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Volume 32, Issue 3,
, Pages 879-889
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A group of amphiphilic cationic polymers, methoxy polyethylene glycol-block-(polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) (PECD), were synthesized by combining ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) methods to form nanoparticles (NPs). The structures of these amphiphilic cationic polymers were characterized by 1H NMR measurement. The PECD NPs have hydrophobic cores covered with hydrophilic PEG and cationic PDMAEMA chains. These self-assembly nanoparticles were characterized by dynamic light scattering (DLS) technique. PECD NPs can effectively condense DNA to form compact complexes of the size 65–160nm suitable for gene delivery. The in vitro gene transfection studies of HeLa and HepG2 cells show that PECD NPs have better transfection efficiency compared to polyethylenimine (PEI) and Lipofectamine 2000 at low dose (N/P=5). The cytotoxicity result shows that PECD NPs/DNA complexes at the optimal N/P ratio for transfection have comparable toxicity with PEI and Lipofectamine. These results indicate that PECD NPs have a great potential to be used as efficient polymeric carriers for gene transfection.
Gene therapy has great potentials to treat various genetic diseases. A key hurdle to the clinical applications of gene therapy is lack of safe and effective delivery carriers. Synthetic non-viral delivery carriers, which are safer to use and easier to produce compared to engineered viruses, have increasingly drawn great interests. Cationic polymers are the major types of the non-viral carriers for gene therapy investigated in the past decade. A large number of polycations have been reported to be capable of affecting gene transfection, including branched or linear polyethylenimine (PEI) and its derivatives , , , poly (l-lysine) (PLL) , polyamidoamine(PAMAM) , , Poly (β-amino ester)s (PAEs) , , , ,  and poly(2-(N,N-dimethylamino)ethyl methacrylate) (PDMAEMA) , ,  etc. These cationic polymers demonstrated attractive features, however, the delivery efficiency still needs to be improved for more effective gene therapy.
Recently, construction of several amphiphilic cationic polymers has been reported , , , , , , , , . Incorporation of hydrophobic components into the cationic polymer backbone is utilized to mimic cationic lipids, which is one of the best transfection reagents and has been used in vivo to treat liver disease as an example. The gene transfection efficiency can be greatly enhanced by hydrophobic modification, which improves cellular uptake through hydrophobic interactions with the cell membranes, and increases endosomal escape of payloads , , . These amphiphilic cationic polymers present advantages over lipids, such as capability of versatile modification and without adverse inflammatory responses in vivo . In addition, amphiphilic cationic polymers can also be used to carry hydrophobic anti-cancer drugs. It presents great potential to employ amphiphilic cationic polymers as gene delivery vehicles for cancer treatment in clinic.
Our previous research has shown that PEGylation of PDMAEMA can reduce the cytotoxicity comparing to non-PEGylated homo-polymer PDMAEMA . PEGylated PDMAEMA for DNA vaccine could improve the priming effect and thereby increases the immunogenicity of intranasal administered DNA vaccine. However, this modification strategy has also shown reduction of gene transfection efficiency in vitro . In this study, we have redesigned an amphiphilic cationic polymer, PECD, to enhance gene transfection efficiency. The PECD was prepared by ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) methods. DNA condensation ability and physiochemical properties of PECD NPs/DNA complexes, including size and zeta potential, were characterized. In vitro gene transfection efficiency and cytotoxicity were evaluated in HeLa, HepG2 and DRG cells. The endosome escape ability and intracellular distribution of PECD NPs/DNA were measured and compared to other known transfection complexes.
γ-(2-Bromo-2-methylpropionate)-ɛ-caprolactone (BMPCL) was synthesized as reported previously , , . ɛ-Caprolactone (Aldrich) was dried over calcium hydride for 48h at room temperature and distilled under reduced pressure. Methoxyl poly (ethylene glycol) (Aldrich, Mn=2000) was dried under vacuum for 24h at 40°C. Stannous octanoate, and N,N-dimethylaminoethyl methacrylate (DMAEMA), copper(I) bromide and 2,2′-bipyridine were purchased from Aldrich and used as received.
