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PURPOSE: To develop optoacoustic, spectrally distinct, actively targeted gold nanoparticle–based near-infrared probes (trastuzumab [TRA], TRA-Aurelia-1, and TRA-Aurelia-2) that can be individually identifiable at multispectral optoacoustic tomography (MSOT) of human epidermal growth factor receptor 2 (HER2)–positive breast tumors. MATERIALS AND METHODS: Gold nanoparticle–based near-infrared probes (Aurelia-1 and 2) that are optoacoustically active and spectrally distinct for simultaneous MSOT imaging were synthesized and conjugated to TRA to produce TRA-Aurelia-1 and 2. Freshly resected human HER2-positive (n = 6) and HER2-negative (n = 6) triple-negative breast cancer tumors were treated with TRA-Aurelia-1 and TRA-Aurelia-2 for 2 hours and imaged with MSOT. HER2-expressing DY36T2Q cells and HER2-negative MDA-MB-231 cells were implanted orthotopically into mice (n = 5). MSOT imaging was performed 6 hours following the injection, and the Friedman test was used for analysis. RESULTS: TRA-Aurelia-1 (absorption peak, 780 nm) and TRA-Aurelia-2 (absorption peak, 720 nm) were spectrally distinct. HER2-positive human breast tumors exhibited a significant increase in optoacoustic signal following TRA-Aurelia-1 (28.8-fold) or 2 (29.5-fold) (P = .002) treatment relative to HER2-negative tumors. Treatment with TRA-Aurelia-1 and 2 increased optoacoustic signals in DY36T2Q tumors relative to those in MDA-MB-231 controls (14.8-fold, P < .001; 20.8-fold, P < .001, respectively). CONCLUSION: The study demonstrates that TRA-Aurelia 1 and 2 nanoparticles operate as a spectrally distinct HER2 breast tumor–targeted in vivo optoacoustic agent. Keywords: Molecular Imaging, Nanoparticles, Photoacoustic Imaging, Breast Cancer Supplemental material is available for this article. © RSNA, 2023

Purpose: While nanoparticles are widely studied as potential theranostic treatments for cancer, weak tumor specificity has hindered clinical translation. Features that contribute to tumor specificity are historically controversial, particularly when using clinically relevant models. Aggressive cancers, such as pancreatic ductal adenocarcinoma (PDAC), stand to benefit from development of highly specific nanoparticles as a theranostic drug delivery system. This work evaluates active targeting and nanoparticle size, in a silica-based nanoparticle for specific accumulation and release of contrast agent within an orthotopically implanted tumor. Methods: Mesoporous silica nanoparticles (MSNs) were synthesized with wormhole-like pores using a silica precursor to coat a surfactant scaffold. Chitosan was attached to MSN surface as a pH-responsive gatekeeper for encapsulated agents. A series of acidification and basification procedures resulted in loading of photoacoustic contrast agent IR780 within MSN pores. MSNs were further functionalized for attachment of V7 peptide to target aggressive and acidic pancreatic cancer. pH-sensitivity and tumor specificity/uptake was validated using an in vitro PDAC cell model (S2VP10L) prior to implantation and assessment in an animal model. Functionalized MSNs were intravenously injected into athymic mice with orthotopically implanted PDAC tumors. Near infrared fluorescence and optoacoustic imaging were used to evaluate the biodistribution of MSNs subsequent to treatment. Results: Zeta potential, DLS, and TEM were utilized to show three differently sized MSNs of 26, 45, and 73 nm and confirm conjugation of chitosan and V7 peptide. Dye-release assays indicated significantly increased agent release from MSNs in acidic pH (~90%) compared to biological pH (~15%) (p=0.001). Treatment of PDAC cell line with MSNs showed highest uptake and specificity with actively targeted 26nm particles and that all actively targeted MSNs exhibited greater specificity than all passively targeted MSNs (p Conclusion: Active targeting outperforms nanoparticle size for facilitation of tumor-specific uptake in an acidic PDAC murine model. Active targeting was necessary for high accumulation of MSNs and contrast agent in the tumor. Nanoparticle size had a secondary, but notable influence on tumor uptake in which smaller sized MSNs resulted in higher tumor specificity. Citation Format: William M. MacCuaig, Abhilash Samykutty, Molly McNally, Ajay Jain, William E. Grizzle, Lacey R. McNally. Comparing influences of active targeting and nanoparticle size on tumor specificity in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2458.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal disease and the leading cause of cancer death worldwide. The survival rate of patients with this form of cancer is about 8%. The physiological barrier of the tumor microenvironment composed of a dense stroma and disorganized blood vessels creates a barrier for early identification and treatment of this deadly disease. In recent years, nanoparticle-based controlled delivery systems were developed to exploit the pathophysiology of biological systems such as acidic tumor microenvironment or the altered tumor-specific enzymes to improve the diagnosis and treatment efficacy. Here, we demonstrate the collagenase IV-mediated tumor site-selective release of the IR-780 imaging probe from the M-Ge-SDC1 nanoparticles, revealing the feasibility of the collagenase IV (MMP-9) responsive target specificity for diagnosing pancreatic cancer by multispectral optoacoustic tomography (MSOT) imaging. Methods: Mesoporous silica nanoparticles (MSN) with wormhole pore topology were synthesized and were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The surface of MSN was conjugated with Gelatin-A to obtain M-Ge. The M-Ge particles were loaded with propidium Iodide (PI) or IR780 infrared imaging dye. The M-Ge surface was further conjugated with Syndecan-1 (SDC1) to improve the target specificity to release imaging cargo from the nanoparticles. Female athymic mice were orthotopically implanted with S2VP10 tumor cells. After a week of tumor implantation, mice were intravenously injected with M-Ge-SDC1 nanoparticles containing IR780 dye and were imaged with MSOT and AMI. Results: In the current study, Mesoporous silica nanoparticles with 27 nm diameter were synthesized. The Gelatin-A crosslinking on the surface of MSN particles as a gatekeeper was developed that could degrade upon contact with collagenase IV in the tumor microenvironment. The conjugation of SDC1 further improved the tumor specificity. The athymic mice orthotopically implanted with S2VP10 cells closely resemble human PDAC. Our results demonstrated that intravenous delivery of M-Ge-SDC1 nanoparticles could enzymatically degrade (MMP-9) and release IR780 at the tumor site and conjugation of SDC1 further improved the tumor specificity to detect the orthotopically implanted pancreatic tumors (p Conclusion: Due to the lack of effective screening tools, PDAC has the lowest survival rate and limited therapeutic efficacy for current FDA-approved drugs compared to other malignancies. Innovative technologies to develop engineered nanoparticles with active targeting moiety and dynamic imaging technology can overcome these limitations. Implementing such systems can enhance PDAC detection that can be translated into the clinic to improve health care. Citation Format: Abhilash Samykutty, Molly McNally, William M. MacCuaig, Jordan Hagood, Girish Mishra, Barish H. Edil, William E. Grizzle, Lacey R. McNally. Matrix metalloproteinase-9 responsive active targeted silica nanoparticles for pancreatic cancer detection by multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 300.