Small hydrophobe substitution on polyethylenimine for plasmid DNA delivery: Optimal substitution is critical for effective delivery

Thapa, Bindu; Plianwong, Samarwadee; Kc, Remant Bahadur; Rutherford, B. S.; Uludağ, Hasan

doi:10.1016/j.actbio.2016.01.025

Cited by 29 publications

(28 citation statements)

References 37 publications

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“…S2, Pearson correlation, p > 0.05). This was quite expected since, as already observed in similar systems [16,19], increasing hydrophobic-moiety degree of substitution initially improves transfection until the attainment of an optimum after which efficiency decreases due to the excessive reduction of the number of amines available for DNA condensation.…”

Section: Transfection Of Vsmcs By Bpei Derivativesmentioning

confidence: 62%

“…Of note, to find out the optimal chemical structures and to draw overall structure-activity relationships, different bPEI backbone MWs and degrees of substitution were tested. [17,19]; the reaction feed ratio and the resulting degree of substitution, as measured by 1 H-NMR, of the resulting polymers are reported in Table 1. As expected, the degree of substitution increased by increasing the feed ratio for every lipid, to give an average yield between 0.54 and 0.56 for all the substituents except St and LA that displayed a significantly lower average yield of 0.37 and 0.38 respectively.…”

Section: Resultsmentioning

confidence: 99%

“…In this study we investigated the efficiency of hydrophobe-substituted bPEI derivatives in the transfection of these cells. Different fatty acid-based substitutes have been investigated, namely stearic acid (St, C18 chain), linoleic acid (LA, C18:2 (6, 9) chain), and propionic acid (PrA, C3 chain), already reported to improve the transfection activity of bPEI on other cell types such as human embryonic kidney cells (293T) [17], rat bone marrow stromal cells (rBMSC) [25] and human breast cancer cells (MDA-231 and MCF-7) [19]. Besides, two new families of bPEI derivatives, carrying α-linoleic acid (αLA, C18:3 (3, 6, 9) chain) and acrylic acid (AcA, C3:1 (1) chain), were synthesised and studied, aiming to evaluate whether an increase in the level of unsaturation in the aliphatic chain of linoleoyl-and propionyl-based substitutes (i.e., an additional double bond, in position 3 and 1, respectively) could lead to a further enhancement in the transfection efficiency of bPEI derivatives on vascular cells.…”

Section: Resultsmentioning

confidence: 99%

“…Reaction mixture was then left stirring overnight (~12 h) at room temperature. Derivatives with propionic acid (PrA) and acryloyl chloride (AoCl) were prepared using EDC/NHS activation method as described in our earlier publication [19]. The crude product was precipitated 3 times in ice-cold diethylether and dried under vacuum for 2 days.…”

Section: Polymer Synthesis and Characterizationmentioning

confidence: 99%

“…These strategies mainly rely on the functionalization of cytocompatible low MW PEI with hydrophobic moieties to improve transfection efficiency, while retaining limited cytotoxicity. A number of different substitutes have been successfully grafted to PEI thus far: cholesterol [14], cholic acid, long-chain dodecyl and hexadecyl moieties [15], lipoic acid [16], saturated and unsaturated lipids of different lengths such as palmitic acid, stearic acid, oleic acid, and linoleic acid [13,17,18] and, recently, the small hydrophobic propionic acid [19].…”

Section: Introductionmentioning

confidence: 99%

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Hydrophobe-substituted bPEI derivatives: boosting transfection on primary vascular cells