Synthesis of PECD
PECD was synthesized by combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP) technique (shown in Scheme 1). γ-(2-Bromo-2-methylpropionate)-ɛ-caprolactone (BMPCL) is one of the monomers which can be used to synthesize degradable polyester copolymers bearing ATRP initiating group . Macroinitiator, mPEG-P(CL-co-BMPCL), was readily prepared by ring-opening polymerization of ɛ-caprolactone and BMPCL using mPEG (Mn=2000) as initiator and Sn(Oct)2 asa
A series of amphiphilic PECD were synthesized via ROP and ATRP polymerization methods. At N/P ratio of 2 and above, all PECDs NPs can effectively bind plasmid DNA to form complexes with sizes around 65–160nm and positive zeta potentials about 10–18 mv. In vitro gene transfection efficiency depends on the type of cell lines, the molecular weight of PDMAEMA grafts and N/P ratios of carriers. PECDs NPs show much better transfection efficiency than Lipofectamine 2000 and PEI in HepG2 cells and
We thank Professor Zhuan Zhou (Institute of Molecular Medicine, PekingUniversity) for providing DRG cells. This project was supported by a grant from National Key Basic Research Program ofChina (2009CB930200), National Grand Program on Key Infectious Disease Control (2008ZX10001-015-10), National Natural Science Foundation of China (No.30970784 and 30772007), Tianjin Natural Science Foundation (No. 09JCYBJC13800), NIH/NCRR/RCMI 2 G12 RR003048, Specialized Research Fund for the Doctoral Program
- P.J. Tarcha et al.
Synthesis and characterization of chemically condensed oligoethylenimine containing beta-aminopropionamide linkages for sirna delivery
- Y.H. Choi et al.
Polyethylene glycol-grafted poly-l-lysine as polymeric gene carrier
J Control Release
- Y. Qiao et al.
The use of pegylated poly [2-(n, n-dimethylamino) ethyl methacrylate] as a mucosal DNA delivery vector and the activation of innate immunity and improvement of hiv-1-specific immune responsesSee AlsoPolyelectrolyte complex nanoparticles based on chitosan and methoxy poly(ethylene glycol) methacrylate-co-poly(methylacrylic acid) for oral delivery of ibuprofenSynthesis and characterization of poly(methoxyl ethylene glycol-caprolactone-co-methacrylic acid-co-poly(ethylene glycol) methyl ether methacrylate) pH-sensitive hydrogel for delivery of dexamethasoneMircera | 75 µg/0.3 ml | Injection | Radiant Pharmaceuticals Ltd. | Indications, Pharmacology, Dosage, Side Effects and moreAmphiphilic and biodegradable methoxy polyethylene glycol-block-(polycaprolactone-graft-poly(2-(dimethylamino)ethyl methacrylate)) as an effective gene carrier
- S.R. Little et al.
Formulation and characterization of poly (beta amino ester) microparticles for genetic vaccine delivery
J Control Release
- T.M. Sun et al.
Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for sirna delivery
- X.B. Xiong et al.
Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient sirna delivery
- K. Zhang et al.
Structure-activity relationships of cationic shell-crosslinked knedel-like nanoparticles: shell composition and transfection efficiency/cytotoxicity
- K. Zhang et al.
Cationic shell-crosslinked knedel-like nanoparticles for highly efficient gene and oligonucleotide transfection of mammalian cells
- C.H. Zhu et al.
Co-delivery of sirna and paclitaxel into cancer cells by biodegradable cationic micelles based on pdmaema-pcl-pdmaema triblock copolymers
- L.Y. Qiu et al.
Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs
Polyion complex stability and gene silencing efficiency with a sirna-grafted polymer delivery system
A biodegradable poly(ester amine) based on polycaprolactone and polyethylenimine as a gene carrier
A versatile vector for gene and oligonucleotide transfer into cells in culture and in-vivo - polyethylenimine
P Natl Acad Sci USA
Novel shielded transferrin-polyethylene glycol-polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer
DNA complexing with polyamidoamine dendrimers: implications for transfection
Poly(beta-amino ester) and cationic phospholipid-based lipopolyplexes for gene delivery and transfection in human aortic endothelial and smooth muscle cells
Hydrophilic and degradable polylactones via copolymerization of ε-caprolactone and oxo-crown ether catalyzed by a bifunctional organic base
2022, Reactive and Functional Polymers
Poly(ε-caprolactone) (PCL) has been one of the most important biomaterials, but its instinct hydrophobicity and slow biodegradation limit its broad applications. Herein, copolymerization of CL and a hydrophilic macrolactone, 2-oxo-15-crown-5 ether (O15C), was achieved through ring opening polymerization catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) using benzyl alcohol as the initiator at room temperature. A series of poly(CL-co-O15C) copolymers with different O15C contents were prepared by simply tuning the feeding ratio of [CL]/[O15C]. They showed molecular weights ranging from 11.0 to 20.6kgmol−1, and polydispersity index between 1.4 and 1.6, characterized by SEC (Size Exclusion Chromatography). Analysis of 1H NMR indicated that the copolymers belong to a random copolymer structure. The introduction of O15C had a significant influence on thermal stability, hydrophilicity and degradability of the copolymers. With increasing the O15C content, the crystalline ability of PCL segment among the copolymers reduced, while the hydrophilic property was improved obviously. Through hydrolysis experiment, the poly(CL-co-O15C) with O15C content of 38mol% exhibited a much faster degradable rate than that of the copolymer with O15C content of 10mol%. Therefore, copolymerization of CL with a crown ether monomer via organic catalyst mediated ROP will be a feasible strategy for modification of polyester materials.
Amphiphilic copolymers in biomedical applications: Synthesis routes and property control
2021, Materials Science and Engineering C
Citation Excerpt :
In spite of the great results achievable with this technique, it must be noted that it isn't quite correct to define a radical polymerization process using a complex macroninitiator as a “one-pot” reaction, since such initiators require complex synthesis reactions as well. A quite common polymer to be used for the synthesis of macroinitiators for polymerization is PCL, which can be easily obtained by ring opening polymerization of ε-CL and functionalized if needed [23,45,52,67,84,85]. The second path to achieve controlled architecture block copolymers is by chemical conjugation of polymers.
The request of new materials, matching strict requirements to be applied in precision and patient-specific medicine, is pushing for the synthesis of more and more complex block copolymers. Amphiphilic block copolymers are emerging in the biomedical field due to their great potential in terms of stimuli responsiveness, drug loading capabilities and reversible thermal gelation. Amphiphilicity guarantees self-assembly and thermoreversibility, while grafting polymers offers the possibility of combining blocks with various properties in one single material. These features make amphiphilic block copolymers excellent candidates for fine tuning drug delivery, gene therapy and for designing injectable hydrogels for tissue engineering. This manuscript revises the main techniques developed in the last decade for the synthesis of amphiphilic block copolymers for biomedical application. Strategies for fine tuning the properties of these novel materials during synthesis are discussed. A deep knowledge of the synthesis techniques and their effect on the performance and the biocompatibility of these polymers is the first step to move them from the lab to the bench. Current results predict a bright future for these materials in paving the way towards a smarter, less invasive, while more effective, medicine.
Cationic cross-linked polymers containing labile disulfide and boronic ester linkages for effective triple responsive DNA release
2020, Colloids and Surfaces B: Biointerfaces
Disruption of DNA carriers triggered by intracellular bio-stimulants has been broadly considered as most convenient strategy for efficient DNA delivery. In this direction, we have designed and synthesized pH, redox and ATP responsive cationic cross-linked polymers (CLPs) having disulfide and reversible boronic ester linkages. These CLPs also contain folate groups that are known for their targeting capability towards cancer cells. Biophysical studies showed that these cationic CLPs exhibited more effective DNA condensation in comparison to cationic linear polymers resulting in the formation of nano-sized polyplexes with sufficient positive zeta potentials and good colloidal stability at neutral pH (∼7.4). More interestingly, the polyplexes prepared from these CLPs have the ability to selectively release complexed DNA under conditions similar to those prevalent in cancer cells such as acidic pH, ATP rich surroundings or presence of glutathione, as revealed by ethidium bromide exclusion assay, agarose gel electrophoresis, AFM measurements, etc. Therefore, these cross-linked polymers have high potential of being effective non-viral gene delivery vehicles.
