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•PDAC is a highly aggressive cancer exhibiting high mortality, that has not significantly improved over decades.•Nanomaterials have great potential to improve the dismal prognosis of ...PDAC.•We summarize the innovative use of nanoparticles to overcome the limitations of current treatments towards PDAC.•We describe the use of nanoparticles for the delivery of single and combinatory agents, for stroma-modulation therapies, and improved immunotherapy against PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to its aggressiveness and the challenges for early diagnosis and treatment. Recently, nanotechnology has demonstrated relevant strategies to overcome some of the major clinical issues in the treatment of PDAC. This review is focused on the pathological hallmarks of PDAC and the impact of nanotechnology to find solutions. It describes the use of nanoparticle-based systems designed for the delivery of chemotherapeutic agents and combinatorial alternatives that address the chemoresistance associated with PDAC, the development of combination therapies targeting the molecular heterogeneity in PDAC, the investigation of novel therapies dealing with the improvement of immunotherapy and handling the desmoplastic stroma in PDAC by remodeling the tumor microenvironment. A special section is dedicated to the design of nanoparticles for unique non-traditional modalities that could be promising in the future for the improvement in the dismal prognosis of PDAC.
The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of ...inorganic‐based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous‐silica‐based nanocarriers with stimuli‐responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site‐specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli‐responsive mesoporous‐silica‐based systems are described.
Recent applications of inorganic nanomaterials in the field of drug delivery have attracted a lot of attention in the last decade. One of the most promising candidates for this matter is mesoporous silica nanoparticles. This review highlights the latest progress in terms of the application of mesoporous silica nanoparticles for intracellular drug delivery.
Nanoparticle-based contrast agents are attracting a great deal of attention for various biomedical imaging and theranostic applications. Compared to conventional contrast agents, nanoparticles ...possess several potential advantages to improve in vivo detection and to enhance targeting efficiency. Silica-based nanoprobes can be engineered to achieve longer blood circulation times, specific clearance pathways, and multivalent binding. In this tutorial review, we summarize the latest progress on designing silica-based nanoprobes for imaging and theranostic applications. The synthesis of both solid silica and mesoporous silica nanoparticles is described, along with different approaches used for surface functionalization. Special emphasis is placed on the application of silica-based nanoprobes in optical, magnetic resonance, and multimodal imaging. The latest breakthroughs in the applications of silica nanoparticles as theranostic agents are also highlighted.
Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy with a dismal survival rate. Recent combination therapies have had a major impact on the improvement of PDAC prognosis. ...Nevertheless, clinically used combination regimens such as FOLFIRINOX and gemcitabine (Gem)/nab‐paclitaxel still face major challenges due to lack of the safe and ratiometric delivery of multiple drugs. Here, a rationally designed mesoporous silica nanoparticle (MSN)‐based platform is reported for the target‐specific, spatiotemporal, ratiometric, and safe co‐delivery of Gem and cisplatin (cisPt). It is shown that systemic administration of the nanoparticles results in synergistic therapeutic outcome in a syngeneic and clinically relevant genetically engineered PDAC mouse model that has rarely been used for the therapeutic evaluation of nanomedicine. This synergism is associated with a strategic engineering approach, in which nanoparticles provide redox‐responsive controlled delivery and in situ differential release of Gem/cisPt drugs with the goal of overcoming resistance to Pt‐based drugs. The platform is also rendered with additional tumor‐specificity via a novel tumor‐associated mucin1 (tMUC1)‐specific antibody, TAB004. Overall, the platform suppresses tumor growth and eliminates the off‐target toxicities of a highly toxic chemotherapy combination.
A multifunctional mesoporous silica nanoparticle (MSN)‐based platform for the target‐specific, spatiotemporal, ratiometric, and safe co‐delivery of gemcitabine (Gem) and cisplatin (cisPt) is developed. This platform efficiently suppresses tumor growth and eliminates the off‐target toxicities of this highly toxic chemotherapy combination in a syngeneic and clinically relevant genetically engineered pancreatic ductal adenocarcinoma (PDAC) mouse model.
