Cancer Chemotherapy
The enhanced permeability and retention (EPR) effect is the first essential step for selective delivery of macromolecular drugs to tumor tissues. The EPR effect is based on the aberrant architecture of tumor blood vessels and the impaired lymphatic draina
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Cancer Chemotherapy Hideaki Nakamura and Hiroshi Maeda
Abstract The enhanced permeability and retention (EPR) effect is the first essential step for selective delivery of macromolecular drugs to tumor tissues. The EPR effect is based on the aberrant architecture of tumor blood vessels and the impaired lymphatic drainage system in tumor tissue. This effect is facilitated by overproduction of multiple vascular mediators such as bradykinin, nitric oxide, prostaglandins, vascular endothelial growth factor (VEGF), and other cytokines in tumor tissue, which may also affect surrounding normal tissues. The biocompatibility, molecular size, and surface charge of macromolecular drugs, i.e., nanomedicines, are critical determinants of tumor-targeted drug delivery based on the EPR effect. However, ineffective treatment can result from the heterogeneity of the EPR effect in tumor tissues, which impedes drug delivery to some tumors. In this chapter, we also discuss how to overcome this problem by using specific therapeutic methods, such as angiotensin (AT) II-induced high blood pressure, angiotensin-converting enzyme inhibitors, nitric oxide-releasing agents, tumor necrosis factor-α, transforming growth factor-β, and heme oxygenase-1 inducer, some of which were demonstrated to be effective in clinical settings.
Abbreviations ACE AT-II BSA CO
Angiotensin-converting enzyme Angiotensin II Bovine serum albumin Carbon monoxide
H. Nakamura • H. Maeda (*) Research Institute for Drug Delivery System and Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan e-mail: [email protected] I.F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience, DOI 10.1007/978-1-4614-9164-4_15, © Springer Science+Business Media New York 2013
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H. Nakamura and H. Maeda
COX CT EPR HIF-1α HO-1 HPMA ISDN IgG NADPH NCS NG NO NOS PEG SCID SEM SERCA SMA TGF-β TNF-α VEGF
15.1
Cyclooxygenase Computer topography Enhanced permeability and retention Hypoxia-inducible factor 1 alpha Heme oxygenase-1 Hydroxypropyl methacrylamide Isosorbide dinitrate Immunoglobulin G Nicotinamide adenine dinucleotide phosphate Neocarzinostatin Nitroglycerin Nitric oxide Nitric oxide synthase Polyethylene glycol Severe combined immune deficiency Scanning electron microscopy Sarcoplasmic/endoplasmic reticulum ATPase Styrene maleic acid Transforming growth factor beta Tumor necrosis factor alpha Vascular endothelial growth factor
Introduction
One primary goal of cancer drug development is to produce safe and effective drugs. At the end of the nineteenth century, Paul Ehrlich proposed the concept of a “magic bullet,” that is, a drug should selectively target pathogens and not harm normal cells of a host. The discovery of antibiotics successfully advanced this concept, because most antibiotics target specific molecules that are unique to bacteria and do not occur in mammalian cells or tissues. Most antibiotics are quite safe and have a large therapeutic safety window. Extension of Ehrlich’s concept led to the development of molecular-targete
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