Co-reporter:Xiaojun Cai;Yongyong Li;Dong Yue;Qiangying Yi;Shuo Li;Donglu Shi;Zhongwei Gu
Journal of Materials Chemistry B 2017 vol. 5(Issue 1) pp:181-181
Publication Date(Web):2016/12/21
DOI:10.1039/C6TB90173E
Correction for ‘Reversible PEGylation and Schiff-base linked imidazole modification of polylysine for high-performance gene delivery’ by Xiaojun Cai et al., J. Mater. Chem. B, 2015, 3, 1507–1517.
Co-reporter:Ya Wen, Haiqing Dong, Yan Li, Aijun Shen and Yongyong Li
Journal of Materials Chemistry A 2016 vol. 4(Issue 4) pp:743-751
Publication Date(Web):18 Dec 2015
DOI:10.1039/C5TB01962A
Biomineralization of a rare earth ion (Gd) is first employed to assemble bovine serum albumin (BSA) into sub-50 nm nanoparticles (Gd@BSA) for theranostic applications, via a straightforward and reproducible strategy. Combination of Gd ions with BSA under mild conditions results in the formation of the Gd@BSA nanosystem, which has been used as the scaffold material to encapsulate a photosensitiser (Ce6) with high efficiency up to 20 wt%. Beyond playing an important role in the assembled process, the incorporation of Gd affords the potential MRI and fluorescence imaging capability of Gd@BSA-Ce6 nanoparticles. In vivo MRI allowed real-time imaging in tumor-bearing mice and showed advantages in terms of circulation time, compared with commercially used Gd–DTPA. Gd@BSA-Ce6 nanoparticles exhibited enhanced tumor-specific distribution, through enhanced permeability and retention effect, and complete cure of tumor-bearing mice after intravenous injection. The nanoparticles did not produce systemic toxicity as revealed by biodistribution and histology toxicity analyses. The results demonstrate the great potential of Gd@BSA-Ce6 nanoparticles as theranostic agents due to their excellent imaging and tumor-growth-inhibition properties.
Co-reporter:Dou Du, Kun Wang, Ya Wen, Yan Li, and Yong Y. Li
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 5) pp:3287
Publication Date(Web):January 13, 2016
DOI:10.1021/acsami.5b11154
Prequenching and selective activation of photosensitizer (PS) are highly desired in photodynamic therapy (PDT) to avoid off-target effect due to nonspecific activation and poor targeting selectivity of PS. In this study, nanographene materials as a unique π-conjugated planar system for electronic transfer were employed as the robust platform for temporarily quenching of PS. Photosensitizer chlorin e6 (Ce6) was integrated onto planar structure of graphene quantum dot (GQD) or graphene oxide (GO) via a reduction cleavable disulfide linker. The formed hybrid nanosystem displayed considerable fluorescence quenching and slight phototoxicity, even under the condition of light irradiation, while the photoactivity of PS could be selectively recovered in the presence of the reducing agent. Compared with graphene oxide system with larger size (around 200 nm), GQD nanosystem exhibited significantly improved tumor accumulation via enhanced permeation and retention effect (EPR effect). The in vivo study demonstrated extremely effective suppression of tumor growth for the group treated with the GQD nanosystem with cleavable linker, revealing the promising application of the presented novel strategy.Keywords: disulfide; EPR effect; graphene quantum dot; photoactivity; photodynamic therapy; redox-responsive
Co-reporter:Yan Li, Zhiyong Wu, Dou Du, Haiqing Dong, Donglu Shi and Yongyong Li
RSC Advances 2016 vol. 6(Issue 8) pp:6516-6522
Publication Date(Web):08 Jan 2016
DOI:10.1039/C5RA23622C
In photodynamic therapy (PDT), selective activation of the photosensitiser in tumor-relevant conditions is highly desirable to avoid side effects. In this study, a graphene quantum dot (GQD) nanosystem, composed of a redox-triggered cleavable PEG shell, was designed and developed for selective recovery of photoactive chlorine e6 (Ce6) in tumor-relevant conditions. In this unique system, the planar π conjugated structure of GQD enables efficient quenching of the photochemical properties of Ce6 in terms of fluorescence and singlet oxygen generation. Once exposed to tumor relevant glutathione (GSH), the disulfide-linked PEG shell undergoes reductive cleavage and subsequent detachment from the GQD scaffold, leading to accelerated release of Ce6 with recovered photoactivity. MTT study against HeLa cells demonstrated the high PDT efficacy of Ce6, regulated by elevated GSH concentration. The studies on in vivo/ex vivo imaging and photodynamic efficacy demonstrated superior biocompatibility of the GQD nanosystem compared with the widely reported graphene oxide (GO)-based nanovehicle. Intravenously injected GQD–SS–PEG/Ce6 showed effective suppression of tumor growth.
