Redox-responsive catiomer based on PEG-ss-chitosan oligosaccharide-ss-polyethylenimine copolymer for effective gene delivery

Jia, Lejiao; Li, Zhenyu; Zhang, Dianrui; Zhang, Qiang; Shen, Jingyi; Guo, Hejian; Tian, Xiaona; Liu, Guangpu; Zheng, Dandan; Qi, Lisi

doi:10.1039/c2py20781h

Cited by 72 publications

(54 citation statements)

References 45 publications

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“…The molecular weight of Boc-PECL was 8800, estimated from the 1 H NMR spectrum ( Figure S2B DTPA, as a stable disulfide-containing reagent, can be conveniently transformed into DTDPA through dehydration reaction, which is effective to conjugate with hydroxyl groups of CPT. 30 Additionally, β-thioester bonds formed as the linker between DTPA and CPT are easily hydrolyzed to release the active moiety by esterase, which is abundant in cells. 31 As shown in Figure 1A, the terminal hydroxyl group of CPT was coupled with anhydride group of DTDPA by esterification using DMAP as a catalyst to produce an intermediate, CPT-ss-COOH.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Folate-Decorated and Reduction-Sensitive Micelles Assembled from Amphiphilic Polymer–Camptothecin Conjugates for Intracellular Drug Delivery

et al. 2014

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It is one of the challenges for a wide clinical application of polymer micelles to address the structure disintegration and premature drug release before reaching a pathological site. In the current study, folic acid (FA)-decorated polymer-drug conjugates (FSC) were synthesized with disulfide linkages between camptothecin (CPT) and amphiphilic poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) copolymers. FSC conjugates were proposed to assemble into micelles with a hydrophobic core of PCL segments and CPT and a hydrophilic corona of PEG segments. The addition of hexadecanol during micelle formation (FSC-16) was proposed to modulate the interactions of hydrophobic segments in micelles and enhance the reductive sensitivity. FSC-16 micelles were obtained with critical micelle concentration of around 2 μg/mL and an average size of around 200 nm, and the conjugated CPT was rapidly released out in response to glutathione. The reductive sensitivity was also demonstrated with respect to the changes of micelle size and morphologies as well as the fluorescent intensity of pyrene loaded in micelles. Benefiting from the FA receptor-mediated uptake and the reduction-sensitive release of CPT, significant cytotoxicity and cell apoptosis were identified for FSC-16 micelles against SKOV-3 cells with strong expressions of FA receptors. Flow cytometry and confocal laser scanning microscopy analyses demonstrated that CPT was distributed into nuclei after cellular uptake and intracellular release from FSC-16 micelles. Thus, the FA-decorated and reduction-sensitive micelles assembled from polymer-drug conjugates show advantages in inhibiting premature release during circulation, enhancing cellular uptake at the tumor tissues, and promoting intracellular release and nuclei location of the active moieties.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Folate-Decorated and Reduction-Sensitive Micelles Assembled from Amphiphilic Polymer–Camptothecin Conjugates for Intracellular Drug Delivery

et al. 2014

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“…25 Briefly, DTPA (5.0 g, 23.8 mmol) was dissolved in 45 mL of acetyl chloride and refluxed at 65-70°C under argon for 3-5 h. After the removal of excess acetyl chloride, the concentrated solution was poured into excess ethyl ether to precipitate DTDPA. Then, CPT (1.04 g, 2.97 mmol) and DMAP (5.71 g, 29.7 mmol) were dissolved in 80 mL of anhydrous pyridine, followed by the addition of DTDPA.…”

Section: Synthesis Of Boc-protected 4-arm-pecl-ss-cpt Copolymersmentioning

confidence: 99%

Tuning multiple arms for camptothecin and folate conjugations on star-shaped copolymers to enhance glutathione-mediated intracellular drug delivery

