Dendrimer and dendrimer–conjugate protein complexes and protein coronas

Abstract

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,...