Co-reporter:Xiaojun Cai, Yongyong Li, Dong Yue, Qiangying Yi, Shuo Li, Donglu Shi and Zhongwu Gu
Journal of Materials Chemistry A 2015 vol. 3(Issue 8) pp:1507-1517
Publication Date(Web):03 Nov 2014
DOI:10.1039/C4TB01724B
Gene carriers made from polylysine are of interest in relation to gene therapy but suffer from the lack of transfection efficiency due to limited stability and endosomal escape ability. To address this problem, we designed and developed Schiff-base linked imidazole modified polylysine with a reversible-PEGylation catiomer (SL-ImPEG-SS-PLL) for high efficiency gene delivery. The reversible PEGylation was introduced for in vivo circulation, as well as selective PEG detachment to augment the cellular internalization, while introducing Schiff-base linked imidazole residues into polylysine was expected to accelerate the endosomal escape of the DNA payload, as well as facilitate intracellular DNA unpacking and release, thus significantly enhancing gene delivery efficiency. The size alteration of the SL-I15mPEG-SS-PLL/pDNA polyplexes in the presence of 10 mM GSH suggests stimulus-induced PEG detachment under tumor relevant reduction conditions. Acid–base titration assays indicate that imidazole residues confer on polylysine remarkable buffering ability. The agarose gel retardation assay suggests that the Schiff-base linkages provide an increased DNA binding ability to protect DNA against nucleases and timely intracellular DNA unpacking to permit DNA dissociation from polylysine and access to transcriptional machinery. Biological efficacy assessment of this multifunctional carrier, using pEGFP and pGL-3 as reporter genes, indicates comparable to or even higher transfection efficiencies than gold standard PEI and their transfection efficiencies are slightly affected by serum. More importantly, in vivo transfection of pEGFP reveals that GFP expression was found not only in some of the important organs, such as the liver, spleen, kidneys and lungs, but also in the transplanted carcinoma. These experimental results suggest that the reversible PEGylation and Schiff-base linked imidazole modification make SL-ImPEG-SS-PLL a great potential candidate for an effective and biocompatible gene delivery system.
Co-reporter:Yan Li, Li Zheng, Haiqing Dong and Yongyong Li
RSC Advances 2015 vol. 5(Issue 90) pp:73752-73759
Publication Date(Web):24 Aug 2015
DOI:10.1039/C5RA12648G
A single-protein-based theranostic nanosystem (SPTN) based on non-covalent interaction between bovine serum albumin (BSA), gadolinium (Gd) and the anticancer hydrophobic drug doxorubicin (DOX) was designed and developed via a facile, environmentally benign approach. Gd was incorporated into the structure of BSA via a simple biomineralization process, while DOX was encapsulated in Gd–BSA nanoparticles via hydrophobic interaction between DOX and BSA, as well as a coordination effect between DOX and Gd. The whole SPTN system was kept in one single BSA molecule to form a single protein based nanosystem with an overall size of around 7 nm favorable for potential renal clearance. The SPTN nanosystem showed not only robust biocompatibility, excellent T1-weighted MR imaging effect but also fine pH-responsive drug release characteristics. Furthermore, in vivo therapeutic efficacy experiment showed that the nanoparticle DOX–Gd–BSA had an obvious therapeutic efficacy toward hepatoma tumor bearing mice.
Co-reporter:Jiashan Zhou, Yan Li, Haiqing Dong, Hua Yuan, Tianbin Ren and Yongyong Li
RSC Advances 2015 vol. 5(Issue 19) pp:14138-14146
Publication Date(Web):08 Jan 2015
DOI:10.1039/C4RA13785J
Polymeric catiomers, which can mimic viruses for gene packing and delivery, have received considerable attention as nonviral vectors for gene therapy. Inspired by the critically important role of the sequence of structural units in various biomolecules, including DNA and protein, in this study, we intend to investigate how the monomer sequence of a polymeric catiomer affects its gene packing capacity and delivery efficiency. The well-documented poly(histidine-co-lysine) was chosen as the scaffold for gene carrier. Four reducible polycations (RPCs) based on sequence-regulated peptides monomers were synthesized. Chemical parameters (namely, composition and molecular weight) of four RPCs were controlled at comparable level except for the monomer sequence. All of the RPCs exhibited low cytotoxicity and effective DNA binding ability. However, these RPCs displayed distinct diversity from each other, especially in their ability of binding to DNA, buffering capacity and transfection efficiency. Using 293T cell as the mode, we found that the regulation of the monomer sequence of polycations could significantly affect their properties for gene delivery, with differences of 100 fold. The sequence effect might be correlated with different chain folding as well as physiochemical properties of RPCs/pDNA complexes, providing new insight for designing gene vector with promising prospects in gene therapy.
