2014
DOI:10.1039/C4PY00024B
A novel galactosamine (Gal)-mediated drug delivery carrier, Gal-conjugated biodegradable poly(ε-caprolactone-co-phosphoester) random copolymer [poly(CL-co-OPEA-Gal)], was developed for enhanced hepatoma-targeting delivery of anti-cancer drug doxorubicin (DOX). The functionalized copolymers were synthesized via a combination of ring-opening polymerization (ROP), photoinduced thiol–ene reaction and amidation reaction. The chemical composition and structures, as well as the molecular weights and molecular weight distributions of these copolymers, were characterized by 1H NMR, 31P NMR and GPC analyses. Morphological study indicated that all the poly(CL-co-OPEA-Gal) nanoparticles (Gal-NPs), DOX-loaded nanoparticles (DOX/Gal-NPs), pristine polymeric nanoparticles without Gal modification (NPs) and DOX-loaded nanoparticles without Gal modification (DOX/NPs) displayed a spherical shape with averaged diameters below 200 nm. The in vitro drug release behavior of DOX/Gal-NPs was featured with a pH-dependent manner due to the degradable components of the random copolymer sensitive to the environmental stimuli. Cellular uptake studies demonstrated that DOX/Gal-NPs can be internalized into HepG2 cells more efficiently compared with HeLa cells owing to specific ligand–receptor interactions between Gal and asialoglycoprotein receptors (ASGPRs) on the surface of HepG2 cells. In vitro cytotoxicity tested by the MTT assay indicated that these random copolymers showed favorable biocompatibility. DOX/Gal-NPs exhibited a higher antitumor efficacy than DOX/NPs against HepG2 cells. These results show that these biodegradable Gal-decorated poly(CL-co-OPEA-Gal) nanoparticles are highly promising for targeted delivery of water-insoluble anti-cancer drugs for hepatocellular carcinoma.
Co-reporter:Jiao Bian;Ying Hao;Jinlin He;Wenling Zhang;Mingzu Zhang
Journal of Polymer Science Part A: Polymer Chemistry 2014 Volume 52( Issue 21) pp:3005-3016
Publication Date(Web):
DOI:10.1002/pola.27361
ABSTRACT
This study is aimed to develop a well-defined ABC triblock terpolymer, poly(ethylethylene phosphate)-block-poly(ε-caprolactone)-block-poly[2-(dimethylamino)ethyl methacrylate] (PEEP-b-PCL-b-PDMAEMA), for co-encapsulating anticancer drug doxorubicin (DOX) and DNA to form polyplexes. The terpolymer is first synthesized via a combination of ring-opening polymerization and atom-transfer radical polymerization techniques, and characterized by 1H NMR and gel permeation chromatography. Subsequently, the self-assembly behavior of the terpolymer and the micelles loaded with DOX or DNA are investigated by dynamic light scattering, ζ potential, transmission electron microscopy, and gel retardation assay, respectively. In vitro release study reveals that much more DOX is released at pH 5.0 than that at pH 7.4 in the same period. The simultaneous delivery of DOX and green fluorescent protein (GFP)-labeled DNA is studied by a fluorescence microscope and the results demonstrate that both drug and GFP–DNA can be efficiently delivered into HeLa cells. This system presents a practical and promising carrier for the co-delivery of drugs and genes. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 3005–3016
Co-reporter:Hairong Wang, Jinlin He, Mingzu Zhang, Yunfeng Tao, Fei Li, Kam Chiu Tam and Peihong Ni
Journal of Materials Chemistry A 2013 vol. 1(Issue 48) pp:6596-6607
Publication Date(Web):15 Oct 2013
DOI:10.1039/C3TB21170C
A series of acid-cleavable ABA-type triblock copolymers, namely poly(ε-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(ε-caprolactone) (PCL-a-PEG-a-PCL), were synthesized via a combination of ring-opening polymerization (ROP) of ε-caprolactone initiated by propargyl alcohol and subsequent “CuAAC” click reaction with azide terminated acetal-containing poly(ethylene glycol). The chemical composition and structures of the copolymers were characterized by 1H NMR and FT-IR spectroscopy, while their molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The critical aggregation concentration (CAC), size parameters and morphologies of micelles self-assembled from PCL-a-PEG-a-PCL were determined by fluorescence probing, dynamic light scattering (DLS), and transmission electron microscopy (TEM), respectively. Since the acetal groups are unstable in weak acidic media, it is anticipated that this class of triblock copolymer micelles can be dissociated in an intracellular environment. This was confirmed by monitoring the size change of micelles with the increase of degradation time under acidic conditions, as well as the molecular weights of degradation products. The pH-triggered release of doxorubicin (DOX) from PCL-a-PEG-a-PCL micelles was studied and compared with a pH-insensitive PCL-b-PEG-b-PCL system without acetal groups, demonstrating that the cleavage of acetal linkages was responsible for the pH-responsive drug release profiles. In vitro cytotoxicity tests against HeLa and L929 cells by MTT assays indicated that the self-assembled micelles displayed very low cytotoxicity. In addition, the intracellular drug release against HeLa cells was further investigated by a live cell imaging system using free DOX as a control. This work provides a facile strategy for the preparation of a new type of biodegradable amphiphilic copolymer as a highly promising intracellular delivery system for hydrophobic drugs.