et al. 2015

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Micelle behaviors have been studied intensively for linear block copolymers, and amphiphilic polymers with a non-linear architecture, including star polymers, dendrimers, and hyperbranched polymers are showing advantages in the loading of anticancer drugs. In the current study, multiarmed amphiphilic copolymers with drug conjugates were developed for the construction of micelles to alleviate premature drug release during circulation and to achieve glutathione (GSH)-mediated intracellular drug delivery.Folic acid (FA) was grafted on some of the arms of 4-armed poly(ethylene glycol) (4-arm-PEG) as the targeting groups of micelles, and ε-caprolactone (ε-CL) was copolymerized with PEG from the rest of the arms, followed by camptothecin (CPT) conjugation through dithiodipropionic acid. The effect of the number of arms used for FA conjugation and the length of PCL blocks on micelle properties, reductive sensitivity, cellular uptake, and antitumor activities were evaluated. The amphiphilic copolymers with starshaped miktoarms were self-assembled into micelles with an average size of around 100 nm and critical micelle concentrations (CMCs) as low as 0.8 μg mL −1 . The distribution of hydrophobic PCL segments in more arms resulted in micelles with lower CMCs, higher structural stability, and greater sensitivity of CPT release in the presence of GSH. But, the conjugation of FA on fewer arms led to lower FA densities and less efficient cellular uptake of the micelles. In view of the performance of cellular uptake, CPT loading, and reduction-sensitive release, micelles from 4-armed copolymers with FA conjugation on two arms and PCL copolymerization on another two arms resulted in the most significant antitumor activities. It is suggested that the composition and arm structure of amphiphilic copolymers with star-shaped miktoarms show significant effects on micelle behavior, and optimal antitumor activities can be achieved through judicious selection of multiple arms for conjugating targeting groups and chemotherapeutic drugs.

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“…The PEI600/DNA complexes also exhibited no toxicity as PU-PEI600/DNA complexes. This phenomenon is attributed to the use of low molecular weight PEI [19] since a higher molecular weight polymer with dense positive charges (e.g., PEI25k) would result in a prominent cytotoxicity due to a great extent of disturbance on cell membrane.…”

Section: The Cytotoxicity and Transfection Assay Of Pu-pei600/dna Commentioning

confidence: 99%

Maleimide-Functionalized PEI600 Grafted Polyurethane: Synthesis, Nano-Complex Formation with DNA and Thiol-Conjugation of the Complexes for Dual DNA Transfection

Hung

Cherng

2015

Polymers

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Abstract:A polyurethane (PU) grafted with small molecular weight polyethylenimine (PEI 600 ) was synthesized. This PU-PEI 600 can assemble DNA via electrostatic interactions into nano-sized polymer/DNA complexes. The complexes exhibited great transfection efficiency in delivering DNA along with a reduced cell toxicity comparing to commercial PEI 25k (M w~2 5,000). In order to establish a system for concurrently delivering two different DNA or RNA molecules for cell reprogramming (e.g., induced pluripotent stem cells) or the necessity of multi-expression (e.g., double knock down), the PU-PEI 600 was further functionalized with maleimide molecules. The novel PU-PEI 600 -maleimide would still effectively interact with assigned DNA and different functions of PU-PEI 600 -maleimide/DNA complexes were self-conjugated in presence of a dithiol molecule (1,6-hexanedithiol). In this study, two reporter genes (pEGFP-C2 and pLanRFP-N) were used and evidence of green/red fluorescence co-expression in cells was observed. This article brings a new concept and a practical method for a plurality of different DNA molecules that are more efficient to be concurrently delivered and co-expressed. This method is very helpful in studying cellular multi-regulation or in the treatment of disease with multiple gene defects in vivo.

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Redox-responsive catiomer based on PEG-ss-chitosan oligosaccharide-ss-polyethylenimine copolymer for effective gene delivery

Cited by 72 publications

References 45 publications

Folate-Decorated and Reduction-Sensitive Micelles Assembled from Amphiphilic Polymer–Camptothecin Conjugates for Intracellular Drug Delivery

Folate-Decorated and Reduction-Sensitive Micelles Assembled from Amphiphilic Polymer–Camptothecin Conjugates for Intracellular Drug Delivery

Tuning multiple arms for camptothecin and folate conjugations on star-shaped copolymers to enhance glutathione-mediated intracellular drug delivery

Maleimide-Functionalized PEI600 Grafted Polyurethane: Synthesis, Nano-Complex Formation with DNA and Thiol-Conjugation of the Complexes for Dual DNA Transfection

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