Co-reporter:Xiaojun Cai;Haiyan Zhu;Haiqing Dong;Yongyong Li;Jiansheng Su;Donglu Shi
Advanced Healthcare Materials 2014 Volume 3( Issue 11) pp:1818-1827
Publication Date(Web):
DOI:10.1002/adhm.201400063
A reversible-PEGylated polylysine is designed and developed for efficient delivery of siRNA. In this unique structure, the ε-amino groups of disulfide linked poly(ethylene glycol) (PEG) and polylysine (mPEG-SS-PLL) are partially replaced by histidine groups, in order to develop the histidylated reversible-PEGylated polylysine (mPEG-SS-PLH), for enhanced endosome escape ability. The transfection efficacy of mPEG-SS-PLH is found to closely correlate with histidine substitution. Its maximum transfection efficiencies are determined, respectively, to be 75%, 42%, and 24%, against 293T, MCF-7, and PC-3 cells. These data indicate that the transfection efficiencies can equal or even outweigh PEI-25k in the corresponding cells (80%, 38.5%, and 20%). The in vivo circulation and biodistribution of the polyplexes are monitored by fluorescent imaging. The in vivo gene transfection is carried out by intravenous injection of pEGFP to BALB/c mice using the xenograft models. The in vivo experimental results show effective inhibition of tumor growth by mPEG-SS-PLH/siRNA–VEGF, indicating its high potential for clinical applications.
Co-reporter:Yongyong Li, Xue Lei, Haiqing Dong and Tianbin Ren
RSC Advances 2014 vol. 4(Issue 16) pp:8165-8176
Publication Date(Web):14 Jan 2014
DOI:10.1039/C3RA46756B
In this work, sheddable, degradable, cationic micelles were designed and developed based on intermediate disulfide-linked poly(ε-caprolactone)-b-poly(N,N-dimethylamino-2-ethylmethacrylate) (PCL-SS-PDMA) diblock copolymers, for glutathione (GSH)-mediated intracellular delivery of anticancer drug doxorubicin (DOX) and gene. The PCL-SS-PDMA diblock polymers with different PDMA block lengths were prepared by a combination of ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP). Driven by hydrophobic interaction, these polymers self-assembled into nanoscaled micelles with size ranging from 70 to 200 nm, and positive surface charges from +24 to +37 mV. The PDMA length was found to determine the surface charge and in turn affect the physiochemical properties and cumulative drug release. More importantly, glutathione mediated intracellular drug release was observed by intracellular fluorescence arising from DOX for the GSH treated cells. The accelerated drug release was induced by the structural disassembly after disulfide cleavage. The PCL-SS-PDMA block polymers exhibited high DNA binding affinity and cellular uptake efficiency. The gene transfection efficiency of PCL-SS-PDMA/DNA complex showed relatively low transfection efficiency in 293 T and HeLa cells, compared to PEI 25K. However, the transfection efficacy dramatically outperformed PEI 25K in human oral carcinoma cell lines (KB and CAL-27 cells). A ten-fold population of the transfected cells was found for the PS-SS-PDMA polymer, compared with PEI. The experimental results show the great potential of the new micelles in gene and drug delivery for cancer therapy.
Co-reporter:Haiqing Dong, Chunyan Dong, Wenjuan Xia, Yongyong Li and Tianbin Ren
MedChemComm 2014 vol. 5(Issue 2) pp:147-152
Publication Date(Web):21 Nov 2013
DOI:10.1039/C3MD00267E
A novel prodrug of pegylated methotrexate conjugates (PMCs) with a high drug-carrying capability and a redox sensitive drug release mechanism was reported for intracellular drug delivery. The PMC was structured in a H-shape with four molecules of anticancer drug methotrexate (MTX) linked to both ends of the PEG main chain via disulfide linkers, resulting in the conjugates with a high and constant drug loading efficiency of up to 26 wt%. The amphiphilic property of PMCs enables them to self-assemble into nanoparticles in aqueous solution, while the cleavable disulfide linkers allow the conjugated MTX to exert its therapeutic activity due to the fast cleavage of disulfide linkers when exposed to the intracellular concentration of glutathione (GSH). Cell proliferation assays performed with HepG2 cancer cells confirmed the pharmacological efficacy.
Co-reporter:Xiaojun Cai, Haiqing Dong, Junping Ma, Haiyan Zhu, Wei Wu, Meng Chu, Yongyong Li and Donglu Shi
Journal of Materials Chemistry A 2013 vol. 1(Issue 12) pp:1712-1721
Publication Date(Web):25 Jan 2013
DOI:10.1039/C3TB00425B
A spatial effect of targeted signal distribution is found in catiomer–gene polyplexes which strongly influences the gene transfection profiles. The nuclear localization sequence PKKKRKV (NLS) is chosen as the target ligand. For a given gene delivery system of constant composition, size, and charge, it is engineered such that the NLS is the only structural variable in polyplexes. This unique architecture of polyplexes relies on successive electrostatic interaction. The structural features of the PKKKRKV sequence in polyplexes are investigated by NMR. The gene transfection profiles of the polyplexes are found to be well correlated with the spatial distribution of the nuclear localization sequence. Upon modification of nuclear localization, the gene transfection efficiency is found to increase remarkably from 40% to 60%. The drastic improvement of gene transfection is explained by a NLS spatial distribution mechanism. High gene transfection based on spatial NLS distribution provides a new base for the design and development of non-viral gene delivery vectors.
