Engineering fibrotic tissue in pancreatic cancer: A novel three-dimensional model to investigate nanoparticle delivery (original) (raw)
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Scientific Reports, 2024
Nanomedicine is a promising approach for tumor therapy but penetration is challenged by complex tumor microenvironments. The purpose of this study is to design nanoparticles and analyze their transport in two abnormal microenvironments through a 2-D simulation. Employing a Computational Fluid Dynamics (CFD) approach, tumor vascular-interstitial models were initially simulated, and the impact of nanoparticles on the velocity profile and pressure gradient within the tumor microenvironment was observed. Through meticulous mesh analysis, it was determined that optimal outcomes were achieved using a quadrilateral meshing method for pancreatic tumor and a quad/tri meshing method for hepatic tumor. Results showed an increase in vessel diameter correlated with elevated blood flow velocity, reaching a maximum of 1.40 × 10^−3 m/s with an expanding cell gap. The simulation results for pressure distribution show that as vessel diameter increases, the velocity of nanoparticles in blood increases and decreases the pressure of blood. Intriguingly, distinct fluid flow patterns in pancreatic and hepatic tumors, emphasize how microenvironmental differences, specifically cell pore size, profoundly impact therapeutic agent transport, with implications for drug delivery strategies in cancer therapy. These simulation-based insights enable researchers to anticipate nanofluid behavior in realistic settings. Future work, incorporating immune cells, will enhance the understanding of nanoparticle efficiency in cancer therapy. Angiogenesis has a non-remedial effect that leads to cancer. It is important to be inhibited before further proliferation of epithelial tissue cells which complicates a tumor's environment. Angiogenesis is triggered by hypoxia 1 and regulated with both activator and inhibitor molecules 2. Unlike vasculogenesis, angiogenesis is strictly a pathological process leading to tumor formation and chronic inflammation 3 , while vasculogenesis occurs in embryonic development. Tumor development is dependent on an uninterrupted blood supply to satisfy nutritional demands. This facilitates vessel development from the prevailing microvasculature throughout tumor neovascularization. The process is managed by vascular endothelial growth factors (VEGF) 4 , which, broadly, are angiogenic factors 5. The imbalance between anti-angiogenic and pro-angiogenic factors leads to initiates tumor angiogenesis 6. An atypical angiogenesis method results in a microvascular system with a typical malformed vessel design and uneven flow patterns 7-9. Hence, the development of a definite tumor microenvironment is achieved. It is the tumor microenvironment that influences the response of tumors to therapy or radiation treatment 10,11. An aggressive response to medicine is exhibited by tumors due to a complex structured vasculature. Natural vascular epithelial tissue contains a hierarchical data structure. Arteries divide into arterioles, which later divide into thin-walled capillaries. Sleek muscle cells (SMCs) maintain vascular stability by wrapping around massive vessel epithelial tissue 12. However, tumor epithelial tissue cells (TECs) are associated with uneven structures, ruffled edges, and long, weak protoplasm projections that stretch across the vessel lumen 13. Nanomedicine has become a well-liked possibility for tumor therapy 14,15. Developments in nanomedicine are emerging, especially to utilize the Enhanced Permeability and Retention (EPR) factor during drug delivery 16,17. The Enhanced Permeability and Retention (EPR) effect is the guiding principle of nanomedicine. It allows low relative molecular mass medication particles to concentrate in tissues and allows for vascular permeability in
Multistage nanoparticle delivery system for deep penetration into tumor tissue
Proceedings of the National Academy of Sciences, 2011
Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are ≈100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half-life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix. drug delivery | cancer therapy | nanomedicine
Interface Focus, 2015
Through nanomedicine, game-changing methods are emerging to deliver drug molecules directly to diseased areas. One of the most promising of these is the targeted delivery of drugs and imaging agents via drug carrier-based platforms. Such drug delivery systems can now be synthesized from a wide range of different materials, made in a number of different shapes, and coated with an array of different organic molecules, including ligands. If optimized, these systems can enhance the efficacy and specificity of delivery compared with those of non-targeted systems. Emerging integrated multiscale experiments, models and simulations have opened the door for endless medical applications. Current bottlenecks in design of the drug-carrying particles are the lack of knowledge about the dispersion of these particles in the microvasculature and of their subsequent internalization by diseased cells (Bao et al . 2014 J. R. Soc. Interface 11 , 20140301 ( doi:10.1098/rsif.2014.0301 )). We describe mul...
Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer
Nano letters, 2018
Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(ε-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(ε-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tum...
International Journal of Molecular Sciences, 2021
Pancreatic cancer is a unique cancer in that up to 90% of its tumour mass is composed of a hypovascular and fibrotic stroma. This makes it extremely difficult for chemotherapies to be delivered into the core of the cancer mass. We tissue-engineered a biomimetic 3D pancreatic cancer (“tumouroid”) model comprised of a central artificial cancer mass (ACM), containing MIA Paca-2 cells, surrounded by a fibrotic stromal compartment. This stromal compartment had a higher concentration of collagen type I, fibronectin, laminin, and hyaluronic acid (HA) than the ACM. The incorporation of HA was validated with alcian blue staining. Response to paclitaxel was determined in 2D MIA Paca-2 cell cultures, the ACMs alone, and in simple and complex tumouroids, in order to demonstrate drug sensitivity within pancreatic tumouroids of increasing complexity. The results showed that MIA Paca-2 cells grew into the complex stroma and invaded as cell clusters with a maximum distance of 363.7 µm by day 21. In...
3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer
Frontiers in digital health, 2021
Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.