Co-reporter:Guoyi Zhang, Mingzu Zhang, Jinlin He and Peihong Ni
Polymer Chemistry 2013 vol. 4(Issue 16) pp:4515-4525
Publication Date(Web):31 May 2013
DOI:10.1039/C3PY00419H
We report here a strategy that allows the preparation of a novel water-soluble polymeric prodrug, paclitaxel–poly(ethyl ethylene phosphate) conjugated with folic acid molecules (abbreviated as PTX–PEEP–FA). PTX was directly used as an initiator for the ring-opening polymerization (ROP) of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) under the catalysis of Sn(Oct)2 to fabricate an amphiphilic PTX–PEEP, followed by covalently conjugating a FA moiety via esterification to obtain the biodegradable and targeted polymeric prodrug PTX–PEEP–FA. The chemical structure of the prodrug was characterized by 1H NMR and MALDI-TOF mass spectroscopy. TEM and DLS measurements showed that these prodrugs could self-assemble in aqueous solution to form micelles with PTX as the core and PEEP–FA as the corona, and the average particle size was less than 130 nm. The hydrophobic PTX core could be further used to load more water-insoluble anti-cancer drugs, such as PTX or doxorubicin (DOX), while the hydrophilic PEEP–FA chain endowed micelles with good stability during systemic circulation and significantly improved controlled-release properties compared to free PTX or DOX. Live cell imaging system was utilized to monitor the cellular uptake process of DOX-loaded PTX–PEEP–FA micelles for HeLa and KB cells, respectively. The results revealed that these drug-loaded micelles with FA on their surface could remarkably improve cell endocytosis. In vitro biological evaluations confirmed that PTX–PEEP–FA, simultaneously acted as both a prodrug and drug delivery carrier, could achieve the aims of increased drug loading efficiency, reduced cytotoxicity, and enhanced targeting efficacy.
Co-reporter:Ying Hao;Jinlin He;Mingzu Zhang;Yunfeng Tao;Jian Liu
Journal of Polymer Science Part A: Polymer Chemistry 2013 Volume 51( Issue 10) pp:2150-2160
Publication Date(Web):
DOI:10.1002/pola.26617
Abstract
A novel kind of pH-sensitive brush copolymer [poly(2-hydroxyethyl methacrylate)-graft-poly(ethylethylene phosphate)]-block-poly[2-(dimethylamino)ethyl methacrylate] [(PHEMA-g-PEEP)-b-PDMAEMA] with biodegradable polyphosphoester as the side chains, and its self-assembled aggregates were developed for nonviral gene delivery. The brush copolymers were synthesized via a combination of single-electron transfer living radical polymerization and ring-opening polymerization. The chemical structures of these brush copolymers were characterized by FTIR, 1H NMR, and 31P NMR measurements. The critical aggregation concentration values of (PHEMA-g-PEEP)-b-PDMAEMA in pH 7.4 buffer solution were determined by the fluorescence probe technique. The interaction of (PHEMA-g-PEEP)-b-PDMAEMA and DNA was studied by agarose gel retardation assay, and the formed complexes were further investigated by means of zeta potential, dynamic light scattering, and transmission electron microscopy measurements. In addition, the in vitro cytotoxicity and transfection tests indicated that these brush copolymers showed low toxicity and favorable transfection efficiency to HeLa cells. All these results demonstrated that these biocompatible brush copolymers may be a promising candidate as nonviral polymeric gene vector. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013
Co-reporter:Huai-chao Wang;Ming-zu Zhang;Pei-hong Ni 倪沛红
Chinese Journal of Polymer Science 2013 Volume 31( Issue 2) pp:218-231
Publication Date(Web):2013 February
DOI:10.1007/s10118-013-1208-9
Two pH-responsive amphiphilic diblock copolymers, namely polyisobutylene-block-poly[2-(N,N-dimethylamino) ethyl methacrylate] (PIB-b-PDMAEMA) and polyisobutylene-block-poly(metharylic acid) (PIB-b-PMAA), were synthesized via oxyanion-initiated polymerization, and their multiple self-assembly behaviors have been studied. An exo-olefin-terminated highly reactive polyisobutylene (HRPIB) was first changed to hydroxyl-terminated PIB (PIB-OH) via hydroboration-oxidation of C=C double bond in the chain end, and then reacted with KH to yield a potassium alcoholate of PIB (PIB-O−K+). PIB-O−K+ was immediately used as a macroinitiator to polymerize DMAEMA monomer, resulting in a cationic diblock copolymer PIB-b-PDMAEMA. With the similar synthesis procedure, the anionic diblock copolymer PIB-b-PMAA could be prepared via a combination of oxyanion-initiated polymerization of tert-butyl methacrylate (tBMA) and subsequent hydrolysis of tert-butyl ester groups in PtBMA block. The functional PIB and block copolymers have been fully characterized by 1H-NMR, FT-IR spectroscopy, and gel permeation chromatography (GPC). These samples allowed us to systematically investigate the effects of block composition on the pH responsivity and various self-assembled morphologies of the copolymers in THF/water mixed solvent. Transmission electron microscopy (TEM) images revealed that these diblock copolymers containing small amount of original PIB without exo-olefin-terminated group are able to self-assemble into micelles, vesicles with different particle sizes and cylindrical aggregates, depending on various factors including block copolymer composition, solvent polarity and pH value.
