Modification of tumour blood flow using the hypertensive agent, angiotensin II

The effects of different doses of angiotensin II (0.02 to 0.5 microgram kg-1 min-1 on mean arterial blood pressure, tissue blood flow and tissue vascular resistance were investigated in BD9 rats. Blood flow was measured using the uptake of 125I- or 14C-labelled iodoantipyrine (125I-IAP and 14C-IAP). Spatial heterogeneity of blood flow within tumours, before and after angiotensin II infusion, was also measured using 14C-IAP and an autoradiographic procedure. Mean arterial blood pressure rose steeply with angiotensin II dose. Blood flow to skeletal muscle, skin overlying the tumour, contralateral skin, small intestine and kidney tended to decline in a dose-dependent manner. Blood flow to the tumour was also reduced (to 80% of control values) but there was no dose response. Blood flow to the heart was slightly increased and blood flow to the brain was unaffected by angiotensin II. Vascular resistance, in all tissues, was increased by angiotensin II infusion. The increase in tumour tissue was similar to that found in skeletal muscle and small intestine and is likely to be caused by a direct vasoconstricting effect of the drug rather than autoregulation of tumour blood flow in the face of an increase in perfusion pressure. The reduction in overall blood flow at the highest perfusion pressure was due to a preferential effect of angiotensin II at the tumour periphery. These results show that some tumours, at least, can respond directly to the effects of vasoactive agents

Protected Graft Copolymer (PGC) in Imaging and Therapy: A Platform for the Delivery of Covalently and Non-Covalently Bound Drugs

Initially developed in 1992 as an MR imaging agent, the family of protected graft copolymers (PGC) is based on a conjugate of polylysine backbone to which methoxypoly(ethylene glycol) (MPEG) chains are covalently linked in a random fasion via N-epsilon-amino groups. While PGC is relatively simple in terms of its chemcial composition and structure, it has proved to be a versatile platform for in vivo drug delivery. The advantages of poly amino acid backbone grafting include multiple available linking sites for drug and adaptor molecules. The grafting of PEG chains to PGC does not compromise biodegradability and does not result in measurable toxicity or immunogenicity. In fact, the biocompatablility of PGC has resulted in its being one of the few 100% synthetic non-proteinaceous macromolecules that has suceeded in passing the initial safety phase of clinical trials. PGC is capable of long circulation times after injection into the blood stream and as such found use early on as a carrier system for delivery of paramagnetic imaging compounds for angiography. Other PGC types were later developed for use in nuclear medicine and optical imaging applications in vivo. Recent developments in PGC-based drug carrier formulations include the use of zinc as a bridge between the PGC carrier and zinc-binding proteins and re-engineering of the PGC carrier as a covalent amphiphile that is capabe of binding to hydrophobic residues of small proteins and peptides. At present, PGC-based formulations have been developed and tested in various disease models for: 1) MR imaging local blood circulation in stroke, cancer and diabetes; 2) MR and nuclear imaging of blood volume and vascular permeability in inflammation; 3) optical imaging of proteolytic activity in cancer and inflammation; 4) delivery of platinum(II) compounds for treating cancer; 5) delivery of small proteins and peptides for treating diabetes, obesity and myocardial infarction. This review summarizes the experience accumulated by various research groups that chose to use PGC as a drug delivery platform

Emerging Techniques in Breast MRI

As indicated throughout this chapter, there is a constant effort to move to more sensitive, specific, and quantitative methods for characterizing breast tissue via magnetic resonance imaging (MRI). In the present chapter, we focus on six emerging techniques that seek to quantitatively interrogate the physiological and biochemical properties of the breast. At the physiological scale, we present an overview of ultrafast dynamic contrast-enhanced MRI and magnetic resonance elastography which provide remarkable insights into the vascular and mechanical properties of tissue, respectively. Moving to the biochemical scale, magnetization transfer, chemical exchange saturation transfer, and spectroscopy (both “conventional” and hyperpolarized) methods all provide unique, noninvasive, insights into tumor metabolism. Given the breadth and depth of information that can be obtained in a single MRI session, methods of data synthesis and interpretation must also be developed. Thus, we conclude the chapter with an introduction to two very different, though complementary, methods of data analysis: (1) radiomics and habitat imaging, and (2) mechanism-based mathematical modeling

