Near Infrared Fluorescence Imaging of Intraperitoneal Ovarian Tumors in Mice Using Erythrocyte-Derived Optical Nanoparticles and Spatially-Modulated Illumination

Abstract

Ovarian cancer is the deadliest gynecological cancer. Cytoreductive surgery to remove primary and intraperitoneal tumor deposits remains as the standard therapeutic approach. However, lack of an intraoperative image-guided approach to enable the visualization of all tumors can result in incomplete cytoreduction and recurrence. We engineered nano-sized particles derived from erythrocytes that encapsulate the near infrared (NIR) fluorochrome, indocyanine green, as potential imaging probes for tumor visualization during cytoreductive surgery. Herein, we present the first demonstration of the use of these nanoparticles in conjunction with spatially-modulated illumination (SMI), at spatial frequencies in the range of 0–0.5 mm−1, to fluorescently image intraperitoneal ovarian tumors in mice. Results of our animal studies suggest that the nanoparticles accumulated at higher levels within tumors 24 h post-intraperitoneal injection as compared to various other organs. We demonstrate that, under the imaging specifications reported here, use of these nanoparticles in conjunction with SMI enhances the fluorescence image contrast between intraperitoneal tumors and liver, and between intraperitoneal tumors and spleen by nearly 2.1, and 3.0 times, respectively, at the spatial frequency of 0.2 mm−1 as compared to the contrast values at spatially-uniform (non-modulated) illumination. These results suggest that the combination of erythrocyte-derived NIR nanoparticles and structured illumination provides a promising approach for intraoperative fluorescence imaging of ovarian tumor nodules at enhanced contrast.

Cell Membrane-Cloaked Nanotherapeutics for Targeted Drug Delivery

“…RBCs are disciform with a hollow center, allowing resistance to osmotic pressure or external shock and flexibility to pass through the capillary. RBC membranes were extensively used for modifying nanoparticles due to their ability to avoid the immune system and achieve long-term circulation [2,25,[27][28][29][30][31]. For example, Hu et al [32] reported that RBC membrane-coated nanoparticles had significantly longer circulation time as compared to that of bare nanoparticles or RBC membrane vesicles.…”

“…The advent of cell membrane cloaking technique in cancer nanotechnology bestows nanoparticles with extended blood circulation period, enhanced immune evasion, localized drug delivery, improved tumor penetration, and accumulation [43,106]. Nanoparticles with a high capacity of anti-cancer drug loading and photodynamic properties were decorated with cell membranes isolated from various cell types, including cancer cells, fibroblasts, platelets, macrophages, RBCs, white blood cells, dendritic cells, and natural killer (NK) cells [7,23,24,27,29,31,107,108]. Cell membranes obtained from cancer cells and immune cells were extensively used especially for cancer immunotherapy due to their inherent immune evasion and homologous tumor-targeting ability [49,109].…”

Membrane Cholesterol Enrichment of Red Blood Cell-Derived Microparticles Results in Prolonged Circulation

“…We refer to these particles as microsized NIR erythrocyte-derived transducers (μNETs) as they can transduce NIR light to emit fluorescence, generate heat, or produce reactive oxygen species. , We have previously investigated the use of μNETs for real-time intravascular fluorescence imaging and photothermal destruction of the microvasculature, similar to vascular malformations found in port wine stain lesions . ICG-doped RBCs have been used to characterize microvascular vasomotion in humans. , We have used nanosized RBC-derived particles containing ICG for NIR fluorescence imaging and photodestruction of tumors in animal models. , The present study is an important step towards the engineering of RBC-derived particles with appropriate biochemical characteristics, based on cholesterol incorporation, to enhance the bioavailability of the particles resulting from reduced clearance by the immune cells. Membrane cholesterol enrichment is also relevant to the fabrication of RBC-based particles containing not only optical materials but also other types of biomedical cargos. , …”

“…15,16 We have used nanosized RBC-derived particles containing ICG for NIR fluorescence imaging and photodestruction of tumors in animal models. 5,40 The present study is an important step towards the engineering of RBC-derived particles with appropriate biochemical characteristics, based on cholesterol incorporation, to enhance the bioavailability of the particles resulting from reduced clearance by the immune cells. Membrane cholesterol enrichment is also relevant to the fabrication of RBC-based particles containing not only optical materials but also other types of biomedical cargos.…”

An Acid Response IR780-Based Targeted Nanoparticle for Intraoperative Near-Infrared Fluorescence Imaging of Ovarian Cancer

“…9 In order to show ovarian tumours clearly by NIR fluorescence imaging during operation, some nanoparticle probes have been designed and achieved excellent results in basic experimental stage. [10][11][12][13] A Phase II clinical trial indicated that OTL38, which consists of folate conjugated to an indocyanine green-like (excitation at 776 nm, emission at 796 nm) near-infrared fluorescent dye termed S0456, was more effective in detecting tumours when using NIR fluorescent imaging during surgery. At least one additional lesion was detected in 48.3% of patients (14/29) by using OTL38-mediated near-infrared fluorescence imaging, but the tumour-to-background fluorescence signal ratio (TBR) of OTL38 was 4.4±1.4.…”