Current status of ATRP-based materials for gene therapy
2020, Reactive and Functional Polymers
Citation Excerpt :
Aiming to face these challenges one of the strategies for improve the polycations performance is to design vectors with varied architectures. Block copolymers, grafted copolymers, hyperbranched, star-shaped polymers, and mult-knot polymers can be produced through ATRP and have shown good results [5,17,65]. Mathew et al.  used traditional ATRP followed by DE-ATRP to produce a hyperbranched polymeric system with a linear pDMAEMA block and hyperbranches of polyethylene glycol methyl ether methacrylate (PEGMEMA) and ethylene dimethacrylate (EGDMA).
Gene therapy is an auspicious alternative to treat diseases. However, the design of efficient vectors remains as a challenge due to the innumerous intracellular and extracellular barriers that should be faced during the gene delivery process. Among some types of carries, polymeric gene vectors have gained increasingly attention. Aiming to improve the polymeric vectors' performance, several strategies have been applied such as diversification of the monomers, synthesis routes, polymers architecture, addition of specific targeting units, shielding domains, and inorganic nanoparticles. Besides, the use of controlled polymerization in the synthesis of these carries have led to improvements, especially ATRP, a very robust and versatile technique. Therefore, the aims of this review are summarizing the recent advances in gene vectors produced through ATRP; propose a division according to the main gene carries characteristics and strategies used to improve their performance; and also provide a critical analysis of the current and future perspectives on the use of ATRP in the synthesis of gene vectors.
Polymeric siRNA gene delivery – transfection efficiency versus cytotoxicity
2019, Journal of Controlled Release
Within the field of gene therapy, there is a considerable need for the development of non-viral vectors that are able to compete with the efficiency obtained by viral vectors, while maintaining a good toxicity profile and not inducing an immune response within the body. While there have been many reports of possible polymeric delivery systems, few of these systems have been successful in the clinical setting due to toxicity, systemic instability or gene regulation inefficiency, predominantly due to poor endosomal escape and cytoplasmic release. The objective of this review is to provide an overview of previously published polymeric non-coding RNA and, to a lesser degree, oligo-DNA delivery systems with emphasis on their positive and negative attributes, in order to provide insight in the numerous hurdles that still limit the success of gene therapy.
Starch-based dual amphiphilic graft copolymer as a new pH-sensitive maltidrug co-delivery system
2018, International Journal of Biological Macromolecules
Amphiphilic dual graft copolymer composed of starch (St) as main chain, poly caprolactone (PCL) and poly (2-ethyl 2-oxazoline) (POX) as hydrophobic and hydrophilic side chains were synthesized and characterized successfully. Firstly, polycaprolactone with propargyl end group prepared and attached to the surface of azido starch (St-N3) which was prepared through incomplete azidation of starch tosylate, by click chemistry reaction. Thereafter, the polymerization of 2-ethyl-2-oxazoline initiated from the remaining tosyl groups of PCL-starch. Finally, polymerization of POX quenched by doxorubicin (DOX) as anticancer drug as well as terminator and curcumin (Cur) physically loaded in to the obtained copolymer. Dual graft copolymer (PCL-St-POX) as the co-delivery system containing covalently conjugated doxorubicin and non-covalently loaded curcumin could be promising biocompatible system to achieve combination therapy. The SEM images showed that resulting copolymer exhibited sphere-shaped particles ranging from 50 to 100 nm which is completely different from ungrafted starch. The release studies also revealed that obtained copolymer is pH-sensitive and the release rate was more favorable at acidic pH (tumor cells) than neutral pH (normal cells) for both drugs.
