Abstract
An ongoing need for new cancer therapeutics exists, especially ones that specifically home and target triple-negative breast cancer. Because triple-negative breast cancer express low or are devoid of estrogen, progesterone, or Her2/Neu receptors, another target must be used for advanced drug delivery strategies. Here, we engineered a nanodrug delivery system consisting of silver-coated gold nanorods (AuNR/Ag) targeting epithelial cell adhesion/activating molecule (EpCAM) and loaded with doxorubicin. This nanodrug system, AuNR/Ag/Dox-EpCAM, was found to specifically target EpCAM-expressing tumors compared to low EpCAM-expressing tumors. Namely, the nanodrug had an effective dose (ED50) of 3 μM in inhibiting 4T1 cell viability and an ED50 of 110 μM for MDA-MD-231 cells. Flow cytometry data indicated that 4T1 cells, on average, express two orders of magnitude more EpCAM than MDA-MD-231 cells, which correlates with our ED50 findings. Moreover, due to the silver coating, the AuNR/Ag can be detected simultaneously by surface-enhanced Raman spectroscopy and photoacoustic microscopy. Analysis by these imaging detection techniques as well as by inductively coupled plasma mass spectrometry showed that the targeted nanodrug system was taken up by EpCAM-expressing cells and tumors at significantly higher rates than untargeted nanoparticles (p < 0.05). Thus, this approach establishes a plasmonically active nanodrug theranostic for triple-negative breast cancer and, potentially, a delivery platform with improved multimodal imaging capability for other clinically relevant chemotherapeutics with dose-limiting toxicities, such as platinum-based or taxane-based therapies.
Highlights
The number of new anti-cancer agents approved by the US Food and Drug Administration (FDA) has decreased by more than 50% over the past decade, and most of the newly approved drugs target molecular entities via the same pathway(s) as previously approved therapeutics.[1, 2]
AuNR/Ags were synthesized with an average length of ~36 nm and an average width of ~12 nm, based on transmission electron microscopy and atomic force microscopy (AFM) measurements (Fig. 1)
Dox was conjugated to PEG via 1-ethyl-3-(3(dimethylamino)- propyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) coupling between the carboxyl terminus of PEG and the primary amine in Dox, which yielded a bulk average 4% (w/w) loading of Dox
Summary
The number of new anti-cancer agents approved by the US Food and Drug Administration (FDA) has decreased by more than 50% over the past decade, and most of the newly approved drugs target molecular entities via the same pathway(s) as previously approved therapeutics.[1, 2] Clinically, these compounds are prescribed at their maximal tolerated dose due to their toxicity, i.e., unwanted off-target side effects.[3]. Drugs are further hampered by the rapid emergence of therapy resistance in the body, hindering long-term clinical success Anthracyclines such as doxorubicin (Dox) are first-line, key components in many anti-cancer treatment strategies, including breast and ovarian cancer, but toxicity remains an important concern.[4, 5] These factors have created a strong, ongoing need to enhance the specificity and effectiveness of therapeutics that are already in clinical use. A number of gold-based nanomaterials are being investigated to deliver other challenged chemotherapeutics to tumors.[8,9,10] The biocompatibility and tunable surface chemistry of these materials enables conjugation of drug moieties to the surface These molecules can be released under the unique environmental conditions of a tumor, e.g., a lower pH, or in response to an external stimulus, in particular laser irradiation. The retention and uptake profiles suggest our nanomaterial-based imaging and delivery strategy warrant further studies in pre-clinical in vivo models
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