Co-reporter:Yongyong Li, Junping Ma, Haiyan Zhu, Xiaolong Gao, Haiqing Dong, and Donglu Shi
ACS Applied Materials & Interfaces 2013 Volume 5(Issue 15) pp:7227
Publication Date(Web):July 1, 2013
DOI:10.1021/am401573b
The objective of this study is to design and develop a green-synthetic, multifunctional hybrid micelles with shell embedded magnetic nanoparticles for theranostic applications. The hybrid micelles were engineered based on complex micelles self-assembled from amphiphilic block copolymers Pluronic F127 and peptide-amphiphile (PA) pal-AAAAHHHD. The reason to choose PA is due to its amphiphilic character and the coordination capability for Fe3+ and Fe2+. The PA incorporation allows the in situ growth of the magnetic iron oxide nanoparticles onto the complex micelles, to yield the nanostructures with shell embedded magnetic nanoparticles at an ambient condition without any organic solvents. The anticancer drug doxorubicin (DOX) can be efficiently loaded into the hybrid micelles. Interestingly, the magnetic nanoparticles anchored on the shell were found to significantly retard the DOX release behavior of the drug loaded hybrid micelles. It was proposed that a cross-linking effect of the shell by magnetic nanoparticles is a key to underlie the above intriguing phenomenon, which could enhance the stability and control the drug diffusion of the hybrid micelles. Importantly, in vitro and in vivo magnetic resonance imaging (MRI) revealed the potential of these hybrid micelles to be served as a T2-weighted MR imaging contrast enhancer for clinical diagnosis.Keywords: green synthesis; hybrid micelles; MR imaging; multifunction; theranostic;
Co-reporter:Tianbin Ren, Wei Wu, Menghong Jia, Haiqing Dong, Yongyong Li, and Zhouluo Ou
ACS Applied Materials & Interfaces 2013 Volume 5(Issue 21) pp:10721
Publication Date(Web):October 2, 2013
DOI:10.1021/am402860v
In the treatment of cancer, multidrug resistance (MDR) has been the major obstacle to the success of chemotherapy. The underlying mechanism relies on the overexpression of drug-efflux transporters that prevent the intracellular transport of the drug. In this study, reduction-cleavable vesicles were designed and developed with efficient glutathione-mediated drug-release behavior for reversing drug resistance. Polymeric vesicles were self-assembled from triblock copolymers with disulfide-bond-linked poly(ethylene glycol) (PEG) and poly(ε-benzyloxycarbonyl-l-lysine) (PzLL). Observations from transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) outline an obvious hollow structure surrounded by a thin outer layer, indicating the successful formation of the vesicles. Using fluorescently detectable doxorubicin hydrochloride (DOX·HCl) as the model drug, a significant acceleration of drug release regulated by glutathione (GSH) was found (>3-fold difference). Upon incubation of the DOX·HCl-loaded polymeric vesicles with the HeLa cervical cancer cell line exposed to glutathione, an enhanced nuclear accumulation of DOX·HCl was observed, elicited by the preferred disassembly of the vesicle structure under reducing conditions. Importantly, by using the gemcitabine hydrochloride (GC·HCl)-resistant breast cancer cell line MDA-MB-231, it was found that cell viability was significantly reduced after treatment with GC·HCl-loaded polymeric vesicles, indicating that these vesicles can help to reverse the drug resistance.Keywords: anticancer drug; multidrug resistance; polymeric vesicles; reduction cleavable;
Co-reporter:Meng Chu, Chunyan Dong, Haiyan Zhu, Xiaojun Cai, Haiqing Dong, Tianbin Ren, Jiansheng Su and Yongyong Li
Polymer Chemistry 2013 vol. 4(Issue 8) pp:2528-2539
Publication Date(Web):05 Feb 2013
DOI:10.1039/C3PY21092H
The aim of the present work was to design a targeting polysaccharide-based cationic polymer for gene delivery. PEI is one of the most widely studied cationic polymers in terms of gene delivery, yet its applications are limited by its inherent drawbacks. To address these drawbacks, the grafted low-molecular-weight branched polyethylenimine (PEI) (1800 Da and 800 Da) with the low cytotoxicity and targeting ligand were integrated into a polymeric system based on biodegradable and biocompatible polysaccharide dextran, to afford a highly efficient gene delivery system. The structure of the grafted polymer (Dextran-g-PEI) was confirmed by nuclear magnetic resonance (NMR). DNA complexation resulted in nanoscale and spherical particles (Dextran-g-PEI/DNA), revealed by transmission electron microscopy (TEM). The sizes of the complexes decreased while the zeta potentials increased with the elevation of the w/w ratio. The agarose gel electrophoresis suggested that complexation process alleviates the DNA degradation by DNase I. Very low cytotoxicity was shown on HeLa, 293T and HepG2 cell lines using MTT cell relative viability assay, a red blood cell aggregation assay as well as hemolytic activity determination, whereas transfection efficiency in vitro of Dextran-g-PEI/DNA complexes was observed by green fluorescent protein assay in 293T, HeLa and HepG2 cells. Cy™3 was used as a molecular probe to evaluate the effect of nuclear targeting ligand (PV7) addition on the cellular uptake of complexes. After the intravenous injection of pEGFP to BALB/c mice xenograft models for transfection in vivo, the expression of green fluorescent protein was observed in the transplanted carcinoma and some of the important organs, such as liver, spleen, kidney and lung. To prove the tumor localization of the polyplexes, the in vivo circulation and biodistribution of the polyplexes were monitored by in vivo fluorescent imaging. Thus it was concluded that Dextran-g-PEI is a potential candidate for effective and biocompatible gene delivery systems.
