Feature Article Cite This: J. Phys. Chem. B XXXX, XXX, XXX−XXX
pubs.acs.org/JPCB
Physical Properties of Biomolecules at the Nanomaterial Interface Cristina Rodriguez-Quijada,†,§ Maria Sánchez-Purrà,†,§ Helena de Puig,‡ and Kimberly Hamad-Schifferli*,†,‡ †
Department of Engineering, University of Massachusetts, Boston, Massachusetts 02125, United States Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡
ABSTRACT: The unique size and material dependent properties of nanoparticles have made them highly attractive for biological and medical applications. However, combining nanoparticles with biomolecules and biological environments has faced many challenges. These interface issues often involve protein denaturation, steric hindrance, and orientational issues for the biomolecule, which can impair function and decrease overall performance of the nanoparticle−biomolecule conjugate. Historically, our understanding of the physical and chemical properties of nanoparticle−biomolecule conjugates as appropriate tools and experimental techniques had to be determined. We discuss here selected examples investigating the fundamental physical properties of the interface between nanoparticles and DNA and proteins and protein coronas and how they have provided insight into the properties of the biomolecule when it is interfaced to a nanoparticle.
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nanoscale morphologies in bone.9,10 Furthermore, nanomaterials can be tailored, where NPs are decorated with multiple species for targeting, imaging, and drug delivery, allowing the NP to act as a carrier for a drug, target an area, and destroy tumor tissue. Currently, there are several nanomedicine therapies now in clinical trials.11,12 However, combining nanomaterials with biology has faced many challenges13,14 and one of its biggest barriers is the physical interface between biomolecules and their biological surroundings.15 Biological environments often lead to unpredictable behavior for inorganic materials. Common biological fluids are typically aqueous solutions with high salt and biomolecular concentrations, which can interact with the surfaces of nanomaterials. Blood and serum are incredibly complex, with over thousands of different species and a protein concentration greater than ∼300 mg/mL. This is in stark contrast to the organic solvents or gaseous phases in which nanomaterials are often produced. Interface issues lead to undesirable side effects of the biotic−abiotic interface. Biofouling manifests in many different forms across multiple length scales (Figure 1).16 On the macroscopic length scale, barnacle adhesion to ship hulls causes hydrodynamic drag, negatively impacting fuel consumption. On the centimeter length scale, medical devices such as implants, stents, catheters, and joint replacements also undergo fouling, where proteins in the blood adsorb to their surfaces, inducing inflammatory responses17,18 and infection.19 These issues can significantly limit device performance, reduce integration and/or increase rejection, and, sometimes causing early device failure. On the
INTRODUCTION Nanomaterials have been of great interest for biological and biomedical applications. The synergistic overlap of materials with biology has led to numerous innovations in using nanoparticles (NPs) for medical imaging, novel therapeutic agents, and drug delivery. This is due to the fact that NPs possess unique physical and chemical properties, such as their optical, magnetic, electrical, and electro-optical properties. In addition, the size of a NP is roughly the same as biomolecular machinery, making them optimally suited for interfacing to biomolecules, inducing change in biological molecules and cells, transport the bloodstream, and also clearance.1,2 Since the initial discovery that nanoparticles can be interfaced to biomolecules, the scientific community has sought to exploit their size dependent material properties to enable new capabilities in medical, biological, and therapeutic applications. The first publications in this area were primarily focused on using semiconductor quantum dots for fluorescent imaging agents3 or self-assembly of NP structures with DNA.4 Examples now include using the size-dependent optical absorption of Au nanoparticles to tune their surface plasmon resonance (SPR) to coincide with the NIR window where tissue absorbs minimally, facilitating through-tissue phototherapies or laser-triggered drug release.5 Additionally, the magnetic properties of NPs have allowed their use as contrast agents for magnetic resonance (MR) imaging in vivo6 or combined multimodal imaging.7 Often, nanomedicine applications have been able to successfully increase the therapeutic efficiency of chemotherapeutic drugs, enabling lowering of its dosage of and thus limiting toxic side effects, or exploiting nanomaterial properties for tumor destruction.8 In addition, nanoparticles and nanomaterials have been used beyond cancer therapies such as tissue engineering such as bone reconstruction, where their size enables matching © XXXX American Chemical Society
Received: January 5, 2018 Revised: February 8, 2018
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DOI: 10.1021/acs.jpcb.8b00168 J. Phys. Chem. B XXXX, XXX, XXX−XXX