Co-reporter:Jiao Bian, Mingzu Zhang, Jinlin He, Peihong Ni
Reactive and Functional Polymers 2013 73(3) pp: 579-587
Publication Date(Web):1 March 2013
DOI:10.1016/j.reactfunctpolym.2012.12.010
This work focuses on the synthesis and self-assembly of biodegradable and anionic double hydrophilic diblock copolymers (DHBCs) poly(ethylethylene phosphate)-block-poly[2-(succinyloxy)ethyl methacrylate] (PEEP-b-PSEMA) with different molecular weights and compositions, which were prepared via a combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and polymer reaction. The chemical structures of these well-defined diblock copolymers were confirmed by 1H NMR and FT-IR analyses. GPC results indicated that the copolymers showed symmetric peak and relatively narrow polydispersities. Subsequently, pH-responsive micellization behaviors of PEEP-b-PSEMA diblock copolymers were investigated by fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) measurements. The results demonstrated that these diblock copolymers were able to self-assemble into micelles with various sizes depending on the variation of pH values. Naproxen (NAP), a poorly water-soluble drug, was selected as the model drug and encapsulated into the core of micelles via dialysis method. The in vitro release behavior of NAP from these micelles was pH-dependent and could be accelerated in the presence of phosphodiesterase I which could promote the degradation of polyphosphoesters. Cytotoxicity tests by MTT assay showed that these block copolymers possessed favorable biocompatibility against HeLa cells, revealing that this kind of biodegradable, biocompatible and pH-responsive block copolymer would be served as a promising material for drug delivery.
Co-reporter:Jinlin He, Mingzu Zhang and Peihong Ni
Soft Matter 2012 vol. 8(Issue 22) pp:6033-6038
Publication Date(Web):27 Apr 2012
DOI:10.1039/C2SM25274K
In situ forming hydrogels allow the modulation of physicochemical properties and are providing new opportunities for biomedical applications. Here, the preparation and characterization of a series of rapidly in situ forming and pH-responsive hydrogels with different crosslinking degrees are reported, which were achieved by accelerated free radical copolymerization of polyphosphoester-based macrocrosslinker and 2-(dimethylamino)ethyl methacrylate (DMAEMA) monomer. The hydrogel formation can be completed very quickly under mild conditions, ranging from several to tens of minutes with varying concentrations of components. The polyphosphoester-based macrocrosslinker was synthesized via a combination of ring-opening polymerization and post-polymerization modification, and it was characterized by 1H NMR, 31P NMR, and GPC measurements. The sol–gel transition was monitored by dynamic time sweep rheological analysis. Moreover, the swelling kinetics, interior morphology, pH-responsive property, in vitro cytotoxicity and drug release of these hydrogels were characterized. The results indicate that these hydrogels show great potential as injectable drug delivery system.
Co-reporter:Haiyan Shao, Mingzu Zhang, Jinlin He, Peihong Ni
Polymer 2012 Volume 53(Issue 14) pp:2854-2863
Publication Date(Web):21 June 2012
DOI:10.1016/j.polymer.2012.05.013
A series of parent block copolyesters poly(ɛ-caprolactone)-block-poly[2-(2-oxo-1, 3, 2-dioxaphospholoyloxy)ethyl acrylate] (PCL-b-POPEA) with different block lengths have been synthesized by ring-opening polymerization (ROP) and four kinds of mercaptans were then used in the postpolymerization modification via Michael-type addition reaction, resulting in several block copolyesters with various functionalities (e.g., hydroxyl, carboxyl, amine, and amino acid) in their pendant groups. The chemical structures of these block copolymers were characterized by FT-IR, NMR spectroscopy and GPC analysis. The self-assembly behaviors of PCL-b-POPEA have been studied by fluorescence probe technique, transmission electron microscopy (TEM) and high-performance particle size (HPPS) instrument. In vitro cytotoxicity test indicated that the block copolymers possess good biocompatibility. Initial in vitro drug loading and release studies using Doxorubicin (DOX) as a model drug demonstrated a faster release in the presence of phosphodiesterase I as compared to the system without enzyme. Moreover, it was found that DOX-loaded nanoparticles displayed higher inhibition to KB cell proliferation in comparison with free DOX. Therefore, the combination of ROP and Michael-type addition reaction provides a general access to various types of multifunctional and biodegradable materials.
Co-reporter:Ying Hao, Mingzu Zhang, Jinlin He, and Peihong Ni
Langmuir 2012 Volume 28(Issue 15) pp:6448-6460
Publication Date(Web):March 26, 2012
DOI:10.1021/la300208n
A novel magnetic-responsive complex composed of polycation, DNA, and polyanion has been constructed via electrostatic interaction. The magnetic nanoparticles (MNPs) were first coated with a polycation, poly[2-(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety (Chol-PDMAEMA30), and then binded with DNA through electrostatic interaction; the complexes were further interacted with the brush-type polyanion, namely poly[poly(ethylene glycol)methyl ether methacrylate]-block-poly[methacrylic acid carrying partial mercapto groups] (PPEGMA-b-PMAASH). The resulting magnetic particle/DNA/polyion complexes could be stabilized by oxidizing the mercapto groups to form cross-linking shell with bridging disulfide (S–S) between PPEGMA-b-PMAASH molecular chains. The interactions among DNA, Chol-PDMAEMA coated MNPs, and PPEGMA-b-PMAASH were studied by agarose gel retardation assay. The complexes were fully characterized by means of zeta potential, transmission electron microscopy (TEM), dynamic light scattering (DLS) measurements, cytotoxicity assay, antinonspecific protein adsorption, and in vitro transfection tests. All these results indicate that this kind of magnetic-responsive complex has potential applications for gene vector.