Co-reporter:Yanna Cui, Haiqing Dong, Xiaojun Cai, Deping Wang, and Yongyong Li
ACS Applied Materials & Interfaces 2012 Volume 4(Issue 6) pp:3177
Publication Date(Web):May 30, 2012
DOI:10.1021/am3005225
Hybrid mesoporous silica nanoparticles (MSNs), which were synthesized using the co-condensation method and engineered with unique redox-responsive gatekeepers, were developed for studying the glutathione-mediated controlled release. These hybrid nanoparticles constitute a mesoporous silica core that can accommodate the guests (i.e., drug, dye) and the PEG shell that can be connected with the core via disulfide-linker. Interestingly, the PEG shell can be selectively detached from the inner core at tumor-relevant glutathione (GSH) levels and facilitate the release of the encapsulated guests at a controlled manner. The structure of the resulting hybrid nanoparticles (MSNs-SS-mPEG) was comprehensively characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD), and nitrogen adsorption/desorption isotherms analysis. The disulfide-linked PEG chains anchored on MSNs could serve as efficient gatekeepers to control the on–off of the pores. Compared with no GSH, fluorescein dye as the model drug loaded into MSNs showed rapid release in 10 mM GSH, indicating the accelerated release after the opening of the pores regulated by GSH. Confocal microscopy images showed a clear evidence of the dye-loaded MSNs-SS-mPEG nanoparticles endocytosis into MCF-7 cells and releasing guest molecules from the pore inside cells. Moreover, in vitro cell viability test using MTT assay indicated that MSNs-SS-mPEG nanoparticles had no obvious cytotoxicity. These results indicate that MSNs-SS-mPEG nanoparticles can be used in the biomedical field.Keywords: controlled release; cytotoxicity; mesoporous silica nanoparticles (MSNs); MSNs-SS-PEG nanoparticles; PEG gatekeeper; reduction-sensitive;
Co-reporter:Haiqing Hu;Jinhai Yu;Yongyong Li;Jian Zhao;Haiqing Dong
Journal of Biomedical Materials Research Part A 2012 Volume 100A( Issue 1) pp:141-148
Publication Date(Web):
DOI:10.1002/jbm.a.33252
Abstract
Herein, a novel Pluronic F127/graphene nanosheet (PF127/GN) hybrid was prepared via an one-pot process including the simultaneous reduction of graphene oxide and assembly of PF127 and GN. The nanohybrid exhibits high water dispersibility and stability in physiological environment with the hydrophilic chains of PF127 extending to the solution while the hydrophobic segments anchoring at the surface of graphene via hydrophobic interaction. The PF127/GN nanohybrid is found to be capable of effectively encapsulating doxorubicin (DOX) with ultrahigh drug-loading efficiency (DLE; 289%, w/w) and exhibits a pH responsive drug release behavior. The superb DLE of the PF127/GN nanohybrid relies on the introduction of GN which is structurally compatible with DOX. Cellular toxicity assays performed on human breast cancer MCF-7 cells demonstrate that the PF127/GN nanohybrid displays no obvious cytotoxicity, whereas the PF127/GN-loaded DOX (PF127/GN/DOX) shows remarkable cytotoxicity to the MCF-7. Cell internalization study reveals that PF127/GN nanohybrid facilitates the transfer of DOX into MCF-7 cells, evidenced by the image of confocal laser scanning microscopy. The above results indicate the potential application of this novel nanocarrier in biomedicine. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.
