Use of Ultrasmall Core-Shell Fluorescent Silica Nanoparticles for Image-Guided Sentinel Lymph Node Biopsy in Head and Neck Melanoma: A Nonrandomized Clinical Trial

Abstract

Importance: Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization.

Objective: To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy.

Design, setting, and participants: This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018.

Interventions: Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine-aspartic acid-tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally.

Main outcomes and measures: The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization.

Results: Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves.

Conclusions and relevance: This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care.

Trial registration: ClinicalTrials.gov Identifier: NCT02106598.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Bradbury, Wiesner, Ma, and Turker reported holding interest in and Drs Wiesner and Bradbury reported being company and/or scientific advisory board members of Elucida Oncology, Inc, which has licensed intellectual property from Memorial Sloan Kettering Cancer Center and Cornell on nanoparticles and their application in oncology. Dr Bradbury reported having a patent for fluorescent silica-based nanoparticles licensed to Elucida Oncology. Dr Wiesner reported holding multiple patents for intellectual property on particles. Dr Patel reported being a coinventor of licensed intellectual property to Elucida Oncology and holding equity in and having a patent licensed by Summit Biomedical Imaging. No other disclosures were reported.

Figures

Figure 1.. Nanoparticle-Aided Fluorescence Detection of a Metastatic Intraparotid Sentinel Lymph Nodes (SLN)

Intradermal injection of a male patient in his 60s with integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine–aspartic acid–tyrosine peptides near a scalp melanoma (A), shown in both composite (green signal) and adjacent fluorescence (white signal) displays. Progressive increase in fluorescence signal, seen as a blush within the nodal bed (B-E) on both composite and fluorescence displays, corresponds with an intraparotid SLN approximately 1.5 to 2 cm deep. F, Fluorescence signal within the ex vivo SLN.

Figure 2.. Real-Time Transcutaneous Visualization of a Postauricular Sentinel Lymph Node (SLN) Using Nanoparticles

A male patient in his 50s with a scalp melanoma was injected peritumorally with integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine–aspartic acid–tyrosine peptides (green signal in A). Focal fluorescence was seen through the intact skin overlying a postauricular SLN (B) using the Spectrum camera system (Quest) for real-time optical imaging guidance. Limited extent of surgical dissection (C) and size of the resection cavity (D) relative to the planned area of dissection unaided (ie, marked line in panel C is approximately 3 times larger than that actually drawn on the basis of the particle signal). Images are derived from the intraoperative video (Video).