et al. 2017

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Gene therapy targeted to vascular cells represents a promising approach for prevention and treatment of pathological conditions such as intimal hyperplasia, in-stent and post-angioplasty restenosis. In this context, polymeric non-viral gene delivery systems are a safe alternative to viral vectors but a further improvement in efficiency and cytocompatibility is needed to improve their clinical success. Herein, a library of 24 branched polyethylenimine (bPEI) derivatives modified with hydrophobic moieties was synthesised, characterised and tested in vitro on primary vascular cells, aiming to identify delivery agents with superior transfection efficiency and low cytotoxicity. Low molecular weight PEIs (0.6, 1.2 and 2 kDa) were grafted with long (C18) and short (C3) aliphatic chains, featuring different unsaturation degrees and degrees of substitution. 0.6 kDa bPEI-based derivatives were generally ineffective in transfection on vascular smooth muscle cells (VSMCs), while among the other derivatives some promising vectors were identified. Forcing polyplexes on the cell surface by means of centrifugation invariably boosted transfection levels but increased cytotoxicity as well. Of note, a propionyl-substituted derivative (PEI2-PrA1, C3:0) was the most effective on both VSMCs and endothelial cells (ECs), with higher and more sustained gene expression in combination with markedly lower cytotoxicity with respect to the gold standard 25 kDa bPEI. In addition, a linoleoyl-substituted derivative (PEI1.2-LA6, C18:2) owing to its high efficiency in VSMCs and relative inefficacy in ECs, combined with tolerable cytotoxicity was proposed as a vector for specific VSMCs targeting.

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Section: Transfection Of Vsmcs By Bpei Derivativesmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Polymer Synthesis and Characterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hydrophobe-substituted bPEI derivatives: boosting transfection on primary vascular cells

et al. 2017

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Novel Polymer Systems for Gene Therapy

Diaz‐Dussan

Peng

Narain

2022

Macromolecular Engineering

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Gene therapy is a novel molecularly directed gene‐editing technique that can be used in treating gene‐related diseases, and its clinical relevance relies on the design of effective therapeutic vectors that are able to deliver and release the nucleic acids to the targeted sites. The use of nanoscale vectors for gene delivery presents various advantages such as improved bioavailability, extended nucleotide half‐life, and reduced off‐target toxicity. Several types of colloidal systems have been developed, including biocompatible polymer carriers, such as nanoparticles, nanocapsules, and branched polymers. A first requisite is biocompatibility; reducing cell cytotoxicity and effective clearance from the organism is one of the major challenges, and particle size is also a key factor in the internalization process. Common cationic gene carriers are summarized here, but their associated cytotoxicity or low efficacy restricted their use at the clinical level. Numerous modifications for enhancing the vectors are introduced, which mainly involved the incorporation of biocompatible units and degradability. Furthermore, several methods in preparing nonviral carrier via controlled radical polymerization and their related postmodification techniques are summarized and discussed. Furthermore, the new generation of therapeutic nanoparticles, which combined selective targeting moieties, and imaging agents, offers a theranostic approach for enhanced gene therapy.

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Polymeric Nonviral Gene Delivery Systems for Cancer Immunotherapy

Cai

et al. 2020

Advanced Therapeutics

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Unlike viral vectors with their undesired safety or immunogenicity concerns, biocompatible polymeric nonviral vectors as gene delivery systems are more promising in gene or cell therapy. Evidence has demonstrated that the rational design of polymeric nonviral gene vectors with optimal structure, charge density, biocompatibility, and stimulus responsiveness can deliver therapeutic genes or gene vaccines (in terms of deoxyribonucleic acid DNA or ribonucleic acid RNA) into tumor‐associated immunocytes (i.e., macrophages, T cells, or dendritic cells) in an effective and controllable manner for enhanced cancer immunotherapy. However, a timely and systematic summary of this subject is lacking. This review presents an overview of polymeric nonviral carriers with immune cell transfection ability and their potential applications in cancer immunotherapy; it also provides a tutorial for designing polymeric immune‐cell genetic modification vector, although there are still few vectors in the product pipeline. With the rapid growth of immunotherapy in cancer treatment and knowledge accumulation in vector structure design, polymeric nonviral gene delivery systems may provide new hope for tumor therapy.

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Small hydrophobe substitution on polyethylenimine for plasmid DNA delivery: Optimal substitution is critical for effective delivery

Cited by 29 publications

References 37 publications

Hydrophobe-substituted bPEI derivatives: boosting transfection on primary vascular cells

Hydrophobe-substituted bPEI derivatives: boosting transfection on primary vascular cells

Novel Polymer Systems for Gene Therapy

Polymeric Nonviral Gene Delivery Systems for Cancer Immunotherapy

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