Characterization of Folic Acid and Poly(amidoamine) Dendrimer Interactions with Folate Binding Protein: A Force-Pulling Study

Leroueil, Pascale R.; DiMaggio, Stassi; Leistra, Abigail N.; Blanchette, Craig D.; Orme, Christine A.; Sinniah, Kumar; Orr, Bradford G.; Holl, Mark M. Banaszak

doi:10.1021/acs.jpcb.5b05391

Cited by 16 publications

(22 citation statements)

References 41 publications

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“…This in silico experiment is of high relevance since force-pulling has recently been performed with atomic force microscopy for characterizing the interaction of PAMAM dendrimer and folate-binding protein. 70 The SDMD-derived HSA-binding affinities for PAMAM dendrimers of different sizes and surface chemistries were consistent with previous experimental measurements. 45 Our results highlighted the importance of surface modifications with zwitterionic ligands to reduce nonspecific protein binding for the design of stealthy NPs.…”

Section: Introductionsupporting

confidence: 88%

Understanding Effects of PAMAM Dendrimer Size and Surface Chemistry on Serum Protein Binding with Discrete Molecular Dynamics Simulations

Wang

Sun

Davis

et al. 2018

ACS Sustainable Chem. Eng.

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Polyamidoamine (PAMAM) dendrimers, a class of polymeric nanoparticles (NPs) with highly-controllable sizes and surface chemistry, are promising candidates for many biomedical applications, including drug and gene delivery, imaging, and inhibition of amyloid aggregation. In circulation, binding of serum proteins with dendritic NPs renders the formation of protein corona and alters the biological identity of the NP core, which may subsequently elicit immunoresponse and cytotoxicity. Understanding the effects of PAMAM size and surface chemistry on serum protein binding is, therefore, crucial to enable their broad biomedical applications. Here, by applying atomistic discrete molecular dynamics (DMD) simulations, we first uncovered the binding of PAMAM with HSA and Ig and detailed the dependences of such binding on PAMAM size and surface modification. Compared to either anionic or cationic surfaces, modifications with neutral phosphorylcholine (PC), polyethylene glycol (PEG), and hydroxyls (OH) significantly reduced binding with proteins. The relatively strong binding between proteins and PAMAM dendrimers with charged surface groups was mainly driven by electrostatic interactions as well as hydrophobic interactions. Using steered DMD (SDMD) simulations, we conducted a force-pulling experiment in silico estimating the critical forces separating PAMAM-protein complexes and deriving the corresponding free energy barriers for dissociation. The SDMD-derived HSA-binding affinities were consistent with existing experimental measurements. Our results highlighted the association dynamics of protein-dendrimer interactions and binding affinities, whose implications range from fundamental nanobio interfacial phenomena to the development of “stealth NPs”.

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Section: Introductionsupporting

confidence: 88%

Understanding Effects of PAMAM Dendrimer Size and Surface Chemistry on Serum Protein Binding with Discrete Molecular Dynamics Simulations

Wang

Sun

Davis

et al. 2018

ACS Sustainable Chem. Eng.

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“…This allows targeting of receptors that are exclusively overexpressed on specific cancer cell surfaces [ 16 ], e.g., the folate receptor (FR) which has been shown to be overexpressed in cancers including ovarian, thyroid, kidney, endometrial, breast and renal cell carcinomas [ 17 ]. These FRs bind avidly to folic acid (FA), a dietary supplement which is intrinsically involved in cellular turnover and accommodates the extreme proliferation of cancer cells [ 18 ]. It was reported that nanocomplexes containing FA enhanced intracellular delivery of anticancer agents [ 19 , 20 ], mRNA [ 15 ] and siRNA [ 12 , 21 , 22 ] in cells overexpressing the FR.…”

Section: Introductionmentioning

confidence: 99%

Folate-Targeted Transgenic Activity of Dendrimer Functionalized Selenium Nanoparticles In Vitro

