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Furthermore, a resulting hostile tumor microenvironment characterized by hypoxia andor extracellular acidosis can reduce the efficacy of anticancer drugs and confer drug resistance. Conversely, the enhanced permeation and retention effect has become the gold standard for developing macromolecular prodrugs and nano-sized drug delivery systems. Preclinically, there are meanwhile numerous in vivo proof-of-concepts that demonstrate not only a better tolerability of nano-sized drug delivery systems but also of enhanced antitumor efficacy compared to the conventional clinical standard. When faced with such a complex and heterogeneous disease as cancer in humans, it is more likely that a tailor-made combination of different therapeutic strategies will achieve the best results. In this respect, combining low-molecular weight cytostatic drugs with nano-sized drug delivery systems appears to be a natural choice for combination therapy that aims at distributing anticancer drugs at higher concentrations in the tumor in a more even manner. To date, such drug delivery approaches have been inadequately explored.

Junichi Matsuo, Shunichi Kimura, Akihiro Yamamura, Cai Ping Koh, Md Zakir Hossain, Dede Liana Heng, Kazuyoshi Kohu, Dominic Chih-Cheng Voon, Hiroshi Hiai, Michiaki Unno, Jimmy Bok Yan So, Feng Zhu, Supriya Srivastava, Ming Teh, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito. (2017) Identification of Stem Cells in the Epithelium of the Stomach Corpus and Antrum of Mice.]