Due to the theragnostic potential of mesoporous silica nanoparticles (MSNs), these were extensively investigated as a novel approach to improve clinical outcomes. Boasting an impressive array of formulations and modifications, MSNs demonstrate significant in vivo efficacy when used to identify or treat myriad malignant diseases in preclinical models. As MSNs continue transitioning into clinical trials, a thorough understanding of the characteristics of effective MSNs is necessary. This review highlights recent discoveries and advances in MSN understanding and technology. Specific focus is given to cancer theragnostic approaches using MSNs. Characteristics of MSNs such as size, shape, and surface properties are discussed in relation to effective nanomedicine practice and projected clinical efficacy. Additionally, tumor-targeting options used with MSNs are presented with extensive discussion on active-targeting molecules. Methods for decreasing MSN toxicity, improving site-specific delivery, and controlling release of loaded molecules are further explained. Challenges facing the field and translation to clinical environments are presented alongside potential avenues for continuing investigations.

Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to drug resistance. Imaging is one of the tools best poised to enable tailoring of cancer therapies. The field of image-guided nanotheranostics has the potential to harness the precision of modern imaging techniques and use this to direct, dictate, and follow site-specific drug delivery, all of which can be used to further tailor cancer therapies on both the individual and population level. The use of image-guided drug delivery has exploded in preclinical and clinical trials although the clinical translation is incipient. This review will focus on traditional mechanisms of targeted drug delivery in cancer, including the use of molecular targeting, as well as the foundations of designing nanotheranostics, with a focus on current clinical applications of nanotheranostics in cancer. A variety of specially engineered and targeted drug carriers, along with strategies of labeling nanoparticles to endow detectability in different imaging modalities will be reviewed. It will also introduce newer concepts of image-guided drug delivery, which may circumvent many of the issues seen with other techniques. Finally, we will review the current barriers to clinical translation of image-guided nanotheranostics and how these may be overcome.

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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<0.0001,n=5). 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.