Co-reporter:Shihua Zhang;Zixu Gu;Ying Hao;Mingzu Zhang
Journal of Polymer Science Part A: Polymer Chemistry 2011 Volume 49( Issue 18) pp:4081-4091
Publication Date(Web):
DOI:10.1002/pola.24851
Abstract
In this work, we have synthesized a polycation and a polyanion via a combination of oxyanion-initiated polymerization and polymer reaction, and then developed a novel approach to prepare a controlled magnetic target gene carrier with magnetic Fe3O4 nanoparticles as core and poly(ethylene glycol) (PEG) segment as corona via layer-by-layer (LbL) assembly and shell-crosslinking. Magnetic nanoparticles (MNPs) were first modified by poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) via radical polymerization. The resulting MNPs were used to compact deoxyribonucleic acid (DNA) through LbL assembly, involving four steps: (1) the binding of DNA to the polycation PDMAEMA on the surface of MNPs; (2) the produced particles in Step 1 with negative charge interacting with additional polycation ethoxy group end-capped PDMAEMA (EtO-PDMAEMA) homopolymer, leading to a positive charge surface; (3) using carboxyl group (-COO-) of poly(methacrylic acid) (PMAA) in a diblock copolymer (MePEG2000-b-PMAASH) as polyanion, which has partial mercapto groups (-SH) in PMAA segment, to interact with the particles produced in Step 2; (4) the shell of the composite nanoparticle was crosslinked by oxidizing the -SH groups of the MePEG2000-b-PMAASH to form disulfide linkage (SS). All the processes of LbL assembly were investigated by agarose gel retardation assay and zeta potential measurements. The in vitro cytotoxicity analysis proves that polyions/DNA MNPs have excellent properties and potential applications as gene carriers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011
Co-reporter:Yaojuan Wu, Peihong Ni, Mingzu Zhang and Xiulin Zhu
Soft Matter 2010 vol. 6(Issue 16) pp:3751-3758
Publication Date(Web):16 Jun 2010
DOI:10.1039/C000979B
In this work, we report a novel microgel composed of star-like polycations and well-defined linear polyanions via ionic interaction. The polycations, the β-CD-g-PDMA star polymers, were prepared via an ATRP method using a derivative of β-cyclodextrin (β-CD) as a macroinitiator to graft 2-(N,N-dimethyamino)ethyl methacrylate (DMAEMA, or DMA for short) with different lengths. The polyanions, including di- and tri- block copolymers (MePEG-b-PMAA60 and PMAA30-b-PEG-b-PMAA30), were first prepared via oxyanion-initiated polymerization of tert-butyl methacrylate (tBMA) using the potassium alcoholate of MePEG or PEG as macroinitiators, and then obtained by carrying out hydrolysis of the PtBMA block to yield the PMAA block. The star polymers and the oppositely charged linear copolymers were characterized by 1H NMR, GPC and FT-IR. The results obtained from TEM and DLS show that the cationic and the anionic polyelectrolytes can self-assemble into micelles, respectively. The polyion complex microgels formed by ionic interaction between the polycation and the polyanions have been proved by SEM, TEM, DLS and rheology testing. Interestingly, the self-assembled morphologies of the polyion complex microgels were different when the chemical structures of the polyanions were a MePEG-b-PMAA60 diblock copolymer or a PMAA30-b-PEG-b-PMAA30 triblock copolymer. We have proposed a self-assembly mechanism to give an explanation for the formation of different complex microgels in the presence of different polyanions (i.e. di- or tri- block copolymer). As the hydrophobic cavity of β-cyclodextrin in the star polymer can interact with appropriately sized guest molecules to form host–guest inclusion complexes, the resultant microgels will have potential applications in drug delivery, especially for oil-soluble drugs.
Co-reporter:Xu Liu, Peihong Ni, Jinlin He and Mingzu Zhang
Macromolecules 2010 Volume 43(Issue 10) pp:4771-4781
Publication Date(Web):April 26, 2010
DOI:10.1021/ma902658n
Novel pH- and temperature-responsive double-hydrophilic diblock copolymers, poly(ethylethylene phosphate)-block-poly[2-(dimethylamino)ethyl methacrylate] (PEEP-b-PDMAEMA), have been synthesized via the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The PEEP block with a bromine-terminated end (PEEP-Br) was first prepared by ROP of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) using 2-hydroxyethyl 2-bromoisobutyrate as a bifunctional initiator and stannous octoate as a catalyst. ATRP was then used to polymerize DMAEMA monomer in a methanol/water mixture with PEEP-Br as a macroinitiator, resulting in diblock copolymers of PEEP-b-PDMAEMA. Their chemical structures were respectively characterized by 1H NMR, 13C NMR, 31P NMR, and FT-IR. Their molar mass distributions were determined by gel permeation chromatography (GPC). The critical aggregation concentration (cac) of PEEP-b-PDMAEMA in aqueous solution, which was measured by the fluorescence probe technique, depends on the block composition. The results measured by static laser light scattering (LLS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) reveal that these diblock copolymers are able to self-assemble into aggregates with different particle sizes and morphologies in aqueous solutions, depending on various pH media. On the other hand, the UV−vis measurement shows that these diblock copolymers exhibit a reproducible temperature-responsive behavior with a lower critical solution temperature (LCST) that is tunable by the block composition and pH. In addition, agarose gel retardation assays, TEM, and zeta potential measurements demonstrate that such double-hydrophilic diblock copolymers can effectively condense DNA, potentially useful for the gene delivery.
