In Vitro Cytotoxicity and Cytokine Production by Lipid-Substituted Low Molecular Weight Branched PEIs Used for Gene Delivery

Sundaram, Daniel Nisakar Meenakshi; Plianwong, Samarwadee; Kc, Remant Bahadur; Ostergaard, Hanne L.; Uludağ, Hasan

doi:10.1016/j.actbio.2022.06.030

Cited by 10 publications

(12 citation statements)

References 83 publications

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“…RBCs were separated from the whole human blood (obtained from Canadian Blood Services, under an approved protocol) as per the Ficoll-Paque protocol . In brief, whole human blood was diluted with equal volumes of HBSS.…”

Section: Methodsmentioning

confidence: 99%

“…The PEI and PEI-derived polymers (>20 kDa) in a high-molecular-weight form display multivalent binding to nucleic acids that lead to stable nanoparticles that can withstand membrane penetration. , However, they also display significant toxicity on sensitive human cells, although PEI cytotoxicity has been successfully reduced by modifying it with peptides, vitamins, amino acids, etc. − The low-molecular-weight PEI (<2 kDa) is relatively nontoxic due to weaker cell membrane interactions but also unable to act as a carrier. Our studies have shown that lipid modifications on low-molecular-weight PEI can convert the noneffective small-molecular-weight PEI into an effective carrier for a range of nucleic acids due to the increased uptake of resultant nanoparticles, so that it can be safely used to deliver siRNA, pDNA, and mRNA in vitro . ,− However, the in vivo delivery efficiency of the modified PEIs for nucleic acids remained to be explored.…”

Section: Introductionmentioning

confidence: 99%

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Biodistribution of Therapeutic Small Interfering RNAs Delivered with Lipid-Substituted Polyethylenimine-Based Delivery Systems

Morales,

Rajendran,

Ansari

et al. 2024

Mol. Pharmaceutics

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Small interfering RNAs (siRNAs) have emerged as a powerful tool to manipulate gene expression in vitro. However, their potential therapeutic application encounters significant challenges, such as degradation in vivo, limited cellular uptake, and restricted biodistribution, among others. This study evaluates the siRNA delivery efficiency of three different lipid-substituted polyethylenimine (PEI)-based carriers, named Leu-Fect A−C, to different organs in vivo, including xenograft tumors, when injected into the bloodstream of mice. The siRNA analysis was undertaken by stem-loop RT-PCR, followed by qPCR or digital droplet PCR. Formulating siRNAs with a Leu-Fect series of carriers generated nanoparticles that effectively delivered the siRNAs into K652 and MV4−11 cells, both models of leukemia. The Leu-Fect carriers were able to successfully deliver BCR-Abl and FLT3 siRNAs into leukemia xenograft tumors in mice. All three carriers demonstrated significantly enhanced siRNA delivery into organs other than the liver, including the xenograft tumors. Preferential biodistribution of siRNAs was observed in the lungs and spleen. Among the delivery systems, Leu-Fect A exhibited the highest biodistribution into organs. In conclusion, lipid-substituted PEI-based delivery systems offer improvements in addressing pharmacokinetic challenges associated with siRNA-based therapies, thus opening avenues for their potential translation into clinical practice.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biodistribution of Therapeutic Small Interfering RNAs Delivered with Lipid-Substituted Polyethylenimine-Based Delivery Systems

Morales,

Rajendran,

Ansari

et al. 2024

Mol. Pharmaceutics

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“…RBCs were separated from the whole human blood (obtained from Canadian Blood Services, under an approved protocol) as per the Ficoll–Paque protocol . In brief, the whole human blood was diluted with equal volume of HBSS.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…RBCs were separated from the whole human blood (obtained from Canadian Blood Services, under an approved protocol) as per the Ficoll−Paque protocol. 35 In brief, the whole human blood was diluted with equal volume of HBSS. 20 mL of diluted blood was carefully layered over 15 mL of Ficoll−Paque plus and centrifuged 40 min at 400 g. The bottom RBCs were collected and washed with HBSS.…”

Section: Preparation and Characterization Of Polyplexesmentioning

confidence: 99%

Tuning the Potency of Farnesol-Modified Polyethylenimine with Polyanionic Trans-Booster to Enhance DNA Delivery

Rajendran,

Morales,

Meenakshi Sundaram

et al. 2024

ACS Biomater. Sci. Eng.

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Low molecular weight polyethylenimine (PEI) based lipopolymers become an attractive strategy to construct nonviral therapeutic carriers with promising transfection efficiency and minimal toxicity. Herein, this paper presents the design and synthesis of novel farnesol (Far) conjugated PEI, namely PEI1.2k-SA-Far7. The polymers had quick DNA complexation, effective DNA unpacking (dissociation), and cellular uptake abilities when complexed with plasmid DNA. However, they were unable to provide robust transfection in culture, indicating inability of Far grafting to improve the transfection efficacy significantly. To overcome this limitation, the commercially available polyanionic Trans-Booster additive, which is capable of displaying electrostatic interaction with PEI1.2k-SA-Far7, has been used to enhance the uptake of pDNA polyplexes and transgene expression. pDNA condensation was successfully achieved in the presence of the Trans-Booster with more stable polyplexes, and in vitro transfection efficacy of the polyplexes was improved to be comparable to that obtained with an established reference reagent. The PEI1.2k-SA-Far7/pDNA/Trans-Booster ternary complex exhibited good compatibility with cells and minimal hemolysis activity. This work demonstrates the exemplary potency of using additives in polyplexes and the potential of resultant ternary complexes for effective pDNA delivery.

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“…However, there was a positive correlation between high transfection efficiency and high toxicity. To tackle the internalization problem of functional nucleic acids, several modification strategies have been proposed [ [21] , [22] , [23] , [24] ]. Anionic polyacrylic acid (PAA) was electrostatically and covalently linked with PEI, which exhibited considerably higher pDNA transfection efficacy than the standard reagent lipofectamine [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Triton modified polyethyleneimine conjugates assembled with growth arrest-specific protein 6 for androgenetic alopecia transdermal gene therapy

Fan¹,

Zhao²,

Xu³

et al. 2023

Materials Today Bio

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In Vitro Cytotoxicity and Cytokine Production by Lipid-Substituted Low Molecular Weight Branched PEIs Used for Gene Delivery

Cited by 10 publications

References 83 publications

Biodistribution of Therapeutic Small Interfering RNAs Delivered with Lipid-Substituted Polyethylenimine-Based Delivery Systems

Biodistribution of Therapeutic Small Interfering RNAs Delivered with Lipid-Substituted Polyethylenimine-Based Delivery Systems

Tuning the Potency of Farnesol-Modified Polyethylenimine with Polyanionic Trans-Booster to Enhance DNA Delivery

Triton modified polyethyleneimine conjugates assembled with growth arrest-specific protein 6 for androgenetic alopecia transdermal gene therapy

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