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Drug Delivery

Drug Delivery - Poster Session A

Poster J3 - Cancer Cell Membrane-Wrapped Gold Nanoshells for Photoacoustic Imaging of Triple-Negative Breast Cancer

Thursday, October 24, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses. The aggressiveness and rapid tumor growth of TNBC hinders development of effective diagnostic imaging techniques, making it difficult to provide timely and accurate diagnoses. Consequently, there are higher recurrence and mortality rates among TNBC patients. Photoacoustic(PA) imaging is a non-invasive imaging modality combining ultrasound and optical imaging, where light-absorbing contrast agents like gold nanoshells(NS) are intravenously-injected and once they arrive at the tumor an externally applied laser is used to irradiate NS, causing them to convert light energy into heat resulting in thermoelastic tissue expansion and production of sound waves detectable by an ultrasound transducer. Recent studies suggest that coating contrast agents with cancer cell-derived membranes can enable immune evasion and improve their tumor-targeting ability. Thus, we wrapped gold NS with 4T1 TNBC murine cell membranes, forming 4T1-NS to enable gold NS to target TNBC tumors. Here, we present in vitro results confirming that 4T1-NS can be synthesized and exhibit greater targeting and uptake by TNBC cells over non-cancerous breast epithelial cells. We also show in vitro with PA imaging that 4T1-NS exhibit greater binding to 4T1 cells compared to NS coated with passivating agent poly(ethylene glycol) (PEG-NS). Similar results were found in vivo where intravenously-administered 4T1-NS exhibited greater accumulation in orthotopic mouse TNBC tumors than PEG-NS, allowing for significant enhancement of PA-image contrast. This work provides a promising biomimetic platform to improve detection of TNBC, and this enhanced diagnostic capability may ultimately lead to improved patient outcomes.

Materials and

Methods:  NS were synthesized following the Oldenburg method and then 4T1-NS were formed by co-extruding the NS with 4T1 TNBC cell membrane vesicles collected via hypotonic cell lysis, differential centrifugation, and physical extrusion through a 400 nm polycarbonate film. Cell uptake of 4T1-NS was analyzed by separately culturing 4T1 TNBC cells and non-cancerous EpH4-Ev breast epithelial cells and incubating the cells with 4T1-NS or PEG-NS for 4 hours. The cells were then imaged by multiphoton microscopy (Figure 1A). For in vitro PA imaging (Figure 1B-D), a tissue-mimicking phantom base consisting of 8% m/v gelatin, 0.2% m/v silica, and 0.1% m/v formaldehyde was prepared. Separately, 4T1 TNBC cells were incubated with 4T1-NS or PEG-NS or saline for 24 hours, rinsed, and mixed with 16% gelatin. The cell-gelatin mixture was then pipetted onto the phantom base to create dome-shaped droplets, which were imaged by PA imaging with a Vevo F2 LAZR-X system. For in vivo studies (Figure 1E-G), female mice bearing 4T1 orthotopic tumors in the mammary fat pad were intravenously injected with 4T1-NS, PEG-NS, or saline through the tail vein, and the tumors were imaged 6 hours post-injection using PA imaging.

Results, Conclusions, and Discussions: Results and discussion
In vitro uptake studies revealed that 4T1-NS preferentially target 4T1 TNBC cells over non-cancerous EpH4-Ev breast epithelial cells (Figure 1A). In vitro PA imaging revealed that 4T1 TNBC cells preferentially bind 4T1-NS over PEG-NS (Figure 1C) and resulting average PA signal intensity was significantly higher for 4T1 cells treated with 4T1-NS than PEG-NS (Figure 1D). In vivo PA imaging of 4T1 tumors reveals that, 6 hours post-tail vein injection, 4T1-NS accumulate in the tumor to a greater extent than PEG-NS (Figure 1F), indicated by a significantly greater increase in PA signal intensity from the pre-injection baseline for 4T1-NS-treated tumors than that of PEG-NS-treated tumors (Figure 1G). Collectively, these results indicate that 4T1-NS can successfully target TNBC cells and tumors to enable timely and accurate detection of TNBC using PA imaging.
Conclusions
These results demonstrate that wrapping gold NS with 4T1 TNBC cell membranes enables the homotypic targeting of TNBC cells and tumors, allowing PA imaging to be used as a diagnostic tool for TNBC patients. Through its efficiency and accuracy, this method of detection could improve the prognosis of TNBC patients.

Acknowledgements (Optional):