Co-reporter:Wenling Zhang;Jinlin He;Zhuang Liu;Xiulin Zhu
Journal of Polymer Science Part A: Polymer Chemistry 2010 Volume 48( Issue 5) pp:1079-1091
Publication Date(Web):
DOI:10.1002/pola.23863
Abstract
A series of well-defined amphiphilic triblock copolymers [polyethylene glycol monomethyl ether]-block-poly(ε-caprolactone)-block-poly[2-(dimethylamino)ethyl methacrylate] (mPEG-b-PCL-b-PDMAEMA or abbreviated as mPEG-b-PCL-b-PDMA) were prepared by a combination of ring-opening polymerization and atom transfer radical polymerization. The chemical structures and compositions of these copolymers have been characterized by Fourier transform infrared spectroscopy, 1H NMR, and thermogravimetric analysis. The molecular weights of the triblock copolymers were obtained by calculating from 1H NMR spectra and gel permeation chromatography measurements. Subsequently, the self-assembly behavior of these copolymers was investigated by fluorescence probe method and transmission electron microscopy, which indicated that these amphiphilic triblock copolymers possess distinct pH-dependent critical aggregation concentrations and can self-assemble into micelles or vesicles in PBS buffer solution, depending on the length of PDMA in the copolymer. Agarose gel retardation assays demonstrated that these cationic nanoparticles can effectively condense plasmid DNA. Cell toxicity tests indicated that these triblock copolymers displayed lower cytotoxicity than that of branched polyethylenimine with molecular weight of 25 kDa. In addition, in vitro release of Naproxen from these nanoparticles in pH buffer solutions was conducted, demonstrating that higher PCL content would result in the higher drug loading content and lower release rate. These biodegradable and biocompatible cationic copolymers have potential applications in drug and gene delivery. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1079–1091, 2010
Co-reporter:Jinlin He;Sai Wang;Haiyan Shao;Mingzu Zhang ;Xiulin Zhu
Journal of Polymer Science Part A: Polymer Chemistry 2010 Volume 48( Issue 9) pp:1919-1930
Publication Date(Web):
DOI:10.1002/pola.23959
Abstract
In this work, a series of biodegradable and pH-responsive hydrogels based on polyphosphoester and poly(acrylic acid) are presented. A novel biodegradable macrocrosslinker α-methacryloyloxyethyl ω-acryloyl poly(ethyl ethylene phosphate) (HEMA-PEOP-Ac) was synthesized by first ring-opening polymerization of the cyclic monomer 2-ethoxy-2-oxo-1,3,2-dioxaphospholane using HEMA as the initiator and Sn(Oct)2 as catalyst, and subsequent conversion of hydroxyl into vinyl group. The hydrogels were then fabricated by the copolymerization of the macromonomer with acrylic acid, and their swelling/deswelling and degradation behaviors were investigated. The results demonstrated that the crosslinking density and pH values of media strongly influenced both the swelling ratio and the degradation rate of the hydrogels. The rheological properties of these hydrogels were also studied from which the storage modulus (G′) showed clear dependence on the crosslinking density. MTT and “live/dead” assay showed that these hydrogels were compatible to fibroblast cells, not exhibiting apparent cytotoxicity even at high concentrations. Moreover, in vitro bovine serum albumin release from these hydrogels was also investigated, and it could be found that the release profiles showed a burst effect followed by a continuous release phase, and the release rate was inversely proportional to the crosslinking density of hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1919–1930, 2010
Co-reporter:Mingzu Zhang, Jinlin He, Jiang Mao, Cuicui Liu, Hairong Wang, Yinfeng Huang, Peihong Ni
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2010 360(1–3) pp: 190-197
Publication Date(Web):
DOI:10.1016/j.colsurfa.2010.02.029
Co-reporter:Cuicui Liu;Jinlin He;Qun Zhao;Mingzu Zhang
Journal of Polymer Science Part A: Polymer Chemistry 2009 Volume 47( Issue 10) pp:2702-2712
Publication Date(Web):
DOI:10.1002/pola.23355
Abstract
A series of well-defined, fluorinated diblock copolymers, poly[2-(dimethylamino)ethyl methacrylate]-b-poly(2,2,2-trifluoroethyl methacrylate) (PDMA-b-PTFMA), poly[2-(dimethylamino)ethyl methacrylate]-b-poly(2,2,3,4,4,4-hexafluorobutyl methacrylate) (PDMA-b-PHFMA), and poly[2-(dimethylamino)ethyl methacrylate]-b-poly(2,2,3,3,4,4,5,5-octafluoropentyl methacrylate) (PDMA-b-POFMA), have been synthesized successfully via oxyanion-initiated polymerization. Potassium benzyl alcoholate (BzO−K+) was used to initiate DMA monomer to yield the first block PDMA. If not quenched, the first living chain could be subsequently used to initiate a feed F-monomer (such as TFMA, HFMA, or OFMA) to produce diblock copolymers containing different poly(fluoroalkyl methacrylate) moieties. The composition and chemical structure of these fluorinated copolymers were confirmed by 1H NMR, 19F NMR spectroscopy, and gel permeation chromatography (GPC) techniques. The solution behaviors of these copolymers containing (tri-, hexa-, or octa- F-atom)FMA were investigated by the measurements of surface tension, dynamic light scattering (DLS), and UV spectrophotometer. The results indicate that these fluorinated copolymers possess relatively high surface activity, especially at neutral media. Moreover, the DLS and UV measurements showed that these fluorinated diblock copolymers possess distinct pH/temperature-responsive properties, depending not only on the PDMA segment but also on the fluoroalkyl structure of the FMA units. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2702–2712, 2009
Co-reporter:Guixiang Sun;Mingzu Zhang;Jinlin He
Journal of Polymer Science Part A: Polymer Chemistry 2009 Volume 47( Issue 18) pp:4670-4684
Publication Date(Web):
DOI:10.1002/pola.23517
Abstract
