Microtechnologies for mimicking tumor-imposed transport limitations and developing targeted cancer therapies (original) (raw)
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Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Proceedings of the National Academy of Sciences, 1998
Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: ( i ) spatially, by growing tumors in subcutaneous or cranial locations and ( ii ) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 μm. This pore cutoff size was reduced in tumo...
Molecular cancer research : MCR, 2006
It is widely recognized that the vasculature of the tumor is inadequate to meet the demands of the growing mass. The malformed vasculature is at least in part responsible for regions of the tumor that are hypoxic, acidotic, and exposed to increased interstitial fluid pressure. These unique aspects of the tumor microenvironment have been shown to act as barriers to conventional chemotherapy or radiation-based therapies. It now seems that while the vasculature initiates these tumor-specific conditions, the cells within the tumor respond to these stresses and add to the unique solid tumor physiology. Gene expression changes have been reported in the tumor for vascular endothelial growth factor, carbonic anhydrase IX, and pyruvate dehydrogenase kinase 1. The activity of these gene products then influences the tumor physiology through alterations in vascular permeability and interstitial fluid pressure, extracellular acidosis, and mitochondrial oxygen consumption and hypoxia, respectivel...
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
Modification of tumor blood flow: Current status and future directions
Seminars in Radiation Oncology, 1998
Suboptimal drug distribution and hypoxia, which can contribute to treatment failure, are a direct consequence of the spatial and temporal heterogeneity in perfusion that occurs in solid tumors. Therefore, improvements in tumor blood flow have wide-ranging therapeutic importance. Paradoxically, controlled decreases in tumor blood flow can also be exploited and, if permanent, induce extensive tumor cell death on their own. We review the current knowledge of the factors controlling tumor blood flow with emphasis on the roles of the endogeneous vasodilator nitric oxide and the endogenous vasoconstrictor endothelin-1. The potential importance and application of approaches that irreversibly damage vascular function, so-called vascular targeting, are also discussed. Emphasis is given to the drug-based approaches to vascular targeting that are now entering clinical evaluation. There is no doubt that increased understanding of the processes that determine blood flow in tumors, coupled with the availability of techniques to monitor blood flow noninvasively in the clinic, will enable strategies for selectively modifying tumor blood flow to be transferred from the laboratory to the clinical setting. Copyright 9 1998by W.B. Saunders Company T he angiogenic stimulus elicited by tumor tissue results in the formation of new blood vessels that differ in many respects from those in normal tissues. These differences include a relative lack of vascular smooth muscle, abnormal and chaotic branching patterns, and absence of innervation. The development and structure of the blood vessel network in tumors can be likened to building a road network without the benefit of a centralized planning strategy or quality control in construction. Such a system, although rapidly responsive to strong local needs, would not provide the most efficient distribution network. It is well established that both the structure and the dynamics of the blood supply of tumors are characterized by spatial and temporal heterogeneity. Therapeutic Importance of Tumor Blood Flow There are many therapeutic implications of a spatially heterogeneous tumor blood flow. Uptake and distribution of blood-borne anticancer agents, including chemicals, antibodies, and gene delivery systems, are compromised. In addition, microregional hypoxia, acidosis, and substrate depletion develop. One
The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer
International Journal of Molecular Sciences
Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially 'omics' technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously 'unsupportive' microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show
Relevance of tumor microenvironment for progression, therapy and drug development
Anti-Cancer Drugs, 2004
Tumor interstitium exhibits a microenvironment that differs from corresponding normal tissues. Tumor phenotype shows, for example, an elevated intracellular pH (pH i ), a lowered extracellular pH (pH e ), a low oxygen concentration and low glucose levels. These differences are caused by cell biological (so called intrinsic) factors, e.g. a higher acidification rate, as well as by more systemic (extrinsic) factors, e.g. poor tumor vascularization. They represent important factors for invasiveness, immune suppression and proliferation, and they imply possibilities for diagnosis, prognosis and therapy. We have developed an experimental data-based computer model, which has simulated the potential role of metabolic effects on tumor progression. We show an experiment on cellular metabolism demonstrating the immunosuppressive impact of low pH e on peripheral blood mononuclear cells. Finally, we review important findings on the tumor microenvironment leading to possibilities for therapy which are currently evolving and which promise higher effectiveness for cancer therapy.
Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules
Proceedings of the National Academy of Sciences of the United States of America, 1999
Cancer therapies using genes and other macromolecules might realize their full clinical potential if they could be delivered to tumor tissue in optimal quantities. Unfortunately, the compromised circulation within tumors poses a formidable resistance to adequate and uniform penetration of these agents. Previously, we have proposed elevated interstitial fluid pressure (IFP) as a major physiological barrier to delivery of macromolecules. Here we postulate that modulation of tumor microvascular pressure (MVP) and associated changes in IFP would enhance macromolecular delivery into a solid tumor. To test our hypothesis, we altered tumor MVP by either periodic injection or continuous infusion of angiotensin II (AII) and measured the resulting changes in IFP and uptake of macromolecules. We used the nicotinyl hydrazine derivative of human polyclonal IgG (HYNIC-IgG) as a nonspecific macromolecule and CC49 antibody as a specific macromolecule. We found that both chronic and periodic modulat...