Systemic Drug Delivery in Gastric Cancer
The tumor microenvironment is a critical factor that induces drug resistance of tumors, which is called Physiological Drug Resistance (PDR). PDR can be further classified into pH-induced Physiological Drug Resistance (PIPDR) and Penetration- Defect Relate
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Rutian Li and Mi Yang
14.1 Physiological Drug Resistance (PDR) and the Role of Copolymeric Nanoparticles in Its Reversion Copolymeric nanoparticles (NPs) have been proven to be effective carriers for the delivery of antitumor agents with some of them have come into clinical use [1–3]. The effectiveness of NPs resides in their enhanced permeability and retention (EPR) effects, rather than on an active targeting strategy [4, 5]. Ultimately, this results in sustained release of drugs from their NP vectors [6]. In this section, we will introduce another important mechanism inherent to copolymeric NPs: their ability to reverse physiological drug resistance (PDR). Although genetic and epigenetic changes in cancer cells have been a major research focus, the tumor microenvironment is also a vital factor that has attracted increasing attention in recent years. This is because solid tumors are three-dimensional structures composed of both cancer and stromal cells in addition to matrix and vascular network
R. Li • M. Yang (*) The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People’s Republic of China
[7]. The physicochemical factors in the tumor microenvironment are quite different from those found in normal tissue. These altered physicochemical factors are significant for the treatment of cancer because they can influence the efficacy of anticancer agents; for instance, the pH of tumor tissue is classic example. The extracellular pH of cancer cells is more acidic than that of normal tissue, whereas the intracellular pH of tumor is nearly equivalent [8]. As to the weakly basic agents that have an acid dissociation constant (Pka) in the range of 7.5–9.5, this unusual intracellular-extracellular pH gradient can influence the effect of these agents. In this scenario, such drugs would be protonated at the extracellular tumor pH value [7]. Since the protonated forms of these agents become much less membrane permeable, they would accumulate predominantly outside of the cell. As such, the intracellular environment would have a low concentration of such weakly basic drugs, leading to a markedly reduced ability to kill cancer cells. Raghunand et al. has defined this phenomenon as “physiological drug resistance”, which is different from the “biochemical drug resistance” (e.g. MDR or drug resistance) that is caused by the changes of signaling pathways and/or protein expression [9]. However, pH is not the solely physiochemical factor influencing drug distribution in tumor tissue. The disorganized vascular network and the absence of a functional lymphatic system of
© Springer Nature Singapore Pte Ltd. 2017 J. Wei, B. Liu (eds.), Personalized Management of Gastric Cancer, DOI 10.1007/978-981-10-3978-2_14
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tumor tissue causes increased interstitial fluid pressure (IFP). Moreover, the composition and structure of the extracellular matrix (ECM) can passively influence the movement of molecules w
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