Abstract
Nanoparticle carriers are effective drug delivery vehicles. Along with other design parameters including size, composition, and surface charge, particle shape strongly influences cellular uptake. How nanoparticle geometry affects targeted delivery under physiologically relevant conditions, however, is inconclusive. Here, we demonstrate that nanoconstruct core shape influences the dynamics of targeting ligand-receptor interactions on cancer cell membranes. By single-particle tracking of translational and rotational motion, we compared DNA aptamer AS1411 conjugated gold nanostars (AS1411-AuNS) and 50-nm gold spheres (AS1411-50NPs) on cells with and without targeted nucleolin membrane receptors. On nucleolin-expressing cells, AS1411-AuNS exhibited faster velocities under directed diffusion and translated over larger areas during restricted diffusion compared to AS1411-50NPs, despite their similar protein corona profiles. On nucleolin-inhibited cells, AS1411-AuNS showed faster rotation dynamics over smaller translational areas, while AS1411-50NPs did not display significant changes in translation. These differences in translational and rotational motions indicate that nanoparticle shape affects how targeting nanoconstructs bind to cell-membrane receptors.
Keywords: nanoparticle shape, single-particle dynamics, differential interference contrast microscopy, protein corona, nucleolin, targeting nanoconstructs
Graphical Abstract
Nanoparticle (NP) shape is an important parameter that influences cellular uptake and intracellular trafficking.1–2 Nanoconstructs—NP cores surrounded by ligand shells—with different particle geometries can promote different interactions with cell membranes based on surface ligand presentation,3 including altered binding kinetics to receptors.3–5 Efforts to prepare nanoconstructs with different shapes have focused on various core materials, including noble metal NPs,6–7 metal organic frameworks,8–9 DNA nanostructures,10 and polymer NPs.11 In cellular environments, the non-specific adsorption of proteins on NP surfaces forms a so-called protein corona that can screen the engineered targeting moieties as well as change the physicochemical properties of NPs.12–13 Although the composition of the protein corona has been shown to depend on NP geometry14–15 and conformation of ligand shell,16 the impact on the subcellular fate of targeting nanoconstructs is unknown.
In situ monitoring of nanoconstruct-cell interactions using NPs as probes can deconvolute the effects of NP shape and protein corona in physiologically relevant conditions. However, because of the intrinsic low optical contrast compared to cells, ligand-functionalized organic NPs and DNA origamis cannot function as probes without conjugation to dyes or inorganic nanoparticles.17–19 In contrast, gold nanoparticles (AuNPs) can be tracked via optical methods because of their strong scattering properties20 and also have advantages as probes because they are biocompatible, can be synthesized into various shapes,21–22 and can be covalently functionalized with diverse ligands.23–25 Anisotropic AuNPs such as gold nanostars (AuNS) show angle-dependent patterns in differential interference contrast (DIC) microscopy26–28 with potential for 3D orientation tracking,29 which can provide information on ligand-receptor binding and endocytosis at the molecular level.
DNA aptamer AS1411, the first aptamer to enter clinical oncology trials,30 is a widely used tumor-targeting ligand that binds to nucleolin (NCL), an overexpressed and ubiquitous protein on the surface of various cancer cell types.31 Previous work showed that AS1411-conjugated AuNS (AS1411-AuNS) are internalized after binding to NCL and shuttled to the peri-nuclear region to induce cell apoptosis with in vitro efficacy higher than free AS1411 aptamer.23, 32 Recently, we found that AuNS nanoconstructs functionalized with targeting versus non-targeting ligands exhibit distinct translational and rotational behavior even with similar protein corona profiles;26 hence, the ligand shell properties are preserved on anisotropic NPs and are critical for NP-cell membrane interactions.24, 26, 32–33 The influence of nanoconstruct shape on the presentation of targeting ligands to receptors on cell membranes has received little attention.
Here we demonstrate that NP shape determines whether engineered nanoconstructs maintain their targeting abilities on cell membranes. By real-time single-particle tracking using DIC-epifluorescence imaging, we compared dynamics of AS1411-conjugated AuNS (AS1411-AuNS) and AuNP spheres (AS1411-50NPs) on NCL-expressing (NCL+) and NCL-inhibited (NCL−) MCF-7 cells. We confirmed AS1411-NCL binding by tracking AS1411-AuNS rotation on NCL+ and NCL− cells; limited angular rotation was observed on NCL+ cells but free, fast rotation on NCL− cells. We then compared translational dynamics of AS1411-AuNS and AS1411-50NPs. Despite similar protein corona profiles, AS1411-AuNS exhibited faster velocities under directed diffusion and translated over larger areas during restricted diffusion compared to AS1411-50NPs. On NCL− cells, AS1411-AuNS showed much shorter translational trajectories, while AS1411-50NPs showed translation similar to that on NCL+ cells, which demonstrates that the two nanoconstructs have different targeting specificities for NCL. Our results suggest that NP core shape should be considered an important design parameter to maintain the targeting properties of nanoconstructs, especially for drug-delivery carriers.