A series of amphiphilic cationic random copolymers, namely poly[2-(methacryloyloxy)ethyl trimethylammonium chloride-co-stearyl methacrylate] or poly(MADQUAT-co-SMA), have been synthesized via conventional free-radical copolymerization using 2,2′-azobisisobutyronitrile (AIBN) as initiator and n-dodecanethiol as chain transfer agent. The resultant products were then characterized by FT-IR, 1H NMR, MALDI-TOF MS measurements. From the number-average molecular weights of the copolymers, we can conclude that these copolymers have oligomeric structure with a limited number of hydrophilic and hydrophobic moieties in a short polymer chain. The reactivity ratios (rMADQUAT = 0.83, rSMA = 0.25) between the hydrophilic MADQUAT monomer and the hydrophobic SMA monomer were calculated by the Finemann and Ross method, which was based on the results of 1H NMR analysis. The surface activity of the random copolymers was studied by the combination of surface tension and contact angle measurement, and the results indicated that these copolymers possess relatively high surface activity. The critical aggregation concentrations (cac) of the copolymers in aqueous solution were determined by fluorescence probe method as well as surface tension measurement. The different nanoparticles of poly(MADQUAT-co-SMA) copolymers formed in pure water or ethanol-water mixture were proved by the particle size and size distribution in the measurement of dynamic light scattering (DLS). Furthermore, using transmission electron microscopy (TEM), we could observe various self-assembly morphologies of these random copolymer. All these results show that the amphiphilic cationic random copolymers have a good self-assembly behavior, even if they are ill-defined copolymers. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4670–4684, 2009
Co-reporter:Cuicui Liu;Xiao Fang;Xiaodong Zhou
Colloid and Polymer Science 2009 Volume 287( Issue 1) pp:45-55
Publication Date(Web):2009 January
DOI:10.1007/s00396-008-1951-6
Amphiphilic diblock copolymers consisting of 2-(N, N-dimethylamino)ethyl methacrylate (DMAEMA, abbreviated as DMA) and stearyl methacrylate (SMA) with different degrees of polymerization and compositions were prepared by reversible addition–fragmentation chain transfer (RAFT) copolymerization. The composition and chemical structures of (co)polymers were confirmed by the measurements of 1H NMR spectroscopy and gel permeation chromatography (GPC). The self-aggregating structures of amphiphilic diblock copolymers with the concentration of 0.1~0.3 wt.% in THF/water mixed solvent was investigated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). It was found that both the morphologies and aggregating particle size resulted from the amphiphilic diblock copolymers depended on the variation of pH values, the lengths of the hydrophobic PSMA chains, and the weight ratio of THF/water mixed solvent.
Co-reporter:Zixu Gu, Yuan Yuan, Jinlin He, Mingzu Zhang and Peihong Ni
Langmuir 2009 Volume 25(Issue 9) pp:5199-5208
Publication Date(Web):March 24, 2009
DOI:10.1021/la804037v
A facile route for DNA encapsulation in triggered intracellular degradable polymer microcapsules has been achieved via electrostatic interaction, using a polycation, that is, poly[(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety (Chol-PDMAEMA30), along with a polyanion named MePEG2000-block-poly(methacrylic acid) carring partial thiol groups (MePEG2000-b-PMAASH). The encapsulation procedure involves three steps: (i) DNA was first complexed with the polycation (Chol-PDMAEMA30); (ii) the complex was then further set into interaction with the anion-containing MePEG2000-b-PMAASH; and (iii) the compound carrier was subsequently obtained by cross-linking the thiol groups of the MePEG2000-b-PMAASH to form disulfide linkages. The interactions between every pair among calf thymus DNA, Chol-PDMAEMA30, and MePEG2000-b-PMAASH were studied by agarose gel retardation assay and ethidium bromide displacement assay. The results indicate that the prepared microcapsules may remain stable during systemic circulation, but degrade and release the carried DNA in a cellular reducing environment. Furthermore, the biophysical properties of the microcapsule have been investigated by ζ-potential, laser light scattering, and transmission electron microscopy (TEM) measurements.
Co-reporter:Jinlin He;Cuicui Liu
Journal of Polymer Science Part A: Polymer Chemistry 2008 Volume 46( Issue 9) pp:3029-3041
Publication Date(Web):
DOI:10.1002/pola.22641
Abstract
The synthesis and self-assembly behavior of pentablock copolymers consisting of Pluronic F127 (PEO100-PPO65-PEO100) and poly(2, 2, 3, 3, 4, 4, 5, 5-octafluoropentyl methacrylate) (POFPMA) is herein described. Using the difunctional potassium alcoholate of F127, K+O–-(PEO100-PPO65-PEO100)-O–K+, as the macroinitiator, the POFPMA-F127-POFPMA pentablock copolymers were synthesized via oxyanion-initiated polymerization. The chain length of POFPMA can be controlled by the original molar ratio of macroinitiator to OFPMA monomer, that is, F-monomer. The composition and chemical structure of POFPMA-F127-POFPMA pentablock copolymers have been characterized by FTIR, 1HNMR, and 19F NMR spectroscopy, and gel permeation chromatography techniques. The solution behavior of POFPMA-F127-POFPMA copolymers was investigated by the methods of surface tension, cloud point, transmission electron microscopy, and high performance particle sizer (HPPS). The results indicate that these Pluronic F127-based block copolymers modified with fluorinated segments possess relatively high surface activity and low cloud points, depending on various factors, such as the length of fluorinated block, the concentration of the copolymers in aqueous solution, and the adscititious inorganic salt. TEM measurements showed that the pentablock copolymers can self-assemble in aqueous solution to form various micellar morphologies. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3029–3041, 2008
Co-reporter:Xiaodong Zhou;Zhangqing Yu;Feng Zhang
Journal of Polymer Science Part A: Polymer Chemistry 2007 Volume 45(Issue 3) pp:471-484
Publication Date(Web):14 DEC 2006
DOI:10.1002/pola.21861
