Poly(I:C)-Mediated Tumor Growth Suppression in EGF-Receptor Overexpressing Tumors Using EGF-Polyethylene Glycol-Linear Polyethylenimine as Carrier

Schaffert, David; Kiss, Melinda; Rödl, Wolfgang; Shir, Alexei; Levitzki, Alexander; Ogris, Manfred; Wagner, Ernst

doi:10.1007/s11095-010-0225-4

Cited by 79 publications

(89 citation statements)

References 54 publications

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“…Higher molecular weight PEG (M n 5 kDa) strongly reduced transfection activity of EGF-PEG-PEI polyplexes. 34,36 Therefore, we used PDP-PEG-NHS (M n 2 kDa) to prepare the EGF-PEG-PAMAM-PEHA conjugate. The chemical structures of the intermediate products, such as PDP-PEG-azide and PDP-PEG-PAMAM-PEHA were characterized by 1 H NMR spectra examination (see Figures SI 5 and SI 6).…”

Section: ' Materials and Methodsmentioning

confidence: 99%

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Nie

Dohmen

et al. 2011

Biomacromolecules

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Up to date, cationic lipids or polycations are widely investigated nonviral gene vectors. 1À4 They form lipoplexes or polyplexes with negatively charged plasmid DNA (pDNA), antisense oligonucleotides (AONs), double stranded RNA (dsRNA) or small interfering RNA (siRNA). 5À8 PAMAM dendrimers are special among the polycationic gene vectors. 9À12 The primary amino groups on PAMAM dendrimer chain termini bind and compress pDNA into polyplexes. The tertiary amino groups in PAMAM dendrimer core supply PAMAM dendrimers with "proton sponge" capacity, which facilitate the endosome escape of PAMAM polyplexes. 13À19 PAMAM dendrimers in higher generations cause more cytotoxicity than the low-generation ones, while the former produce higher transfection yields. 20,21 To exploit the full potential of PAMAM dendrimer as gene carriers, it is crucial to develop novel PAMAM dendrimers with high gene transfer ability but low cytotoxicity. In our recent studies, oligoamines with different nitrogen densities were applied for oligoethylenimine (OEI) or poly(propylene imine) (PPI) dendrimer modification, a positive correlation between oligoamine chain length and transfection efficiency was found. This was attributed to the increased proton sponge effects of oligo (ethylene amines) with higher chain lengths. 38,45 For gene delivery in vivo, the polyplexes are usually destabilized by serum protein absorption induced aggregation and physiological salt-triggered dissociation. 22 PEG modification minimizes these disadvantages and elongates the circulation retention time of polyplexes. 23,24 On the other hand, PEG shielding suppresses transfection efficiency by reducing intracellular uptake and endosome escape of polyplexes. 25,26 Targeting ligands such as serum protein transferrin, antibodies, or growth factors have been incorporated into polyplexes to obtain higher targeted cell specificity and recovery the depressed transfection efficacy by PEG shielding. 27À29 The epidermal growth factor receptor (EGFR) is highly expressed in a wide variety of human tumors, such as lung, breast and hepatocellular cancers. 30 The binding of EGF to EGFR triggers the fast internalization of EGF conjugated polyplexes. 31 Our previous studies demonstrated that the EGF-PEG conjugated polyethylenimine (EGF-PEG-PEI) polyplexes delivered pDNA or dsRNA into targeted cells or tumor xenograft much more efficiently than EGF free ones. 32À36 With the knowledge from oligoamine-modified OEI/PPI vectors and EGF conjugated PEI polyplexes, we hypothesized that the transfection efficiency of low generation PAMAM dendrimers can be enhanced by introducing oligoamines and EGF moiety into their chain termini. In the present communication, we describe the synthesis of an EGF-PEG functionalized PAMAM linearÀdendritic architectural copolymer. The PEG-PAMAM ABSTRACT: Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined mul...

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Section: ' Materials and Methodsmentioning

confidence: 99%

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Nie

Dohmen

et al. 2011

Biomacromolecules

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“…[61][62][63][64][65] The EGF-R, which is upregulated in tumors including epithelial tumors, glioblastoma, and hepatocellular carcinoma, is another widely investigated target of immunoliposomes. 66,67) Incorporation of EGF into PEGylated nanoparticles was also demonstrated for targeting to the EGF-R. [68][69][70] other molecules overexpressed on tumors such as nucleosome, cd19, membrane type 1 matrix metalloproteinase (MT1-MMP), GAH, Gd2, and heparinbinding EGF-like growth factor were targeted by immunoliposomes. [71][72][73][74][75][76][77] Aptamers are single-stranded dNA or RNA, can specifically bind molecules, and are beginning to be used as targeting ligands for drug delivery systems.…”

Section: -28)mentioning

confidence: 99%

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Hatakeyama

Akita

Harashima

2013

Biological & Pharmaceutical Bulletin

415

276

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Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.

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“…PEIs are available as linear or branched polymers. Linear PEI (LPEI) is prepared by hydrolysis of propionamides from poly(2-ethyl-2-oxazoline) [4]. Branched PEIs (BPEIs) are obtained by a polymerization reaction of aziridine [19], which results in a highly branched polyamine network capable of nucleic acid complexation.…”

Section: Protecting the Payload: Polymeric Backbonesmentioning

confidence: 99%

“…Moreover, synthetic long dsRNA that mimicks the viral RNA intermediates present in cells bearing infections can act as immunostimulatory, antiproliferative and pro-apoptotic agents. Examples include poly-inosine-cytosine dsRNA, poly(I:C), a dsRNA analog composed of mismatched poly(inosine) and poly(cytosine) strands, that in combination with epidermal growth factor (EGF) receptor-targeted carriers show a promising approach for cancer treatment [3][4][5], and small conditional RNAs which form long dsRNA only in target cancer cells and in this way selectively mediate cell death [6].…”

Section: Introductionmentioning

confidence: 99%

Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers

Lächelt

Wagner

2011

Front. Chem. Sci. Eng.

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Polymer-based conjugates are an interesting option and challenge for the design of nano-sized drugdelivery systems, as they require advanced conjugation chemistry and precise engineering. In the case of nucleic acid therapy, non-viral carriers face several biological barriers during the delivery process, namely 1) protection of the cargo from extracellular degradation, 2) avoidance of non-specific interactions with non-targeted tissues, 3) efficient entry into the target cells, 4) intracellular trafficking to the site of action and 5) cargo release. To take on these obstacles, multifunctional conjugates can act as "smart polymers" with microenvironment-sensing dynamics to facilitate the separate delivery steps. Synthesis of defined polymer architectures with precise functionalization enables structure-activity relationships to be investigated and the integration of key functions for efficient delivery. Thus bioresponsive polymer conjugates, which are equipped with molecular devices responding to the certain microenvironments within the delivery pathway (e. g. pH, redox potential, enzymes) can be assembled. This review focuses on the modular engineering and conjugation of multifunctional polymeric structures for the utilization as "tailor-made" nucleic acid carriers.

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Poly(I:C)-Mediated Tumor Growth Suppression in EGF-Receptor Overexpressing Tumors Using EGF-Polyethylene Glycol-Linear Polyethylenimine as Carrier

Abstract: The optimized LPEI-PEG2 kDa-EGF conjugate displays reduced chemical complexity and efficient poly(I:C)-mediated killing of EGFR overexpressing tumors in vitro and in vivo.

Cited by 79 publications

References 54 publications

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Invading target cells: multifunctional polymer conjugates as therapeutic nucleic acid carriers

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