Scheme 1 depicts representative single-particle dynamics of targeting constructs on cancer cell membranes. We prepared AS1411-AuNS and AS1411-50NPs with the same surface ligand density (Table S1) to investigate effects of particle geometry on AS1411-NCL interactions. We compared the single-particle dynamics of the two nanoconstructs on both NCL+ and NCL− MCF-7 cells to confirm the specificity of AS1411-nanoconstructs towards NCL. NCL− cells were prepared by pre-incubating MCF-7 cells with a NCL inhibitor to determine how blocking the NCL receptor would change nanoconstruct motion (SI, Methods). 30-s video streams were acquired to track individual AS1411-AuNS and AS1411-50NPs motion on cell membranes with either expressing or blocked NCL.
Figure 1 illustrates how the single-particle dynamics of AS1411-AuNS and AS1411-50NPs on cancer cell membranes were characterized via multi-channel and multi-wavelength imaging. Figures 1a–b depict a series of DIC images of AS1411-nanoconstructs on a glass substrate under rotation over 180° in increments of 45°; AS1411-AuNS showed angle-dependent DIC image patterns because of their anisotropic structure. AS1411-50NPs did not show significant changes at different angles because of symmetry, and moreover, were difficult to distinguish from spherical cellular vesicles by DIC microscopy alone (Figure S1).
We carried out single-channel DIC imaging of AS1411-AuNS at 700 nm, near the localized surface plasmon resonance of the AuNS, which showed high signal-to-noise ratios for both cellular features and nanoconstruct probes (Figure 1c). We conjugated Cy5-labeled AS141134 to the 50-nm spheres and tracked particle motions with multi-channel DIC-epifluorescence imaging (Figure 1d). NP motion was tracked in the epifluorescence channel (λ = 689 nm) by the Cy5 signal; the DIC channel (λ = 543 nm)20 was used to locate the particles with respect to the cell membrane. We identified the image plane of the cell membrane by optical sectioning (Figure S2, S3).
We first evaluated rotation of the nanoconstructs because of their relevance to ligand/receptor binding and clustering.35 Figure 2 shows that AS1411-AuNS on NCL+ cells and on NCL− cells have distinct rotational behaviors, indicating that targeting specificity of AS1411-AuNS to NCL was maintained in vitro. AS1411-AuNS exhibited a constant DIC pattern over several seconds on NCL+ cells (Figure 2a and S4). In contrast, AS1411-AuNS on NCL− cells fluctuated rapidly over a similar time period (Figure 2b), indicating a higher degree of rotational freedom for AS1411-AuNS when NCL was unavailable for binding. We calculated the contrast for AuNS in each frame, which we define as the average intensity of the circular AuNS pattern normalized against the background after subtracting the background intensity, (I − Ibkg)/Ibkg (SI Methods).27–28 On NCL+ cells, the contrast remained mostly constant, either positive (bright) or negative (dark); on NCL− cells, fast changes from negative to positive were observed (Figure 2c–d).
To distinguish between large and small angular changes during construct rotation, we defined the maximum contrast duration instead of the previous rotational frequency analysis method.26 We quantified the longest time when the nanoconstruct contrast remained the same sign over the 30-s stream; on average, the maximum duration for AS1411-AuNS was ~1.8 times longer on NCL+ cells compared to NCL− cells (Figure 2e). We also confirmed that rotational dynamic variations between AuNS/NCL+ and AuNS/NCL− were not from cell behavior changes after NCL blocking by comparing rotations of non-targeting control aptamer-conjugated AuNS on NCL+ and NCL− cells; no statistical difference was observed between the two cases (p > 0.05) (Figure S5). This result supports that the faster rotation of AS1411-AuNS on NCL− cells may be attributed to the unavailability of NCL for binding. A viability test with increased inhibitor concentration also established that the concentration used to block NCL did not induce cytotoxicity (Figure S6).
To determine whether the protein corona affected single-particle motion, we characterized the composition for AS1411-AuNS and AS1411-50NPs (SI Methods).26 The protein corona profiles for both nanoconstructs were almost identical (Figure S7, Table S2), with serum albumin being the most abundant protein (23% for AS1411-AuNS, 18% for AS1411-50NPs). Although alpha-2-HS-glycoprotein, known to target scavenger receptor-A,36 was found in the protein corona of both nanoconstructs (7% for AS1411-AuNS, 6% for AS1411-50NPs), this receptor is not expressed on MCF-7 cell membranes.37 Therefore, the protein corona does not influence the nanoconstruct targeting abilities to NCL or corresponding single-particle dynamics of AS1411-nanoconstructs during live-cell imaging.
