Molecular Architecture Governs Cytotoxicity and Gene Transfection Efficacy of Polyethylenimine Based Nanoplexes in Mammalian Cell Lines

Tay, Chor Yong; Menon, Nandita; Leong, David Tai; Tan, Lay Poh

doi:10.1007/s10904-014-0135-8

Cited by 9 publications

(3 citation statements)

References 46 publications

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“…9 Numerous experimental studies have addressed several important aspects of PEI-based delivery vectors. In particular, the impact of molecular weight 10 and polymer architecture 11 (linear vs branched topology) on transfection efficiency and cytotoxicity has been considered. Similar to PLL, several modifications of PEI have been studied, including copolymers of PEI with polyethyleneglycol 12 and uronic acid 13 as well as peptide-conjugated PEI-based polymers.…”

Section: ■ Introductionmentioning

confidence: 99%

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

et al. 2016

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Synthetic cationic polymers represent a promising class of delivery vectors for gene therapy. Here, we employ atomistic molecular dynamics simulations to gain insight into the structure and properties of complexes of DNA with four linear polycations: polyethylenimine (PEI), poly-l-lysine (PLL), polyvinylamine (PVA), and polyallylamine (PAA). These polycations differ in their polymer geometries, protonation states, and hydrophobicities of their backbone chains. Overall, our results demonstrate for the first time the existence of two distinct patterns of binding of DNA with polycations. For PEI, PLL, and PAA, the complex is stabilized by the electrostatic attraction between protonated amine groups of the polycation and phosphate groups of DNA. In contrast, PVA demonstrates an alternative binding pattern as it gets embedded into the DNA major groove. It is likely that both the polymer topology and affinity of the backbone chain of PVA to the DNA groove are responsible for such behavior. The differences in binding patterns can have important biomedical implications: embedding PVA into a DNA groove makes it less sensitive to changes in the aqueous environment (pH level, ionic strength, etc.) and could therefore hinder the intracellular release of genetic material from a delivery vector, leading to lower transfection activity.

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Section: ■ Introductionmentioning

confidence: 99%

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

et al. 2016

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“…To the best of our knowledge, this is the first study in which the polyplex/membrane binding is explored in detail. PEI was chosen as a cationic polymer in our study as it is often considered as one of the most efficient polymer agent for DNA delivery. , Furthermore, PEI has extensively been studied both experimentally , and computationally. ,,, We considered DNA/PEI complexes with various polycation contents (or N/P ratios), ranging from an almost fully neutralized DNA molecule to a highly overcharged polyplex. For all DNA/PEI complexes considered, we employed both biased and unbiased computer simulations to explore polyplex/membrane binding.…”

Section: Introductionmentioning

confidence: 99%

“…PEI was chosen as a cationic polymer in our study as it is often considered as one of the most efficient polymer agent for DNA delivery. 25,26 Furthermore, PEI has extensively been studied both experimentally 27,28 and computationally. 8,9,11,12 We considered DNA/PEI complexes with various polycation contents (or N/P ratios), ranging from an almost fully neutralized DNA molecule to a highly overcharged polyplex.…”

Section: ■ Introductionmentioning

confidence: 99%

Molecular-Level Insight into the Interactions of DNA/Polycation Complexes with Model Cell Membranes

Gurtovenko

2019

J. Phys. Chem. B

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The interactions of DNA/polycation complexes (polyplexes) with cell membranes are crucial for understanding the molecular mechanisms behind polycation-mediated delivery of nucleic acid therapeutics into the target cells. In this study, we employed both biased and unbiased atomic-scale computer simulations to get an insight into such interactions. To this end, we considered complexes of DNA with linear polyethylenimine (PEI) with various polycation contents, ranging from an almost fully neutralized DNA to a highly overcharged polyplex. Our findings clearly show that the free energy gradually increases when a polyplex approaches the surface of a zwitterionic (neutral) phospholipid membrane from bulk water, implying the lack of attractive polyplex/membrane interactions. Remarkably, overcharging of DNA molecules by polycations enhances the repulsion between the polyplex and the zwitterionic lipid membrane. The observed repulsion is most likely driven by the dehydration of a polyplex upon its partitioning into the zwitterionic lipid membrane as well as by the loss of conformational entropy of PEI chains. We also demonstrate that cationic polymer chains are able to protect DNA from the dehydration as well as from contacts with lipid molecules. Interestingly, the absence of local minima in the free energy profiles does not exclude transient weak adsorption of a polyplex on the zwitterionic membrane surface. We show that such spontaneous adsorption can indeed be initiated by the interactions of loose polycation chains of the polyplex with polar head groups of lipids. Overall, our computational findings contribute considerably to the understanding of the initial stages in polycation-mediated DNA transfection. In particular, we demonstrate that a zwitterionic lipid bilayer represents an energetic barrier for polyplexes, so that a proper model of the cell membrane should account for the anionic surface charge of the membrane (e.g., due to the presence of proteoglycans).

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Reality Check for Nanomaterial‐Mediated Therapy with 3D Biomimetic Culture Systems

Tay

Muthu

Chia

et al. 2016

Adv Funct Materials

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The recent progresses in tissue engineering and nanomaterial‐based therapeutics/theranostics have led to the ever increasing utilization of 3D in vitro experimental models as the bona fide culture systems to evaluate the therapeutic/theranostic effects of nanomedicine. Compared to the use of conventional 2D culture platforms, 3D biomimetic cultures offer unmatched advantages as relevant physiological and pathological elements can be incorporated to allow better characterization of the engineered bio‐nanomaterials in the targeted tissue‐specific microenvironment. In this Feature Article, the current state‐of‐the‐art 3D in vitro models that have been developed for the evaluation of biosafety and efficacy of nano‐ therapeutics/theranostics targeting the colon, blood–brain barrier (BBB), lungs, skin tumor models to bridge the nanomedicine bench to pre‐clinical ravine are reviewed. Furthermore, the critical physicochemical parameters of the bio‐nanomaterials that govern its transport and biodistribution in a complex 3D microenvironment will be highlighted. The major challenges and future prospects of evaluating nanomedicine in the third dimension will also be discussed.

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Molecular Architecture Governs Cytotoxicity and Gene Transfection Efficacy of Polyethylenimine Based Nanoplexes in Mammalian Cell Lines

Cited by 9 publications

References 46 publications

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

Atomic-Scale Molecular Dynamics Simulations of DNA–Polycation Complexes: Two Distinct Binding Patterns

Molecular-Level Insight into the Interactions of DNA/Polycation Complexes with Model Cell Membranes

Reality Check for Nanomaterial‐Mediated Therapy with 3D Biomimetic Culture Systems

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