Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT

Abstract

The solid concentration of pulmonary mucus (wt%) is critical to respiratory health. In patients with respiratory disease, such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disorder (COPD), mucus hydration is impaired, resulting in high wt%. Mucus with high wt% is a hallmark of pulmonary disease that leads to obstructed airways, inflammation, and infection. Methods to measure mucus hydration in situ and in real-time are needed for drug development and personalized therapy. We employed plasmonic gold nanorod (GNR) biosensors that intermittently collide with macromolecules comprising the mucus mesh as they self-diffuse, such that GNR translational diffusion (DT) is sensitive to wt%. GNRs are attractive candidates for bioprobes due to their anisotropic optical scattering that makes them easily distinguishable from native tissue using polarization-sensitive OCT. Using principles of heterodyne dynamic light scattering, we developed diffusion-sensitive optical coherence tomography (DS-OCT) to spatially-resolve changing DT in real-time. DS-OCT enables, for the first time, direct monitoring of changes in nanoparticle diffusion rates that are sensitive to nanoporosity with spatial and temporal resolutions of 4.7 μm and 0.2 s. DS-OCT therefore enables us to measure spatially-resolved changes in mucus wt% over time. In this study, we demonstrate the applicability of DS-OCT on well-differentiated primary human bronchial epithelial cells during a clinical mucus-hydrating therapy, hypertonic saline treatment (HST), to reveal, for the first time, mucus mixing, cellular secretions, and mucus hydration on the micrometer scale that translate to long-term therapeutic effects.

Light-responsive nanomedicine for biophotonic imaging and targeted therapy

“…In particular, OCT has been highly useful in ophthalmology to analyze optic nerves and the retinal nerve layer and in measuring the stiffness of the cornea [85]. Light-responsive NPs are useful in OCT imaging and enable further applications based on the measurement of back-reflected or backscattered light [24,25]. For example, the Oldenburg group reported that gold nanorods could provide anisotropic optical scattering which enabled facile tracking in native tissue using polarization-sensitive OCT [24].…”

“…In the subsequent paper, as shown in Fig. 7, they used gold nanorod-based OCT to monitor the results of pulmonary disease treatment [25]. High solid concentration of pulmonary mucus is a common symptom in respiratory diseases including chronic obstructive pulmonary disorder and cystic fibrosis, and impaired mucus hydration promotes inflammation, infection, and obstructed airways.…”

“…After clinical mucus-hydrating therapy or hypertonic saline treatment, mucus mixing, mucus hydration, and cellular secretions were determined by analyzing the D T of the nanorods with OCT. This study demonstrated the potential of OCT using light-responsive NPs for therapeutic monitoring, which may be used in the body with real-time endoscopic OCT in the near future [25]. Additionally, tumor targetability of gold NPs and tumor microvasculature were monitored by OCT [86].…”

“…(B) Diffusion sensitive (DS), HH (horizontal in and horizontal out), and HV HH (horizontal in and vertical out) OCT data from nanorod-containing mucus after treatment of isotonic saline. Reproduced with permission from [25]. …”

Co association of mucus modulating agents and nanoparticles for mucosal drug delivery

“…Blackmon and co-workers have recently published an elegant method demonstrating real time increases in the pore size, and corresponding reduction in the steric barrier properties, of mucus in mucus secreting cell cultures upon exposure to osmotically active agents (hypertonic saline) that drive cellular fluid secretion and hence increase mucus hydration. This study utilizes mucus secreting Calu-3 [40] or cultured human bronchial epithelial cells [41] as the model mucosa and diffusion sensitive optical coherence tomography to image the hydration of the mucus, which is determined by the diffusivity of gold nanorods. It may be argued that there are kinetic challenges connected to the use of hypertonic solutions of osmotically active agents to induce increased cellular fluid secretion without affecting the mucus volume in the first instance, which could initially lead to an increased steric barrier by mucus de-swelling.…”