Since translation of nanoconstructs after NP-receptor binding can provide insight on the lateral diffusion of surface receptors,38–40 we carried out single-particle tracking of AS1411-AuNS and AS1411-50NPs to probe shape-dependent translational dynamics. We processed the tracked particles by mean square displacement (MSD) analysis categorized into four diffusion modes: directed diffusion (DD), simple diffusion (SD), restricted diffusion (RD), and stationary (ST).26 For each nanoconstruct, the diffusion mode with the best MSD fit was assigned (Figure 3a and S8). Generally, AS1411-AuNS showed a drastic decrease in trajectory length on NCL− cells for all three types of motion: DD, SD, RD, while the trajectory lengths of AS1411-50NPs did not change significantly (Figure 3b).
Furthermore, we quantitively compared the translational motion of the two differently shaped nanoconstructs. The proportion of AS1411-AuNS under DD decreased from 51.8% to 15.8% after NCL was blocked, while the percentage of AS1411-AuNS under RD increased from 35.7% to 60.5% (Figures 4a–b). In addition, AS1411-AuNS that were ST were only observed on NCL− cells. AS1411-50NPs showed a lower percentage decrease in DD after NCL blocking (37.8% to 20.6%) compared to AS1411-AuNS; however, RD accounted for the highest population on both NCL+ and NCL− cells (37.8% and 47.1%, respectively). Different from AS1411-AuNS, ST particles were observed for AS1411-50NPs on both NCL+ and NCL− cells (Figures 4c–d). The change in diffusion mode distribution after NCL inhibition confirms that AS1411-AuNS binds to NCL, consistent with rotational dynamics results (Figure 2). We attribute the high percentage of AS1411-AuNS going through DD on NCL+ cells to NCL clustering being highly dependent on the presence of intact actin filaments41 in the cytoskeleton, which are responsible for directed movement on the cell membrane.
We further compared the diffusion parameters, including velocity and confinement length. For nanoconstructs under DD, AS1411-AuNS translated at ~1.7 times faster velocities compared to AS1411-50NPs (Figure 4e). For nanoconstructs with RD, AS1411-AuNS showed ~2 times higher confinement lengths compared to AS1411-50NPs on NCL+ cell membranes (Figure 4f). These differences in translational dynamics indicate that AS1411-AuNS and AS1411-50NPs bind to receptors with different diffusion dynamics. When NCL was blocked, the confinement lengths of AS1411-AuNS under RD decreased ~0.4 times, while spheres increased by ~1.2 times. The significant decrease in AS1411-AuNS confinement lengths on NCL− cells provides additional support that AS1411-AuNS bind specifically to NCL. For AS1411-50NPs, however, NCL inhibition did not significantly change the confinement lengths, which suggests that NCL was not the dominant receptor interacting with AS1411-50NPs. Therefore, the two nanoconstructs have different targeting selectivity towards NCL because of differences in their core shapes.
In summary, we demonstrated that nanoconstruct core shape governs single-particle dynamics during in vitro targeted ligand-receptor interactions on cancer cells. The differences in translation of AS1411-AuNS and AS1411-50NPs suggest that the two constructs show different targeting specificity towards NCL. We hypothesize that the branched structure of the AuNS core provides multiple areas of contact and ligand presentation and enables multivalent binding between AS1411 to the NCL receptor, while AS1411-50NPs only provides a single limited area of contact. Our study indicates that NP shape is a critical factor in determining ligand-receptor interactions that will affect downstream effects during targeted delivery.
Supplementary Material
Acknowledgments
This work was supported by the National Institute of Health (NIH) under awards 5 R01 GM131421-02 (P.C., T.L., T.W.O.) and 1R01GM115763. This work made use of the EPIC facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the IIN, and Northwestern’s MRSEC program (NSF DMR-1720139). Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. Metal analysis was performed at the Northwestern University Quantitative Bio-element Imaging Center generously supported by NASA Ames Research Center NNA06CB93G. We are grateful for the support from Northwestern University High Throughput Analysis Laboratory.
Footnotes
Supporting Information available: The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental methods; AS1411 nanoconstruct properties; differentiation of 50-nm spheres from cellular organelles; rotational motions of AS1411-AuNS on NCL+ and NCL− cells; effect of NCL inhibition on cAS1411-AuNS dynamics; the influence of endostatin on MCF-7 cell health; protein corona composition; determination of single-particle translational modes
The authors declare no competing financial interest.
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