Poly(fluoroalkyl mathacrylate)-block-poly(butyl methacrylate) diblock copolymer latices were synthesized by a two-step process. In the first step, a homopolymer end-capped with a dithiobenzoyl group [poly(fluoroalkyl mathacrylate) (PFAMA) or poly(butyl methacrylate) (PBMA)] was prepared in bulk via reversible addition–fragmentation chain transfer (RAFT) polymerization with 2-cyanoprop-2-yl dithiobenzoate as a RAFT agent. In the second step, the homopolymer chain-transfer agent (macro-CTA) was dissolved in the second monomer, mixed with a water phase containing a surfactant, and then ultrasonicated to form a miniemulsion. Subsequently, the RAFT-mediated miniemulsion polymerization of the second monomer (butyl methacrylate or fluoroalkyl mathacrylate) was carried out in the presence of the first block macro-CTA. The influence of the polymerization sequence of the two kinds of monomers on the colloidal stability and molecular weight distribution was investigated. Gel permeation chromatography analyses and particle size results indicated that using the PFAMA macro-CTA as the first block was better than using the PBMA RAFT agent with respect to the colloidal stability and the narrow molecular weight distribution of the F-copolymer latices. The F-copolymers were characterized with 1H NMR, 19F NMR, and Fourier transform infrared spectroscopy. Comparing the contact angle of a water droplet on a thin film formed by the fluorinated copolymer with that of PBMA, we found that for the diblock copolymers containing a fluorinated block, the surface energy decreased greatly, and the hydrophobicity increased. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 471–484, 2007
Co-reporter:Feng Zhang;Qingfeng Xiong;Zhangqing Yu
Journal of Polymer Science Part A: Polymer Chemistry 2005 Volume 43(Issue 13) pp:2931-2940
Publication Date(Web):20 MAY 2005
DOI:10.1002/pola.20759
In the presence of β-cyclodextrin (β-CD), reversible addition–fragmentation chain transfer (RAFT) polymerization has been successfully applied to control the molecular weight and polydispersity [weight-average molecular weight/number-average molecular weight (Mw/Mn)] in the miniemulsion polymerization of butyl methacrylate, with 2-cyanoprop-2-yl dithiobenzoate as a chain-transfer agent (or RAFT agent) and 2,2′-azoisobutyronitrile (AIBN) as an initiator. β-CD acted as both a stabilizer and a solubilizer, assisting the transportation of the water-insoluble, low-molecular-weight RAFT agent into the polymerization loca (i.e., droplets or latex particles) and thereby ensuring that the RAFT agent was homogeneous in the polymerization loca. The polymers produced in the system of β-CD exhibited narrower polydispersity (1.2 < Mw/Mn < 1.3) than those without β-CD. Moreover, the number-average molecular weight in the former case could be controlled by a definite amount of the RAFT agent. Significantly, β-CD was proved to have a favorable effect on the stability of polymer latex, and no coagulum was observed. The effects of the concentrations of the RAFT agent and AIBN on the conversion, the molecular weight and its distribution, and the particle size of latices were investigated in detail. Furthermore, the influences of the variations of the surfactant (sodium dodecyl sulfate) and costabilizer (hexadecane) on the RAFT/miniemulsion polymerization were also studied. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2931–2940, 2005
Co-reporter:Zixu Gu, Jun Cheng, Mingzu Zhang, Jinlin He, Peihong Ni
Polymer (7 April 2017) Volume 114() pp:79-87
Publication Date(Web):7 April 2017
DOI:10.1016/j.polymer.2017.02.073
Co-reporter:Yue Sun, Xueqiong Du, Jinlin He, Jian Hu, Mingzu Zhang and Peihong Ni
Journal of Materials Chemistry A 2017 - vol. 5(Issue 20) pp:NaN3782-3782
Publication Date(Web):2017/04/12
DOI:10.1039/C7TB00440K
“Intelligent” crosslinked nanoparticles (NPs) provide great advantages in enhancing drug bioavailability and reducing side effects in anticancer therapeutics. In this study, a novel biodegradable polyphosphoester-based functional copolymer prodrug PTX-(PBYP-g-MPA)-b-PEEP was prepared to construct pH/redox dual-responsive core-crosslinked nanoparticles (DOX/CCL NPs), in which paclitaxel (PTX) was conjugated to the polyphosphoester to form an amphiphilic prodrug and doxorubicin (DOX) was encapsulated inside the prodrug NPs. At first, PTX was used as an initiator to polymerize 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP) and 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) by one-pot sequential ring-opening polymerization, yielding a biodegradable polymeric prodrug PTX-PBYP-b-PEEP. Subsequently, a radical-mediated thiol–yne “click” reaction was performed between the alkynyl groups on the PBYP segment and the thiol group of 3-mercaptopropionic acid (MPA) to form a functional carboxyl group at the side chain. The potential positively charged DOX·HCl can be physically encapsulated via electrostatic interaction with the carboxyl group and hydrophobic interaction. Afterwards, the DOX/CCL NPs with cleavable disulfide (S–S) linkages can be formed by partial crosslinking through amidation between the pendant carboxyl groups and cystamine. These NPs possess multifunctional characteristics used for in vitro drug release. Notably, a redox-responsive crosslinker, cystamine dihydrochloride, and synergetic non-covalent interactions not only stabilize the nanoparticles, achieve high DOX-loading capacity of drug loading content (DLC, 14.6%) and drug loading efficiency (DLE, 73.1%), but also endow the DOX/CCL NPs with controlled drug release capacity, which is due to the cleavage of S–S bonds in the presence of 10 mM glutathione (GSH) and weakened electrostatic interaction caused by the protonation of carboxyl groups at a lower pH (5.0). Moreover, these pH/redox dual-responsive DOX/CCL NPs can be steadily internalized by HeLa cells, exhibiting high-efficiency cellular proliferation inhibition. This study presents a promising strategy for controlled intracellular drug release in cancer therapy.
