Polymeric siRNA delivery targeting integrin-β1 could reduce interactions of leukemic cells with bone marrow microenvironment

Sundaram, Daniel Nisakar Meenakshi; Kucharski, Cezary; Kc, Remant Bahadur; Tarman, Ibrahim Oğuzhan; Uludağ, Hasan

doi:10.1016/j.bbiosy.2021.100021

Cited by 4 publications

(3 citation statements)

References 51 publications

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“…In the present work, PHPA and GA were used as single and triple linkers, respectively, to allow 1:1 and up to 1:3 PEI/lipid conjugations. Lauryl (12-C), oleyl (1-18-C), and linolenoyl (3-18-C) were the three lipids chosen for conjugations because of their previously successful use in gene carrier designs, including our own work . PHPA and GA reaction to lipids could be easily carried out in the presence of Et 3 N and relying on the efficient EDC/NHS coupling for conjugation between the PEI amines and carboxyl groups of PHPA/GA linkers.…”

Section: Resultsmentioning

confidence: 99%

“…Lauryl (12-C), oleyl (1-18-C), and linolenoyl (3-18-C) were the three lipids chosen for conjugations because of their previously successful use in gene carrier designs, including our own work. 29 PHPA and GA reaction to lipids could be easily carried out in the presence of Et 3 N and relying on the efficient EDC/NHS coupling for conjugation between the PEI amines and carboxyl groups of PHPA/GA linkers. For the purification of lipopolymers, precipitation/centrifugation was sufficient to remove the unreacted lipid and PEI.…”

Section: Synthesis and Initial Screeningmentioning

confidence: 99%

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Transfection Efficacy and Cellular Uptake of Lipid-Modified Polyethyleneimine Derivatives for Anionic Nanoparticles as Gene Delivery Vectors

Rajendran

Ogundana

Morales

et al. 2023

ACS Appl. Bio Mater.

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Cationic polyethylenimine (PEI)-based nonviral gene carriers have been desirable to overcome the limitations of viral vectors in gene therapy. A range of PEI derivatives were designed, synthesized, and evaluated for nonviral delivery applications of plasmid DNA (pDNA). Linolenic acid, lauric acid, and oleic acid were covalently conjugated with low-molecular-weight PEI (M w ∼ 1200 Da) via two different linkers, gallic acid (GA) and p-hydroxybenzoic acid (PHPA), that allows a differential loading of lipids per modified amine (3 vs 1, respectively). 1H NMR spectrum confirmed the expected structure of the conjugates as well as the level of lipid substitution. SYBR Green binding assay performed to investigate the 50% binding concentration (BC50) of lipophilic polymers to pDNA revealed increased BC50 with an increased level of lipid substitution. The particle analysis determined that GA- and PHPA-modified lipopolymers gave pDNA complexes with ∼300 and ∼100 nm in size, respectively. At the polymer/pDNA ratio of 5.0, the ζ-potentials of the complexes were negative (−6.55 to −10.6 mV) unlike the complexes with the native PEI (+11.2 mV). The transfection experiments indicated that the prepared lipopolymers showed higher transfection in attachment-dependent cells than in suspension cells based on the expression of the reporter green fluorescent protein (GFP) gene. When loaded with Cy3-labeled pDNA, the lipopolymers exhibited effective cellular uptake in attachment-dependent cells while the cellular uptake was limited in suspension cells. These results demonstrate the potential of lipid-conjugated PEI via GA and PHPA linkers, which are promising for the modification of anchorage-dependent cells.

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis and Initial Screeningmentioning

confidence: 99%

Transfection Efficacy and Cellular Uptake of Lipid-Modified Polyethyleneimine Derivatives for Anionic Nanoparticles as Gene Delivery Vectors

Rajendran

Ogundana

Morales

et al. 2023

ACS Appl. Bio Mater.

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“…We have previously established safe low molecular weight (LMW) PEI polymers with lipid substitutions (PEI‐L) for different indications, such as breast cancer, acute lymphoblastic leukemia, chronic myeloid leukemia, and bone regeneration (Meenakshi Sundaram et al, 2021; Thapa et al, 2019; Tsekoura et al, 2021; Valencia‐Serna et al, 2019). Given the success of these LMW PEI‐L, the aim of this report was to broaden its applicability to fulfill the unmet needs in piggyBac delivery as an alternate nonviral delivery system with the advantage of being a low molecular weight PEI and low toxicity along with high transfection efficiency.…”

Section: Introductionmentioning

confidence: 99%

An optimized polymeric delivery system for piggyBac transposition

Meenakshi Sundaram,

Bahadur K. C.,

et al. 2024

Biotech & Bioengineering

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The piggyBac transposon/transposase system has been explored for long‐term, stable gene expression to execute genomic integration of therapeutic genes, thus emerging as a strong alternative to viral transduction. Most studies with piggyBac transposition have employed physical methods for successful delivery of the necessary components of the piggyBac system into the cells. Very few studies have explored polymeric gene delivery systems. In this short communication, we report an effective delivery system based on low molecular polyethylenimine polymer with lipid substitution (PEI‐L) capable of delivering three components, (i) a piggyBac transposon plasmid DNA carrying a gene encoding green fluorescence protein (PB‐GFP), (ii) a piggyBac transposase plasmid DNA or mRNA, and (iii) a 2 kDa polyacrylic acid as additive for transfection enhancement, all in a single complex. We demonstrate an optimized formulation for stable GFP expression in two model cell lines, MDA‐MB‐231 and SUM149 recorded till day 108 (3.5 months) and day 43 (1.4 months), respectively, following a single treatment with very low cell number as starting material. Moreover, the stability of the transgene (GFP) expression mediated by piggyBac/PEI‐L transposition was retained following three consecutive cryopreservation cycles. The success of this study highlights the feasibility and potential of employing a polymeric delivery system to obtain piggyBac‐based stable expression of therapeutic genes.

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