Pillay

Daniels

Singh

2020

IJMS

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Current chemotherapeutic drugs, although effective, lack cell-specific targeting, instigate adverse side effects in healthy tissue, exhibit unfavourable bio-circulation and can generate drug-resistant cancers. The synergistic use of nanotechnology and gene therapy, using nanoparticles (NPs) for therapeutic gene delivery to cancer cells is hereby proposed. This includes the benefit of cell-specific targeting and exploitation of receptors overexpressed in specific cancer types. The aim of this study was to formulate dendrimer-functionalized selenium nanoparticles (PAMAM-SeNPs) containing the targeting moiety, folic acid (FA), for delivery of pCMV-Luc-DNA (pDNA) in vitro. These NPs and their gene-loaded nanocomplexes were physicochemically and morphologically characterized. Nucleic acid-binding, compaction and pDNA protection were assessed, followed by cell-based in vitro cytotoxicity, transgene expression and apoptotic assays. Nanocomplexes possessed favourable sizes (<150 nm) and ζ-potentials (>25 mV), crucial for cellular interaction, and protected the pDNA from degradation in an in vivo simulation. PAMAM-SeNP nanocomplexes exhibited higher cell viability (>85%) compared to selenium-free nanocomplexes (approximately 75%), confirming the important role of selenium in these nanocomplexes. FA-conjugated PAMAM-SeNPs displayed higher overall transgene expression (HeLa cells) compared to their non-targeting counterparts, suggesting enhanced receptor-mediated cellular uptake. Overall, our results bode well for the use of these nano-delivery vehicles in future in vivo studies.

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“…Recent reports have suggested that the strong binding avidity is also due to a network of van der Waals and electrostatic interactions that form between the FBP and dendrimer. 34,35 The dendrimer-FBP interactions are initiated by a folate-keyed interaction after which a slow-onset tight binding occurs between the dendrimer and receptor. While it seems clear that an optimized ligand conjugation is needed for target cell specificity and initiating cellular interactions, these new findings suggest that other features of the dendritic structure also play a role in governing their cellular interactions and targeting capabilities.…”

Section: Specific Biological Interactions Of Dendrimers Mediated By Surface Ligandsmentioning

confidence: 99%

Dendrimer‐based nanocarriers: a versatile platform for drug delivery

Hsu

Bugno

Lee

et al. 2016

WIREs Nanomed Nanobiotechnol

147

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Advances in nanotechnology have had profound impacts on therapeutic delivery, leading to the development of nanomaterials engineered with large carrying capabilities and targeting functionalities. Among the nanomaterials, dendrimers have garnered particular attention from researchers owing to their well-defined structure, near-monodispersity, and ease of multifunctionalization. As hyperbranched, three-dimensional macromolecules, dendrimers can be engineered to target and deliver a wide range of therapeutic agents, including small molecules, peptides, and genes, reducing their systemic toxicities and enhancing efficacies. In this review, we provide a comprehensive overview of the commonly employed dendrimer-based nanocarrier designs, including dendrimer conjugates, Janus dendrimers, and linear-dendritic block copolymers. The discussion will progress through the basic synthetic strategies of dendrimer-based nanocarriers, followed by the potential clinical applications related to their unique structural properties. Finally, the major challenges that these nanocarriers are currently facing in their clinical translation and possible solutions to address these issues will be discussed, with the aim to provide researchers in the drug delivery field a good understanding of the potential utilities of dendrimer-based nanocarriers. WIREs Nanomed Nanobiotechnol 2017, 9:e1409. doi: 10.1002/wnan.1409 For further resources related to this article, please visit the WIREs website.

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Characterization of Folic Acid and Poly(amidoamine) Dendrimer Interactions with Folate Binding Protein: A Force-Pulling Study

Cited by 16 publications

References 41 publications

Understanding Effects of PAMAM Dendrimer Size and Surface Chemistry on Serum Protein Binding with Discrete Molecular Dynamics Simulations

Understanding Effects of PAMAM Dendrimer Size and Surface Chemistry on Serum Protein Binding with Discrete Molecular Dynamics Simulations

Folate-Targeted Transgenic Activity of Dendrimer Functionalized Selenium Nanoparticles In Vitro

Dendrimer‐based nanocarriers: a versatile platform for drug delivery

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