Co-reporter:Xiaojun Cai, Chunyan Dong, Haiqing Dong, Gangmin Wang, Giovanni M. Pauletti, Xiaojing Pan, Huiyun Wen, Isaac Mehl, Yongyong Li, and Donglu Shi
Biomacromolecules 2012 Volume 13(Issue 4) pp:
Publication Date(Web):March 9, 2012
DOI:10.1021/bm2017355
A dual stimulus-responsive mPEG-SS-PLL15-glutaraldehyde star (mPEG-SS-PLL15-star) catiomer is developed and biologically evaluated. The catiomer system combines redox-sensitive removal of an external PEG shell with acid-induced escape from the endosomal compartment. The design rationale for PEG shell removal is to augment intracellular uptake of mPEG-SS-PLL15-star/DNA complexes in the presence of tumor-relevant glutathione (GSH) concentration, while the acid-induced dissociation is to accelerate the release of genetic payload following successful internalization into targeted cells. Size alterations of complexes in the presence of 10 mM GSH suggest stimulus-induced shedding of external PEG layers under redox conditions that intracellularly present in the tumor microenvironment. Dynamic laser light scattering experiments under endosomal pH conditions show rapid destabilization of mPEG-SS-PLL15-star/DNA complexes that is followed by facilitating efficient release of encapsulated DNA, as demonstrated by agarose gel electrophoresis. Biological efficacy assessment using pEGFP-C1 plasmid DNA encoding green fluorescence protein and pGL-3 plasmid DNA encoding luciferase as reporter genes indicate comparable transfection efficiency of 293T cells of the catiomer with a conventional polyethyleneimine (bPEI-25k)-based gene delivery system. These experimental results show that mPEG-SS-PLL15-star represents a promising design for future nonviral gene delivery applications with high DNA binding ability, low cytotoxicity, and high transfection efficiency.
Co-reporter:Xiao-Jun Cai, Hai-Qing Dong, Wen-Juan Xia, Hui-Yun Wen, Xue-Quan Li, Jin-Hai Yu, Yong-Yong Li and Dong-Lu Shi
Journal of Materials Chemistry A 2011 vol. 21(Issue 38) pp:14639-14645
Publication Date(Web):15 Aug 2011
DOI:10.1039/C1JM11693B
Engineered PEG-detachable catiomers were developed as non-viral gene vectors to detach the PEG layers responsive to the intracellular reducing environment. These catiomers were found to exhibit high DNA binding ability and reduced cytotoxicity, as evidenced in agarose gel electrophoresis and MTT assays. The size of the mPEG-SS-PLL/DNA complexes was around 100 nm with a regular spherical shape, as observed under transmission electron microscopy (TEM). The complexes were stably dispersed in an aqueous medium with 10% serum. However, fast aggregation was observed in the presence of 10 mM glutathione (GSH) due to detachment of the PEG segment via disulfide cleavage. These complexes showed high transfection efficiency in 293T and Hela cells under optimized conditions. The experimental results indicated that the mPEG-SS-PLL catiomers may have promising potential as a non-viral gene vector.
Co-reporter:Xue-Quan Li, Hui-Yun Wen, Hai-Qing Dong, Wei-Ming Xue, Giovanni M. Pauletti, Xiao-Jun Cai, Wen-Juan Xia, Donglu Shi and Yong-Yong Li
Chemical Communications 2011 vol. 47(Issue 30) pp:8647-8649
Publication Date(Web):01 Jul 2011
DOI:10.1039/C1CC12495A
A novel amphiphilic camptothecin prodrug that spontaneously arranges into nanomicelles which preferentially release the cytotoxic drug under tumor-relevant reductive conditions is designed.
Co-reporter:Hui-Yun Wen, Hai-Qing Dong, Wen-juan Xie, Yong-Yong Li, Kang Wang, Giovanni M. Pauletti and Dong-Lu Shi
Chemical Communications 2011 vol. 47(Issue 12) pp:3550-3552
Publication Date(Web):16 Feb 2011
DOI:10.1039/C0CC04983B
The synthesis and biological efficacy of novel nanomicelles that rapidly disassemble and release their encapsulated payload intracellularly under tumor-relevant glutathione (GSH) levels are reported. The unique design includes a PEG-sheddable shell and poly(ε-benzyloxycarbonyl-L-lysine) core with a redox-sensitive disulfide linkage.
Co-reporter:Haiqing Dong;Yongyong Li;Huiyun Wen;Meng Xu;Lijian Liu;Zhuoquan Li;Fangfang Guo;Donglu Shi
Macromolecular Rapid Communications 2011 Volume 32( Issue 6) pp:
Publication Date(Web):
DOI:10.1002/marc.201000693
Co-reporter:Kang Wang;Hai-Qing Dong;Hui-Yun Wen;Meng Xu;Cao Li;Yong-Yong Li;Helen N. Jones;Dong-Lu Shi;Xian-Zheng Zhang
Macromolecular Bioscience 2011 Volume 11( Issue 1) pp:65-71
Publication Date(Web):
DOI:10.1002/mabi.201000247
Co-reporter:Tian-Bin Ren, Yue Feng, Zhong-Hai Zhang, Lan Li and Yong-Yong Li
Soft Matter 2011 vol. 7(Issue 6) pp:2329-2331
Publication Date(Web):15 Feb 2011
DOI:10.1039/C1SM05020F
We report on the preparation and drug delivery application of shell sheddable micelles based on disulfide-linked star-shaped copolymer of poly(ε-caprolactone) and poly(ethyl glycol) (6sPCL-SS-PEG). Interestingly, the micelles exhibit high stability normally and rapid destabilization under a reduction environment, eliciting GSH dependent cytotoxicity of drug-loaded formulations on tumor cells.