Protected Graft Copolymer (PGC) in Imaging and Therapy: A Platform for the Delivery of Covalently and Non-Covalently Bound Drugs

Initially developed in 1992 as an MR imaging agent, the family of protected graft copolymers (PGC) is based on a conjugate of polylysine backbone to which methoxypoly(ethylene glycol) (MPEG) chains are covalently linked in a random fasion via N-ε-amino groups. While PGC is relatively simple in terms of its chemcial composition and structure, it has proved to be a versatile platform for in vivo drug delivery. The advantages of poly amino acid backbone grafting include multiple available linking sites for drug and adaptor molecules. The grafting of PEG chains to PGC does not compromise biodegradability and does not result in measurable toxicity or immunogenicity. In fact, the biocompatablility of PGC has resulted in its being one of the few 100% synthetic non-proteinaceous macromolecules that has suceeded in passing the initial safety phase of clinical trials. PGC is capable of long circulation times after injection into the blood stream and as such found use early on as a carrier system for delivery of paramagnetic imaging compounds for angiography. Other PGC types were later developed for use in nuclear medicine and optical imaging applications in vivo. Recent developments in PGC-based drug carrier formulations include the use of zinc as a bridge between the PGC carrier and zinc-binding proteins and re-engineering of the PGC carrier as a covalent amphiphile that is capabe of binding to hydrophobic residues of small proteins and peptides. At present, PGC-based formulations have been developed and tested in various disease models for: 1) MR imaging local blood circulation in stroke, cancer and diabetes; 2) MR and nuclear imaging of blood volume and vascular permeability in inflammation; 3) optical imaging of proteolytic activity in cancer and inflammation; 4) delivery of platinum(II) compounds for treating cancer; 5) delivery of small proteins and peptides for treating diabetes, obesity and myocardial infarction. This review summarizes the experience accumulated by various research groups that chose to use PGC as a drug delivery platform

Tumor vasculature and microenvironment during progression and treatment : insights from optical microscopy

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010.Vita. Cataloged from PDF version of thesis.Includes bibliographical references.In addition to cancer cells, solid tumors consist of a variety of cell types and tissues defining a complex microenvironment that influences disease progression and response to therapy. To fully characterize and probe the tumor microenvironment, new tools are needed to quantitatively assess microanatomical and physiological changes during tumor growth and treatment. Particularly important, is the metabolic microenvironment defined in tumors by hypoxia (low p02) and acidity (low pH). These parameters have been shown to influence response to radiation therapy and chemotherapy. However, very little is known about spatio-temporal changes in p02 and pH during tumor progression and therapy. By modifying the technique of intravital multiphoton microscopy (MPM) to perform phosphorescence quenching microscopy, I developed a non-invasive method to quantify oxygen tension (p02) in living tissue at high three-dimensional resolution. To probe functional changes in the metabolic microenvironment, I measured in vivo P02 during tumor growth and antiangiogenic (vascular targeted) treatment in preclinical tumor models. Nanotechnology is rapidly emerging as an important source of biocompatible tools that may shape the future of medical practice. Fluorescent semiconductor nanocrystals (NCs), also known as quantum dots, are a powerful tool for biological imaging, cellular targeting and molecular sensing.(cont.) I adapted novel fluorescence resonance energy transfer (FRET) -based nanocrystal (NC) biosensors for use with MPM to qualitatively measure in vivo extracellular pH in tumors at high-resolution. While intravital multiphoton microscopy demonstrates utility and adaptability in the study of cancer and response to therapy, the requisite high numerical aperture and exogenous contrast agents result in a limited capacity to investigate substantial tissue volumes or probe dynamic changes repeatedly over prolonged periods. By applying optical frequency domain imaging (OFDI) as an intravital microscopic tool, the technical limitations of multiphoton microscopy can be circumvented providing unprecedented access to previously unexplored, critically important aspects of tumor biology. Using entirely intrinsic mechanisms of contrast within murine tumor models, OFDI is able to simultaneously, rapidly, and repeatedly probe the microvasculature, lymphatic vessels, and tissue microstructure and composition over large volumes. Using OFDI-based techniques, measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy were demonstrated, thereby highlighting the potential of OFDI to facilitate the exploration of pathophysiological processes and the evaluation of treatment strategies.by Ryan M. Lanning.Ph.D