Radiation grafting of N-vinylcaprolactam onto nano and macrogels of chitosan: Synthesis and characterization
Carbohydrate Polymers, Volume 155, 2017, pp. 303-312
The aim of this study was to synthesize chitosan hydrogels, in macro- and nano-size, grafted with N-vinylcaprolactam (NVCL) using gamma radiation, and evaluate their potential application as a drug delivery system, using 5-fluorouracil (5-FU) as a model drug. The effect of dose and monomer concentration in the grafting process was studied, and the materials were characterized by FTIR, TGA, DLS, SEM and AFM. Higher grafting percentages were observed for the nanogels system. Although both the grafted macro- and nanogels, (net-CS)-g-NVCL, showed a response to pH (4.75) and temperature (31–33°C), the nanogels showed a better swelling response to both stimuli because of their higher surface area. Both systems were able to load 5-FU in small amounts (2–3.5mgg−1) and the release was sustained for more than 12h, showing that the modified macro and nanogels can be a potential alternative for the administration of drugs.
Percutaneous Endoscopic Cervical Discectomy (PECD): An Analysis of Outcome, Causes of Reoperation
World Neurosurgery, Volume 102, 2017, pp. 583-592
Percutaneous endoscopic cervical discectomy (PECD) is regarded as an effective treatment modality in cervical disc herniation, including radicular pain and lateral location of disc herniation. This study aimed to evaluate the clinical and radiologic outcomes of PECD along with the causes of reoperation and the technique itself.
Between January 2007 and November 2012, 101 patients underwent PECD at the Busan Wooridul Hospital. Three patients underwent a 2-level PECD. The mean follow-up period was 34 months (range, 18–72 months). The mean age was 46.1 years; the most common operation was at the C5–C6 level (n= 45), followed by C6–C7 (n=35), C4–C5 (n= 16), and C3–C4 (n= 8). The clinical outcomes were evaluated via the visual analog scale of the neck and arm according to the Neck Disability Index and the modified Macnab criteria. Among 101 patients, 12 underwent an additional operation at the index level. Five patients had aggravated stenosis by disc height narrowing, 4 had recurred disc, 2 had remained disc, and 1 had sustained symptoms.
After PECD, there was a significant improvement in the visual analog scale and Neck Disability Index scores (P < 0.001). According to the modified Macnab criteria, excellent concordance was achieved in 65 patients, good in 22, fair in 2, and poor in 12. The reoperation performed on 12 patients improved their clinical outcomes. The mean duration was 4.8 months (2 days to 18 months) until reoperation. There were 3 PECD revisions, 3 artificial disc replacements, 2 corpectomies, 2 anterior cervical discectomies and fusion with cages, and 2 transfers to another hospital. The common feature was older age (P=0.016) and male sex (P= 0.031). Preoperative radiologic findings were characterized by the foraminal disc (P= 0.04), disc degeneration at the index level (P=0.05), combined bony spur (P= 0.001), concomitant adjacent level degeneration (P= 0.019), cervical kyphosis (P= 0.015), and segmental angle deterioration after PECD (P= 0.038). No statistical correlation was seen between the operation level and herniation size (P > 0.05).
In total, 87% patients showed successful clinical outcome. Poor and fair outcomes at initial PECD were overcome by revision surgery, which improved outcomes. Although PECD is a promising minimally invasive procedure for cervical disc treatment, the indications for PECD should be considered carefully.