Co-reporter:Tian-Bin Ren, Wen-Juan Xia, Hai-Qing Dong, Yong-Yong Li
Polymer 2011 Volume 52(Issue 16) pp:3580-3586
Publication Date(Web):20 July 2011
DOI:10.1016/j.polymer.2011.06.013
A novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was demonstrated for intracellular drug delivery. These micelles are composed of an mPEG shell and polypeptide core, characterized by FT-IR, 1H NMR, fluorescence techniques, TEM, and DLS. Interestingly, they would undergo a fast sheddable process when encounter the reduction sensitive condition, indicated by the aggregation phenomena in the presence of DTT, a reduction agent, which could cleave the disulfide bond between the micellar core and shell and consequently leading to the aggregation of hydrophobic core. Cytotoxicity study revealed that copolymers in this system have good biocompatibility and their self-assembled micelles showed a high drug loading efficiency for DOX, a hydrophobic drug model, and released DOX quantitatively in response to the intracellular level of reducing potential. Cellular uptake experiments demonstrated that the fluorescently labeled micelles could be successfully internalized into human liver carcinoma HepG2 cells, evidenced by confocal laser scanning microscopy. Above results indicate that the copolymers may have great potential in drug delivery to achieve improved cancer therapy.In this paper, a novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was developed for intracellular drug delivery. These carriers were biodegradability, biocompatibility, and biofuctionality due to the component and structure of polypeptide analogous with natural biomolecules. Meanwhile, these micelles showed a high drug loading efficiency for DOX and released DOX quantitatively in response to the intracellular level of reducing potential.
Co-reporter:Haiyan Zhu ; Chunyan Dong ; Haiqing Dong ; Tianbin Ren ; Xuejun Wen ; Jiansheng Su ;Yongyong Li
ACS Applied Materials & Interfaces () pp:
Publication Date(Web):
DOI:10.1021/am501928p
Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lysn-r-Hism) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lysn-r-Hism was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lysn-r-Hism showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis.
Co-reporter:Xiao-Jun Cai, Hai-Qing Dong, Wen-Juan Xia, Hui-Yun Wen, Xue-Quan Li, Jin-Hai Yu, Yong-Yong Li and Dong-Lu Shi
Journal of Materials Chemistry A 2011 - vol. 21(Issue 38) pp:NaN14645-14645
Publication Date(Web):2011/08/15
DOI:10.1039/C1JM11693B
Engineered PEG-detachable catiomers were developed as non-viral gene vectors to detach the PEG layers responsive to the intracellular reducing environment. These catiomers were found to exhibit high DNA binding ability and reduced cytotoxicity, as evidenced in agarose gel electrophoresis and MTT assays. The size of the mPEG-SS-PLL/DNA complexes was around 100 nm with a regular spherical shape, as observed under transmission electron microscopy (TEM). The complexes were stably dispersed in an aqueous medium with 10% serum. However, fast aggregation was observed in the presence of 10 mM glutathione (GSH) due to detachment of the PEG segment via disulfide cleavage. These complexes showed high transfection efficiency in 293T and Hela cells under optimized conditions. The experimental results indicated that the mPEG-SS-PLL catiomers may have promising potential as a non-viral gene vector.
Co-reporter:Xiaojun Cai, Haiqing Dong, Junping Ma, Haiyan Zhu, Wei Wu, Meng Chu, Yongyong Li and Donglu Shi
Journal of Materials Chemistry A 2013 - vol. 1(Issue 12) pp:NaN1721-1721
Publication Date(Web):2013/01/25
DOI:10.1039/C3TB00425B
A spatial effect of targeted signal distribution is found in catiomer–gene polyplexes which strongly influences the gene transfection profiles. The nuclear localization sequence PKKKRKV (NLS) is chosen as the target ligand. For a given gene delivery system of constant composition, size, and charge, it is engineered such that the NLS is the only structural variable in polyplexes. This unique architecture of polyplexes relies on successive electrostatic interaction. The structural features of the PKKKRKV sequence in polyplexes are investigated by NMR. The gene transfection profiles of the polyplexes are found to be well correlated with the spatial distribution of the nuclear localization sequence. Upon modification of nuclear localization, the gene transfection efficiency is found to increase remarkably from 40% to 60%. The drastic improvement of gene transfection is explained by a NLS spatial distribution mechanism. High gene transfection based on spatial NLS distribution provides a new base for the design and development of non-viral gene delivery vectors.