Arteriogenesis

Cardiovascular occlusive diseases, such as myocardial infarction or stroke, are still the major cause of morbidity and mortality worldwide and are, particularly during the SARS-CoV-2 pandemic, drastically increasing. Arteriogenesis, which describes the process of natural arterial bypass growth, is a tissue- and life-saving process, which is given to us by mother nature to compensate for the function of a stenosed coronary or peripheral artery non-invasively. Since our first investigations on the mechanisms of collateral artery growth, more than 20 years ago, a lot of progress has been made, which we aim to make accessible in the current book. We present the available animal models and share information on the used state of the art techniques. We describe how fluid shear stress, the trigger for arteriogenesis, is translated into biochemical signal transduction cascades, and we also highlight the functional role of extracellular RNA and Il10. We address the problematic features of arteriogenesis in patients suffering from diabetes mellitus, and provide an overview of currently available or potentially therapeutic approaches to promote arteriogenesis in patients. We focus on the combination of ultrasound and microbubbles, the permanent occlusion of the internal mammary arteries, and simple exercise training. We believe that we have come much closer to achieving our goal of understanding the mechanisms of arteriogenesis, enabling clinicians to promote collateral artery growth in patients and cure vascular occlusive diseases

UNDERSTANDING ANATOMICAL PERFUSION AND STRATEGIES TO OPTIMIZE VASCULARITY IN FREE TISSUE TRANSFER FOR AUTOLOGOUS BREAST RECONSTRUCTION USING THE DEEP INFERIOR EPIGASTRIC ARTERY PERFORATOR (DIEP) FLAP

Breast cancer is the commonest cancer that affects women in the United Kingdom (UK). Autologous free tissue transfer using abdominal tissue remains an excellent option for breast reconstruction following mastectomy, given greater availability of tissue and lower donor site morbidity associated with muscle-sparing approaches (perforator-based). This research evaluated microvascular anatomy of Deep Inferior Epigastric Artery Perforator (DIEP) flaps, the role of linking vessels on dynamic perfusion in bilateral breast reconstruction and strategies to augment flap vascularity. For the ex-vivo anatomical studies, three and four-dimensional computed tomographic angiography (CTA) were used to evaluate patterns of the microvascular blood supply of individual perforators and corresponding perfusion patterns in the hemi-abdomen. This was combined with an in-vivo clinical study of women undergoing bilateral DIEP breast reconstruction following mastectomy, where both preoperative CTA and intra-operative Laser-Assisted Indocyanine Green Fluorescence Angiography (LA-ICGFA) were used to evaluate perforator anatomy and dynamic perfusion zones of individual perforators. Finally, an experimental in-vivo animal model was used to investigate strategies of pretreatment of perforator flaps with negative pressure wound therapy to augment vascularity of perforator flaps prior to flap harvest. The vascular territories of individual perforator within hemi-DIEP flaps demonstrated variable patterns with unique patterns of perfusion. Concepts including early capture of large calibre direct linking vessels to adjacent perforators or the superficial inferior epigastric artery (SIEA) territories, mostly found in the supra-scarpa’s and subdermal layers of the flap, played a key role in defining overall perfusion area and dynamic perfusion patterns not previously described. In conclusion, this work reported the characterization of the microvasculature within abdominal based perforator flaps to better understand the variation in dynamic perfusion. It also explored the potential role of non-invasive negative pressure treatment to augment flap perfusion that may be translated into the clinical setting.Royal College of Surgeons of England Blond Research Fellowship Restoration of Appearance and Function Trust (RAFT) U