Co-reporter:Ying Hao, Jinlin He, Sen Li, Jian Liu, Mingzu Zhang and Peihong Ni
Journal of Materials Chemistry A 2014 - vol. 2(Issue 27) pp:NaN4249-4249
Publication Date(Web):2014/04/15
DOI:10.1039/C4TB00334A
An emerging strategy for synergistic gene and drug therapy is establishing a new paradigm for the synthesis of diversified and functional block copolymers with applications ranging from gene and drug delivery to fluorescence detection. In this paper, we report on a novel amphiphilic block copolymer containing a fluorescent coumarin derivative (CE), an acid-cleavable (acetal group, -a-) linkage between hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) and poly[poly(ethylene glycol)methyl ether methacrylate] (PPEGMA) blocks, abbreviated as CE-PCL-a-(PDMAEMA-co-PPEGMA), which was synthesized by a combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP) and CuAAC “click” reaction. The chemical composition and structures of these copolymers were fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The micelles self-assembled from these block copolymers could simultaneously encapsulate anti-cancer drug doxorubicin (DOX) and DNA to form a micelleplex with the hydrophilic brush-type PPEGMA on the surface, and the loaded cargoes could be released after the acetal linkage was cleaved under intracellular acidic conditions. Subsequently, the formed micelles as the drug and gene co-delivery vectors were investigated by employing gel retardation assay, zeta potential, dynamic light scattering (DLS), and transmission electron microscopy (TEM). A fluorescence spectrometer was further used to evaluate the fluorescence of polymers. Finally, in vitro drug release, cytotoxicity and transfection were also studied. All these results indicated that this acid-cleavable and fluorescent block copolymer would hold significant potential as a combined drug and DNA carrier.
Co-reporter:Hairong Wang, Jinlin He, Mingzu Zhang, Yunfeng Tao, Fei Li, Kam Chiu Tam and Peihong Ni
Journal of Materials Chemistry A 2013 - vol. 1(Issue 48) pp:NaN6607-6607
Publication Date(Web):2013/10/15
DOI:10.1039/C3TB21170C
A series of acid-cleavable ABA-type triblock copolymers, namely poly(ε-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(ε-caprolactone) (PCL-a-PEG-a-PCL), were synthesized via a combination of ring-opening polymerization (ROP) of ε-caprolactone initiated by propargyl alcohol and subsequent “CuAAC” click reaction with azide terminated acetal-containing poly(ethylene glycol). The chemical composition and structures of the copolymers were characterized by 1H NMR and FT-IR spectroscopy, while their molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The critical aggregation concentration (CAC), size parameters and morphologies of micelles self-assembled from PCL-a-PEG-a-PCL were determined by fluorescence probing, dynamic light scattering (DLS), and transmission electron microscopy (TEM), respectively. Since the acetal groups are unstable in weak acidic media, it is anticipated that this class of triblock copolymer micelles can be dissociated in an intracellular environment. This was confirmed by monitoring the size change of micelles with the increase of degradation time under acidic conditions, as well as the molecular weights of degradation products. The pH-triggered release of doxorubicin (DOX) from PCL-a-PEG-a-PCL micelles was studied and compared with a pH-insensitive PCL-b-PEG-b-PCL system without acetal groups, demonstrating that the cleavage of acetal linkages was responsible for the pH-responsive drug release profiles. In vitro cytotoxicity tests against HeLa and L929 cells by MTT assays indicated that the self-assembled micelles displayed very low cytotoxicity. In addition, the intracellular drug release against HeLa cells was further investigated by a live cell imaging system using free DOX as a control. This work provides a facile strategy for the preparation of a new type of biodegradable amphiphilic copolymer as a highly promising intracellular delivery system for hydrophobic drugs.
Co-reporter:Qingqing Zhang, Jinlin He, Mingzu Zhang and Peihong Ni
Journal of Materials Chemistry A 2015 - vol. 3(Issue 24) pp:NaN4932-4932
Publication Date(Web):2015/05/14
DOI:10.1039/C5TB00623F
A new kind of reduction-cleavable polymer-camptothecin (CPT) prodrug has been developed, in which the polymer backbone consists of a biodegradable diblock polyphosphoester (PBYP-b-PEEP), and a modified CPT is linked onto the pendant alkynes of PBYP via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to yield the polymeric prodrug, abbreviated as (PBYP-g-ss-CPT)-b-PEEP. The resulting prodrug could self-assemble into uniform prodrug micelles in aqueous solution. Since the releasable disulfide carbonate between the CPT and the polyphosphoester would be disrupted under an intracellular reducing environment, the disassociation of prodrug micelles could result in a rapid release of the CPT parent drug. The chemical structures of the intermediate polymers and a polymeric prodrug have been fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The self-assembly behavior of the prodrug was investigated by the fluorescence probe method, dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses. The DLS results indicated that these prodrug micelles were relatively stable in neutral pH media, but could be degraded under the reductive conditions. The in vitro drug release studies showed that the CPT release from prodrug micelles was proceeded in a glutathione (GSH)-dependent manner. A methyl thiazolyl tetrazolium (MTT) assay demonstrated that the prodrug micelles could efficiently inhibit the proliferation of HepG2 cells. In addition, the intracellular uptake of prodrug micelles could efficiently release CPT into HepG2 cells, which was observed using a live cell imaging system. All these results indicated that this GSH-responsive polymeric prodrug has high potential for reduction-triggered cancer chemotherapy.
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