Co-reporter:Ya Wen, Haiqing Dong, Yan Li, Aijun Shen and Yongyong Li
Journal of Materials Chemistry A 2016 - vol. 4(Issue 4) pp:NaN751-751
Publication Date(Web):2015/12/18
DOI:10.1039/C5TB01962A
Biomineralization of a rare earth ion (Gd) is first employed to assemble bovine serum albumin (BSA) into sub-50 nm nanoparticles (Gd@BSA) for theranostic applications, via a straightforward and reproducible strategy. Combination of Gd ions with BSA under mild conditions results in the formation of the Gd@BSA nanosystem, which has been used as the scaffold material to encapsulate a photosensitiser (Ce6) with high efficiency up to 20 wt%. Beyond playing an important role in the assembled process, the incorporation of Gd affords the potential MRI and fluorescence imaging capability of Gd@BSA-Ce6 nanoparticles. In vivo MRI allowed real-time imaging in tumor-bearing mice and showed advantages in terms of circulation time, compared with commercially used Gd–DTPA. Gd@BSA-Ce6 nanoparticles exhibited enhanced tumor-specific distribution, through enhanced permeability and retention effect, and complete cure of tumor-bearing mice after intravenous injection. The nanoparticles did not produce systemic toxicity as revealed by biodistribution and histology toxicity analyses. The results demonstrate the great potential of Gd@BSA-Ce6 nanoparticles as theranostic agents due to their excellent imaging and tumor-growth-inhibition properties.
Co-reporter:Xiaojun Cai, Yongyong Li, Dong Yue, Qiangying Yi, Shuo Li, Donglu Shi and Zhongwu Gu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 8) pp:NaN1517-1517
Publication Date(Web):2014/11/03
DOI:10.1039/C4TB01724B
Gene carriers made from polylysine are of interest in relation to gene therapy but suffer from the lack of transfection efficiency due to limited stability and endosomal escape ability. To address this problem, we designed and developed Schiff-base linked imidazole modified polylysine with a reversible-PEGylation catiomer (SL-ImPEG-SS-PLL) for high efficiency gene delivery. The reversible PEGylation was introduced for in vivo circulation, as well as selective PEG detachment to augment the cellular internalization, while introducing Schiff-base linked imidazole residues into polylysine was expected to accelerate the endosomal escape of the DNA payload, as well as facilitate intracellular DNA unpacking and release, thus significantly enhancing gene delivery efficiency. The size alteration of the SL-I15mPEG-SS-PLL/pDNA polyplexes in the presence of 10 mM GSH suggests stimulus-induced PEG detachment under tumor relevant reduction conditions. Acid–base titration assays indicate that imidazole residues confer on polylysine remarkable buffering ability. The agarose gel retardation assay suggests that the Schiff-base linkages provide an increased DNA binding ability to protect DNA against nucleases and timely intracellular DNA unpacking to permit DNA dissociation from polylysine and access to transcriptional machinery. Biological efficacy assessment of this multifunctional carrier, using pEGFP and pGL-3 as reporter genes, indicates comparable to or even higher transfection efficiencies than gold standard PEI and their transfection efficiencies are slightly affected by serum. More importantly, in vivo transfection of pEGFP reveals that GFP expression was found not only in some of the important organs, such as the liver, spleen, kidneys and lungs, but also in the transplanted carcinoma. These experimental results suggest that the reversible PEGylation and Schiff-base linked imidazole modification make SL-ImPEG-SS-PLL a great potential candidate for an effective and biocompatible gene delivery system.
Co-reporter:Xue-Quan Li, Hui-Yun Wen, Hai-Qing Dong, Wei-Ming Xue, Giovanni M. Pauletti, Xiao-Jun Cai, Wen-Juan Xia, Donglu Shi and Yong-Yong Li
Chemical Communications 2011 - vol. 47(Issue 30) pp:NaN8649-8649
Publication Date(Web):2011/07/01
DOI:10.1039/C1CC12495A
A novel amphiphilic camptothecin prodrug that spontaneously arranges into nanomicelles which preferentially release the cytotoxic drug under tumor-relevant reductive conditions is designed.
Co-reporter:Hui-Yun Wen, Hai-Qing Dong, Wen-juan Xie, Yong-Yong Li, Kang Wang, Giovanni M. Pauletti and Dong-Lu Shi
Chemical Communications 2011 - vol. 47(Issue 12) pp:NaN3552-3552
Publication Date(Web):2011/02/16
DOI:10.1039/C0CC04983B
The synthesis and biological efficacy of novel nanomicelles that rapidly disassemble and release their encapsulated payload intracellularly under tumor-relevant glutathione (GSH) levels are reported. The unique design includes a PEG-sheddable shell and poly(ε-benzyloxycarbonyl-L-lysine) core with a redox-sensitive disulfide linkage.
Co-reporter:Xiaojun Cai, Yongyong Li, Dong Yue, Qiangying Yi, Shuo Li, Donglu Shi and Zhongwei Gu
Journal of Materials Chemistry A 2017 - vol. 5(Issue 1) pp:NaN181-181
Publication Date(Web):2016/12/08
DOI:10.1039/C6TB90173E
Correction for ‘Reversible PEGylation and Schiff-base linked imidazole modification of polylysine for high-performance gene delivery’ by Xiaojun Cai et al., J. Mater. Chem. B, 2015, 3, 1507–1517.
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