Avidity Mechanism of Dendrimer–Folic Acid Conjugates

Dongen, Mallory A. van; Silpe, Justin E.; Dougherty, Casey A.; Kanduluru, Ananda Kumar; Choi, Seok Ki; Orr, Bradford G.; Low, Philip S.; Holl, Mark M. Banaszak

doi:10.1021/mp5000967

Cited by 50 publications

(95 citation statements)

References 60 publications

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Section: R a F Tmentioning

confidence: 99%

“…Methotrexate and folic acid conjugated PAMAM dendrimer trigger the folic acid receptor corona in a two-step process with fused specific/non-specific mechanisms: first the ligand binds to the target protein leading to a conformational change; the holoprotein formed in the first step gives a favorable surface for interaction with free apoprotein leading to further aggregation onto the dendrimer-protein complex. 10,59 Dendrimers can also be used tandemly with other nanoparticles to optimize their biological response.Antibody conjugated dendrimer-encapsulated gold nanoparticles can afford enhanced sensitivity for protein detection due to protein amplifications on dendrimer surface. 60 The increased sensitivity utilized the high density of reactive arms on the dendrimer surface, leading to higher local concentration of antibody and subsequently target proteins.…”

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confidence: 99%

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Dendrimer and dendrimer–conjugate protein complexes and protein coronas

Chen

Holl

2017

Can. J. Chem.

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Dendrimers and dendrimer conjugates are widely employed for biological applications such as bio-imaging and drug delivery. Understanding the interaction between dendrimers and their biological environment is key to evaluating the efficacy and safety of these materials. Proteins can form an adsorbed layer, termed a "protein corona", on dendrimers in either a non-specific or specific fashion. A tight-binding, non-exchangeable corona is defined as a "hard" corona whereas a loosely bound, highly exchangeable corona is called a "soft" corona. Recent research indicates that small molecules conjugated to the polymer surface can induce protein structural change leading to tighter protein-dendrimer binding and further protein aggregation. This "triggered" corona formation on dendrimer and dendrimer conjugates is reviewed and discussed along with the existing hard/soft corona model. This review describes the triggered corona model in order to further the understanding of protein corona formation.Keywords: dendrimer, PAMAM, protein, corona, aggregation, conjugate Dendrimers and dendrimer conjugates are widely used in biomedical research in drug delivery, bio-imaging, and transport scaffolds. [1][2][3] The multiple functional group containing arms on the dendrimer surface provide a multivalent system that can be readily modified. The functional groups can be conjugated to a drug, targeting agent, and/or imaging dye, or they can be left unconjugated. The unconjugated arms still contribute to surface properties such hydrophobicity, charge density, and potential for hydrogen bonding. [4][5][6][7][8] Proteins can interact with the dendrimer surface in a specific fashion with conjugated ligands or in non-specific fashion, or in a combination of both. [9][10][11][12] Proteins that are adsorbed onto the dendrimer surface form a colloidal layer called a "protein corona". 14 This adsorption avidity is governed by the binding affinity between the protein and the dendrimer, either forming a loosely bound, rapidly exchanging "soft" corona or a tightly bound slow exchanging "hard" corona. 15, 16 Proteins can also form a complex with the dendrimer conjugates in a more specific fashion, which is usually accompanied by protein structural change. This complex formation can also lead to a subsequent protein corona formation -defined as the "triggered" corona in this review (Fig. 1). 10 This triggered corona formation involves two steps: tight protein binding and conformational change in the first step and subsequent apo-protein corona formation. Binding to the conjugated ligand can be quite tight and dissociation constants for the holoprotein as low as 2 nM have been reported. 10 The triggered apoprotein corona can either be "soft" or "hard" since that is administered by the avidity between the apo-and holoproteins. Assessment of the formation of protein complex and corona upon interaction with dendrimer allows a better understanding of the dendrimer's biodistribution and ultimate biological fate. 24 After dendrimer conjugation,...

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Section: R a F Tmentioning

confidence: 99%

mentioning

confidence: 99%

Dendrimer and dendrimer–conjugate protein complexes and protein coronas

Chen

Holl

2017

Can. J. Chem.

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“…Binding of the substrates D-glucose and sodium reduced hydrophobicity, whereas binding of phlorizin, an inhibitor of glucose transport, induced a more hydrophobic conformation less suitable for trans-membrane transport [47]. A recent study points to another effect of the ligand-induced changes in surface hydrophobicity of FBP [48]. Binding between a certain type of chemotherapeutic agents, dendrimer conjugates of folic acid, and immobilized FBP is a two-step mechanism.…”

Section: Surface Hydrophobicitymentioning

confidence: 99%

“…Binding between a certain type of chemotherapeutic agents, dendrimer conjugates of folic acid, and immobilized FBP is a two-step mechanism. The first step is keyed by binding of conjugated folic acid, which in the second step brings the dendrimer arms of the conjugate into close contact with the protein [48]. The authors assume that the initial binding of conjugated folate to FBP results in a conformational change with exposure of a hydrophilic surface that enables an irreversible van der Waals interaction with the dendrimer.…”

Section: Surface Hydrophobicitymentioning

confidence: 99%

The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Holm

Bruun²,

Hansen

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…We demonstrated that rp-HPLC can be used to separate trailing and branching defects in poly(amidoamine) (PAMAM) dendrimers 2−5 and separate species with different numbers of hydrophobic ligands (dyes, drugs, targeting agents) attached to the hydrophilic backbone. 6−10 AFM allowed for direct, representative imaging of samples and surfaces with nanometer precision in the x and y directions and subnanometer precision vertically. 11−21 Importantly, AFM is a topographic technique, measuring the volume of imaged features along with surface morphology and material properties.…”

Section: Introductionmentioning

confidence: 99%

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

2018

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Characterization of materials with biological applications and assessment of physiological effects of therapeutic interventions are critical for translating research to the clinic and preventing adverse reactions. Analytical techniques typically used to characterize targeted nanomaterials and tissues rely on bulk measurement. Therefore, the resulting data represent an average structure of the sample, masking stochastic (randomly generated) distributions that are commonly present. In this Perspective, we examine almost 20 years of work our group has done in different fields to characterize and control distributions. We discuss the analytical techniques and statistical methods we use and illustrate how we leverage them in tandem with other bulk techniques. We also discuss the challenges and time investment associated with taking such a detailed view of distributions as well as the risks of not fully appreciating the extent of heterogeneity present in many systems. Through three case studies showcasing our research on conjugated polymers for drug delivery, collagen in bone, and endogenous protein nanoparticles, we discuss how identification and characterization of distributions, i.e., a molecular view of the system, was critical for understanding the observed biological effects. In all three cases, data would have been misinterpreted and insights missed if we had only relied upon spatially averaged data. Finally, we discuss how new techniques are starting to bridge the gap between bulk and molecular level analysis, bringing more opportunity and capacity to the research community to address the challenges of distributions and their roles in biology, chemistry, and the translation of science and engineering to societal challenges.

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Avidity Mechanism of Dendrimer–Folic Acid Conjugates

Cited by 50 publications

References 60 publications

Dendrimer and dendrimer–conjugate protein complexes and protein coronas

Dendrimer and dendrimer–conjugate protein complexes and protein coronas

The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

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