Polyhedral oligomeric silsesquioxanes (POSS) have attracted considerable attention in the design of novel organic-inorganic hybrid materials with high performance capabilities. Features such as their ...well-defined nanoscale structure, chemical tunability, and biocompatibility make POSS an ideal building block to fabricate hybrid materials for biomedical applications. This review highlights recent advances in the application of POSS-based hybrid materials, with particular emphasis on drug delivery, photodynamic therapy and bioimaging. The design and synthesis of POSS-based materials is described, along with the current methods for controlling their chemical functionalization for biomedical applications. We summarize the advantages of using POSS for several drug delivery applications. We also describe the current progress on using POSS-based materials to improve photodynamic therapies. The use of POSS for delivery of contrast agents or as a passivating agent for nanoprobes is also summarized. We envision that POSS-based hybrid materials have great potential for a variety of biomedical applications including drug delivery, photodynamic therapy and bioimaging.
A gold nanoparticle (AuNP)-capped mesoporous silica nanosphere (MSN)-based intracellular drug delivery system (PR-AuNPs-MSN) for the photoinduced controlled release of an anticancer drug, paclitaxel, ...inside of human fibroblast and liver cells was synthesized and characterized. We found that the mesopores of MSN could be efficiently capped by the photoresponsive AuNPs without leaking the toxic drug, paclitaxel, inside of live human cells. This "zero premature release" characteristic is of importance for delivery of toxic drugs in chemotherapy. Furthermore, we demonstrated that the cargo-release property of this PR-AuNPs-MSN system could be easily controlled by low-power photoirradiation under biocompatible and physiological conditions. We envision that our results would play a significant role in designing new generations of carrier materials for intracellular delivery of a variety of hydrophobic toxic drugs.
In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis ...of this type of MSN materials is described along with the current methods for controlling the structural properties and chemical functionalization for biotechnological and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.
Cancer immunotherapy recently transforms the traditional approaches against various cancer malignancies. Immunotherapy includes systemic and local treatments to enhance immune responses against ...cancer and involves strategies such as immune checkpoints, cancer vaccines, immune modulatory agents, mimetic antigen-presenting cells, and adoptive cell therapy. Despite promising results, these approaches still suffer from several limitations including lack of precise delivery of immune-modulatory agents to the target cells and off-target toxicity, among others, that can be overcome using nanotechnology. Mesoporous silica nanoparticles (MSNs) are investigated to improve various aspects of cancer immunotherapy attributed to the advantageous structural features of this nanomaterial. MSNs can be engineered to alter their properties such as size, shape, porosity, surface functionality, and adjuvanticity. This review explores the immunological properties of MSNs and the use of MSNs as delivery vehicles for immune-adjuvants, vaccines, and mimetic antigen-presenting cells (APCs). The review also details the current strategies to remodel the tumor microenvironment to positively reciprocate toward the anti-tumor immune cells and the use of MSNs for immunotherapy in combination with other anti-tumor therapies including photodynamic/thermal therapies to enhance the therapeutic effect against cancer. Last, the present demands and future scenarios for the use of MSNs for cancer immunotherapy are discussed.
Therapeutic success in the treatment of pancreatic ductal adenocarcinoma (PDAC) is hindered by the extensive stroma associated to this disease. Stroma is composed of cellular and non-cellular ...components supporting and evolving with the tumor. One of the most studied mediators of cancer cell-stroma crosstalk is sonic hedgehog (SHh) pathway leading to the intense desmoplasia observed in PDAC tumors. Herein, we demonstrate that the use of mesoporous silica nanoparticles (MSNs) containing an SHh inhibitor, cyclopamine (CyP), and the combination of chemotherapeutic drugs (Gemcitabine (Gem)/cisplatin (cisPt)) as the main delivery system for the sequential treatment led to the reduction in tumor stroma along with an improvement in the treatment of PDAC. We synthesized two versions of the MSN-based platform containing the SHh inhibitor (CyP-MSNs) and the drug combination (PEG-Gem-cisPt-MSNs). In vitro and in vivo protein analysis show that CyP-MSNs effectively inhibited the SHh pathway. In addition, the sequential combination of CyP-MSNs followed by PEG-Gem-cisPt-MSNs led to effective stromal modulation, increased access of secondary PEG-Gem-cisPt-MSNs at the tumor site, and improved therapeutic performance in HPAF II xenograft mice. Taken together, our findings support the potential of drug delivery using MSNs for stroma modulation and to prevent pancreatic cancer progression.
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