Synthesis and characterization of N-vinylcaprolactam/N,N-dimethylacrylamide grafted onto chitosan networks by gamma radiation
Radiation Physics and Chemistry, Volume 119, 2016, pp. 228-235
N-vinylcaprolactam (NVCL) and N,N-dimethylacrylamide (DMAAm) were grafted onto crosslinked chitosan by gamma radiation, using direct and indirect (pre-irradiation oxidative) methods. The binary graft systems were synthesized in one and two steps to evaluate the influences of architecture on the properties of the polymeric material. Maximum grafting percentages were obtained by the direct method. The different systems obtained were characterized by FTIR and TGA. The equilibrium swelling time of the (net-CS)-g-NVCL/DMAAm and [(net-CS)-g-NVCL]-g-DMAAm systems was 75 and 25min, respectively, while crosslinked CS required about 24h. Thermal and pH sensitivity were conserved in all systems; the pH response in [(net-CS)-g-NVCL]-g-DMAAm (LCST: 37°, pH: 5.2) is more defined than (net-CS)-g-NVCL/DMAAm (LCST: 37°C, pH: 3.8). Grafting radiation showed to be an effective technique to modify CS hydrogels.
Posterior Percutaneous Endoscopic Cervical Diskectomy: A Single-Center Experience of 252 Cases
World Neurosurgery, Volume 120, 2018, pp. e63-e67
Posterior percutaneous endoscopic cervical foraminotomy and diskectomy has remarkably evolved with successful results. Although percutaneous endoscopic cervical diskectomy (PECD) has gained popularity, the risk of surgical failure may be a major obstacle to performing PECD. We analyzed unsuccessful cases requiring reoperation. The objective of this article was to find common causes of surgical failure and elucidate the limitations of the conventional PECD technique.
Surgery-related complications were reviewed from the initial 252 cases of a single surgeon. The patients had cervical disk herniation or radiculopathy and underwent percutaneous endoscopic surgical management. We investigated clinical outcomes and complications. A retrospective review was performed on all patients who had undergone PECD between April 2013 and April 2016. Unsuccessful PECD was defined as a case requiring reoperation within 6 weeks after primary surgery. Chart review was done, and pre-, intra-, and postoperative radiographic reviews were performed. All unsuccessful PECD cases were classified according to the type of herniated disc, location of herniation, extruded disk migration, working channel position, and intra- and postoperative findings.
The mean operative time was 89.4 minutes (range, 60–180 minutes). The mean intraoperative blood loss was 20.3 mL (range, 10–800 mL). Cerebrospinal fluid leakage occurred in 1 patient and healed well. The follow-up period ranged from 24 to 60 months. The mean score on the visual analog scale improved from 8.67 ± 1.30 preoperatively to 7.83 ± 1.40 at 1 month postoperatively to 1.67±1.30 at the final follow-up (P < 0.05), with a recovery rate of 67.9% ± 21.2%.
Surgeons should be aware of the specific complications for the PECD approach.
Synthesis of polyunsaturated fatty acid-containing glucuronosyl-diacylglycerol through direct glycosylation
Tetrahedron Letters, Volume 58, Issue 30, 2017, pp. 2915-2918
We describe a total synthesis of a polyunsaturated fatty acid (PUFA)-containing glucuronosyldiacylglycerol (GlcADG), which is a surrogate glycolipid whose synthesis is remarkably upregulated in plant membranes under phosphorus-depleted conditions. Glycosylation between the glucuronide donor bearing 3,4-dimethoxybenzyl (DMPM) protecting groups and di-acylglycerol acceptor proceeded smoothly in the presence of gold(I) catalyst to provide the protected α-isomer of GlcADG as the major product.
Post-grafting and characterization of mesoporous silica MCM-41 with a thermoresponsive polymer TEVS/NIPAAm/β-cyclodextrin
Materials Letters, Volume 196, 2017, pp. 26-29
Mesoporous silica MCM-41 was grafted with a thermoresponsive terpolymer composed of triethoxyvinylsilane, N-isopropylacrylamide, and β-cyclodextrin (TEVS/NIPAAm/βCD). The terpolymer was grafted to the surface of MCM-41 (MCM-T) by coupling TEVS via silane chemistry. Grafting was a function of the NIPAAm/βCD molar ratio. MCM-T samples showed sensitivity to temperature (lower critical solution temperature, LCST) close to that of NIPAAm. The new material was capable of easily adsorbing ibuprofen and released it above its LCST.
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