Feature Article
The Journal of Physical Chemistry B
have a sophisticated understanding of the synthesis mechanism of NPs, such as the kinetics of their nucleation and also growth, and what influences them individually. This understanding has allowed control over their compositional architecture, resulting in complex core−shell or Janus structures, where the composition and dimensions of the core vs shell can be separately tuned. Manipulation of NP surface chemistry has also made great progress, where surface ligands can be exchanged with others or removed to customize the NP surface hydrophobicity, modifying its solubility and stability in different solvents.20 The motivation to utilize nanomaterials in biology was initially driven by the chemists, physicists, and materials scientists in nanoscience and nanotechnology studying their physical properties. Thus, progress in biointerfacing nanomaterials has lagged somewhat behind the synthetic capabilities of NPs. The biological applications for NPs have included using their properties for fluorescent biological labels, such as fluorescent quantum dots. Also, because gold can be heated by optical excitation, there have been many applications that exploit the photothermal properties of gold such as phototriggered drug release and photothermal therapy for tumors. Surface functionalization with biomolecules (DNA, siRNA, and proteins) has been explored for gene therapy and targeting strategies to receptors that are overexpressed in specific cell types. Initial attempts to use nanomaterials in biology were ̈ where nanomaterials were simply added to somewhat naive, biological environments or incubated with biomolecules. Once it was recognized that nonspecific adsorption had detrimental effects, it was realized that interface effects could not be ignored. Addressing interface issues was largely done on an ad hoc basis, where specific surface chemistries were utilized as simple “fixes” to the problem, and not contributing to the bigger picture of nanobio interface issues. Since then, we have progressed toward a broader scope in our understanding of biointerface issues, and there are now multiple approaches for optimizing the nanobio interface and controlling its multitude of interactions. Furthermore, we have been able to take it beyond simply manipulating the interface properties, where it is now recognized that the nanobio interface has many unique properties that we can leverage to our advantage. This review seeks to provide a perspective on nanobio interfaces and their physical characterization. This field has faced major challenges, so we will discuss in depth some of the fundamental studies of the nanobio interface, and show how the understanding of the interface has allowed us to not only manipulate it but also engineer its advantageous properties.
Figure 1. Length scales of biological and inorganic systems and biotic−abiotic interface undesirable interface issues that can occur.
microscopic length scale, bacterial biofilms can form, enhancing virulence and/or causing pathogenicity. Finally, on the nanoscale, nanomaterials can suffer from irreversible nonspecific adsorption, and also protein corona formation, the adsorption of proteins from the surrounding media onto the NP. This can cause protein denaturation and loss of biological function, compromising the function of the NP−biomolecule conjugate. While all of these interface issues are highly undesirable, from a biointerfacing point of view, the nanoscale issues are the hardest to ignore due to the high surface to volume ratios of nanomaterials. For example, half of the atoms of a 2 nm Au nanoparticle are on the surface. Compared to bulk 2D surfaces, NP surfaces are much more complicated. NPs are not hard spheres, as schematics tend to suggest, but instead are three-dimensional species with unique physical and chemical behavior. Inorganic NPs are small crystals with different crystal facets, edges, and vertices. Additionally, they have dangling surface bonds, and often have a mixture of different surface vacancies. To lower their surface energy, NP surfaces often reconstruct but their surface reconstructions are not as well-defined as those observed in bulk planar surfaces, resulting in surface structures that are physically and chemically different from the bulk. Because of this, nanomaterial surfaces have been of great scientific interest due to their unique properties, which can lead to increased chemical reactivity and unique alloying properties not accessible by the bulk material. Additionally, NPs synthesized by solution synthesis approaches have surface passivating ligands to prevent aggregation and impart stability, so their role is critical for particle solubility. These all underscore the fact that NP surfaces are not simply extensions of bulk surfaces. NPs first generated much interest in the scientific community because of their size-dependent physical properties. In order to understand these properties, control over their synthesis was critical. Today, we now have exquisite synthetic control over the shape, size, and composition of solution-synthesized NPs, with routine achievement of high monodispersity (
