The feasibility of multi-wavelength photoplethysmography for the real-time sensing of absorptive and scattering agents in pulsatile blood is discussed. The use of pulsatile signals extracted from trans-illumination of an accessible section of tissue allows us to calculate the concentration of the optically extinctive species in the pulsatile blood. This technology, initially used for pulse oximetry and dye densitometry, can be applied to monitor in vivo concentration and clearance of various absorptive species. Recently, our prototype has been used monitor the concentration of therapeutic gold nanoparticles, antimalarial quinine, and the antifungal agent amphotericin B. The assessment of the optical properties, device specifications, and signal quality for each compound are presented. We observe that this technology can be used to monitor numerous extinctive drug and nano-materials that present features in the 350-1100 nm range. The rationale for using this technology in a clinical setting would be to improve outcomes by real-time pharmacological feedback and/or control at point of care in addition to the elimination of invasive blood draws for collection of data.
KEYWORDS: Blood, In vivo imaging, Nanoparticles, Absorption, Signal attenuation, Therapeutic agents, Oxygen, LabVIEW, Signal detection, Photoplethysmography
A novel multi-wavelength photoplethysmograph (PPG), previously utilized to quantify optically absorptive circulating gold nanoparticles, has demonstrated the potential to enhance therapeutic treatment predictability as pharmacokinetic metrics are provided throughout the intravenous delivery and clearance phase of amphotericin b (injected in the lipid form Abelcet®) in real-time. This report demonstrates how the PPG could be used to assess the real-time bioavailability of intravenously delivered optically-absorbing therapeutic agents. The drug currently under investigation is antifungal amphotericin b (absorption peak ~355 nm). We describe how the algorithm has been adapted to quantify the concentration of amphotericin b in the pulsatile, circulating blood based on its extinction at three wavelengths (355, 660 and 940 nm) corresponding to the peaks of amphotericin b and wavelengths for oxygen saturation measurements, respectively. We show an example of the system collecting data representing the baseline, injection, and the clearance phases. The PPG device showed a measurement range of concentrations between 0.0987 mg/mL to 0.025mg/ml in blood. An examination of the data obtained suggests that the system is well suited to sense the concentration of amphotericin b at a therapeutic dose (≈5 mg/kg/day).
More than a decade into the development of gold nanoparticles for cancer therapies, with multiple clinical trials underway, ongoing pre-clinical research continues towards better understanding in vivo interactions with the goal of treatment optimization through improved best practices. In an effort to collect information for healthcare providers, enabling informed decisions in a relevant time frame, instrumentation for real-time plasma concentration (multi-wavelength pulse photometry) and protocols for rapid elemental analysis (energy dispersive X-Ray fluorescence) of biopsied tumor tissue have been developed in a murine model. An initial analysis, designed to demonstrate the robust nature and utility of the techniques, revealed that area under the bioavailability curve (AUC) alone does not currently inform tumor accumulation with a high degree of accuracy (R2=0.32), This finding suggests that the control of additional experimental and physiological variables may yield more predictable tumor accumulation. Subject core temperature are blood pressure were monitored, but did not demonstrate clear trends. An effort to modulate AUC has produced an adjuvant therapy which is employed to enhance circulation parameters, including the AUC, of nanorods and gold nanoshells. Preliminary studies demonstrated a greater than 300% increase in average AUC through the use of a reticuloendothelial blockade agent versus control groups. Given a better understanding of the relative importance of the physiological factors which impact rates of tumor accumulation, a proposed set of experimental best practices is presented.
A novel multi-wavelength photoplethysmograph (PPG), previously utilized to quantify optically absorptive circulating gold nanoparticles, has demonstrated the potential to enhance therapeutic treatment predictability as pharmacokinetic metrics are provided throughout the intravenous delivery phase of quinine in real-time. This report demonstrates how the PPG could be used to assess the real-time bioavailability of other types of intravenously delivered optically-absorbing nanoparticles and drugs. The drug currently under investigation is anti-malarial quinine (absorption peak ~350 nm). We describe how the algorithm has been adapted to quantify the concentration of quinine in the pulsatile, circulating blood based on its extinction at three wavelengths (340, 660 and 940 nm). We show an example of the system collecting data representing the baseline, injection, and the clearance phases. An examination of the raw signal suggests that the system is well suited to sense the concentration of quinine in the therapeutic range (10mg/kg).
Researchers employ increasingly complex sub-micron particles for oncological applications to deliver bioactive
therapeutic or imaging compounds to known and unknown in vivo tumor targets. These particles are often
manufactured using a vast array of compounds and techniques resulting in a complex architecture, which can be
quantified ex vivo by conventional metrology and chemical assays. In practice however, experimental homogeneity
using nanoparticles can be difficult to achieve. While several imaging techniques have been previously shown to
follow the accumulation of nanoparticles into tumor targets, a more rapid sensor that provides a quantifiable estimate
of dose delivery and short-term systemic response could increase the clinical efficacy and greatly reduce the
variability of these treatments. We have developed an optical device, the pulse photometer, that when placed on an
accessible location will estimate the vascular concentration of near-infrared extinguishing nanoparticles in murine
subjects. Using a technique called multi-wavelength photoplethysmography, the same technique used in pulse
oximetry, our pulse photometer requires no baseline for each estimate allowing it to be taken on and off of the
subject several times during experiments employing long circulating nanoparticles. We present a formal study of
our prototype instrument in which circulation half-life and nanoparticle concentration of gold nanorods is
determined in murine subjects with the aid of light anesthesia. In this study, we show good agreement between
vascular nanorod concentrations (given in optical density) as determined by our device and with UV-VIS
spectrophotometry using low volume blood samples.
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