Photodynamic therapy (PDT) is an emerging technology for tumor treatment in which photosensitizer (PS)-mediated light irradiation reduces oxygen, producing high levels of reactive oxygen species (ROS) that can cause vascular injury and effectively kill tumor cells. However, the naturally hypoxic tumor microenvironment is the main obstacle that hinders the photodynamic response in vivo and prevents its extensive application to tumor treatment. Moreover, PDT-mediated oxygen consumption further increases tumor hypoxia, potentially causing a variety of adverse consequences, such as angiogenesis, tumor invasion, and metastasis. To overcome these limitations caused by hypoxia, multiple strategies have been investigated, including the use of oxygen carriers and reactive oxygen supply materials, the regulation of tumor microenvironments, and multimodal therapy including PDT. In this review, we summarize the latest progress in the development of strategies to relieve tumor hypoxia for improved PDT efficacy and better therapeutic effects.

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Background: Although dynamics and uses of modified nanoparticles (NPs) as orally administered macromolecular drugs have been researched for many years, measures of molecule stability and aspects related to important transport-related mechanisms which have been assessed in vivo remain as relatively under characterized. Thus, our aim was to develop a novel type of oral-based delivery system for insulin and to overcome barriers to studying the stability, transport mechanisms, and efficacy in vivo of the delivery system. Methods: NPs we developed and tested were composed of insulin (INS), dicyandiamidemodified chitosan (DCDA-CS), cell-penetrating octaarginine (r8), and hydrophilic hyaluronic acid (HA) and were physically constructed by electrostatic self-assembly techniques. Results: Compared to free-insulin, levels of HA-DCDA-CS-r8-INS NPs were retained at more desirable measures of biological activity in our study. Further, our assessments of the mechanisms for NPs suggested that there were high measures of cellular uptake that mainly achieved through active transport via lipid rafts and the macropinocytosis pathway. Furthermore, investigations of NPs indicated their involvement in caveolae-mediated transport and in the DCDA-CS-mediated paracellular pathway, which contributed to increasing the efficiency of sequential transportation from the apical to basolateral areas. Accordingly, high efficiency of absorption of NPs in situ for intestinal loop models was realized. Consequently, there was a strong induction of a hypoglycemic effect in diabetic rats of NPs via orally based administrations when compared with measures related to free insulin. Conclusion: Overall, the dynamics underlying and influenced by HA-DCDA-CS-r8-INS may hold great promise for stability of insulin and could help overcome interference by the epithelial barrier, and thus showing a great potential to improve the efficacy of orally related treatments.

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