Monoclonal antibody–polyethyleneimine conjugates targeting Her-2/neu or CD90 allow cell type-specific nonviral gene delivery

Strehblow, Claudia; Schuster, Maj; Möritz, Thomas; Kirch, Hans-Christoph; Opalka, Bertram; Petri, Jean Bernhard

doi:10.1016/j.jconrel.2004.10.033

Cited by 32 publications

(22 citation statements)

References 15 publications

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“…The use of SPDP as a cross-linker has produced mixed results with PEI and Trastuzumab. Efficient binding and uptake was reported of a Trastuzumab-polyethylenimine(25 kDa)-poly-ethylene glycol conjugate cross-linked with SPDP [26], and antigen-nonspecific EGFR expression was observed with a Trastuzumab-PEI (25 kDa) conjugate [27]. The authors tried cross-linking a PEI with a maleimide group to a monovalent antibody fragment cleaved at the disulfide bridges at the hinge of the heavy chains and resulted in antigen-specific gene delivery.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine

et al. 2015

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Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Results: Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. Conclusion: The results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine

et al. 2015

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“…A synthetic cyclic peptide, designed to target the CD4 receptor, was attached to the surface of the gold nanoparticle via an SPDP linker molecule that facilitated conjugation to the branched polyethyleneimine. 56 The design of the peptide was based on the amino acid sequence of an anti-CD4 monoclonal antibody. In previous studies, the peptide was found to bind to the CD4 receptor and furthermore inhibit cellular functions that depend on this receptor.…”

Section: Peptide Functionalizationmentioning

confidence: 99%

Synthesis, Characterization and Biocompatibility of a Multifunctional Gold Nanoparticle System for the Delivery of Single-Stranded RNA to Lymphocytes

et al. 2018

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The use of RNA macromolecules as therapeutic agents for HIV and other infectious diseases is promising but limited by suboptimal delivery to the target site. With HIV infection, this is particularly challenging since lymphocytes are particularly difficult to transfect. This paper describes an innovative strategy for the intracellular delivery of a novel single-stranded RNA (oligoribonucleotide) with putative anti-HIV activity. This strategy is based on a PEGylated gold nanoparticle scaffold covalently linked to the thiol-modified oligoribonucleotide via a cleavable N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) linker molecule. The nanoparticle was then coated with a cationic polymer (polyethyleneimine) to facilitate cell entry and endosomal escape. A synthetic anti-CD4 cyclic targeting peptide was attached to the polyethyleneimine-coated nanoparticle via an SPDP linker molecule, in an attempt to enhance uptake and selectivity. Synthesis, characterization, SPDP and RNA loading, cytotoxicity and antiviral activity of the nanoparticle are described. Approximately 45 000 strands of RNA were taken up per lymphocyte. Uptake was limited by relatively inefficient loading of RNA onto the gold nanoparticle surface (1 strand per 4.8 nm 2 of nanoparticle surface area) and significant aggregation of the nanoparticle in physiological solutions. No antiviral activity was demonstrated, possibly due to insufficient intracytoplasmic delivery of the RNA.

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“…[15] In some cases, linear PEI (22k) even showed higher transfection efficiency than branched PEI (25k) for plasmid DNA delivery. [16] To reduce the cytotoxicity of PEI concomitantly maintaining the delivery efficiency, cleavable and biodegradable PEI polymers have been synthesized. [17] Poly(b-amino ester)s are biodegradable cationic polymers with ester linkages in the backbone, which facilitates the decomplexation of polyelectrolyte complexes at low pH endosomal conditions [ Figure 1(D)].…”

Section: Cationic Polymers For Gene Deliverymentioning

confidence: 99%

“…However, direct and non-specific conjugation of polymers to the amine groups of antibodies could often damage the binding activities significantly. [16] In order to compare the binding affinities of PEI-Ab conjugates, three different PEI-Ab conjugates were prepared by different coupling procedures. [16] Monoclonal antibodies (anti-CD90 antibody, Trastuzumab) were covalently conjugated to PEI using two different heterobifunctional crosslinkers, SPDP and N-succinimidyl -4-(maleimidomethyl) cyclohexancarboxylate (SMCC), respectively.…”

Section: Antibodiesmentioning

confidence: 99%

Functional Polymers for Targeted Delivery of Nucleic Acid Drugs

Mok

Park

2009

Macromolecular Bioscience

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Cationic polymers have been chemically modified with a variety of targeting molecules such as peptides, proteins, antibodies, sugars and vitamins for targeted delivery of nucleic acid drugs to specific cells. Stimuli-sensitive polymers exhibiting different size, charge and conformation in response to physiological signals from specific cells have also been utilized for targeted delivery. To achieve target-specific delivery of nucleic acids, conjugation chemistry is critical to produce stable nanosized polyplexes tethered with cell-recognizable ligands for facile cellular uptake via a receptor-mediated endocytic pathway. In this review, synthetic strategies of functional cationic polymers with various targeting ligands are presented.

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Monoclonal antibody–polyethyleneimine conjugates targeting Her-2/neu or CD90 allow cell type-specific nonviral gene delivery

Cited by 32 publications

References 15 publications

Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine

Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine

Synthesis, Characterization and Biocompatibility of a Multifunctional Gold Nanoparticle System for the Delivery of Single-Stranded RNA to Lymphocytes

Functional Polymers for Targeted Delivery of Nucleic Acid Drugs

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