Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Abstract

Pre-existing tumor hypoxia and oxygen consumption by photodynamic therapy (PDT) always generate an inadequate oxygen supply, which often contributes to other therapy resistance, especially for aerobic treatments such as chemotherapy. In order to overcome this problem, we synthesized a chitosan (CS)-capped pH-/NIR-dual responsive and perfluorocarbon-based oxygen self-enriching photodynamic therapy nanosystem which could codeliver oxygen, photosensitizer, and chemotherapeutic drug. Simultaneously, in vitro results revealed that DOX release was stimulated by the acidic pH value with CS as a pH-responsive layer and rising temperature caused by the photothermal effect with an 808 nm laser, which could effectively reduce the nonspecific toxicity caused by premature drug release. Furthermore, due to the higher oxygen-carrying capability of perfluorocarbon, the decreased expression of the hypoxia-inducible factor-1α (HIF-1α) of tumors, as well as the significantly intense photodynamic effect and longer singlet ( 1 O 2 ) lifetime of the loaded photosensitizer, the elevated cytotoxicity was improved. More importantly, both in vitro and in vivo results showed that drug-loaded nanoparticles with oxygen-abundant properties achieved a similar anticancer therapy in both normoxic and hypoxic conditions against the difficulty led by deficient oxygen, as well as a good cellular internalization. Summarily, all these results pointed out that such a pH-/NIR-dual responsive drug carrier could enhance the synergetic anticancer therapy of chemotherapy and PDT by alleviation of tumor hypoxia, which provided a tempting controllable and multifunctional therapeutic application.

Cascade strategy for glucose oxidase-based synergistic cancer therapy using nanomaterials

“…As detailed above, the TME represents palpable hypoxia, which poses a formidable challenge to cancer therapeutics. 66 In response to this, hypoxia-mediated controlled drug release systems have emerged in recent years and are being studied as a potential novel stimuli-responsive mechanism. 31 The hypoxia-responsive controlled release system depends on the hypoxia-triggered chemical bond rupture and alterations in the hydrophobicity of polymer materials.…”

Recent advances in anti-multidrug resistance for nano-drug delivery system

“…Although it is a way to combat hypoxia-induced resistance to oxygen delivered to tumor tissues, the oxygen supplement also offers more vitality to tumor cells. Thus, the solutions to hypoxia-induced resistance are the general need for synergetic therapy (Zhuang et al., 2021 ). Hypoxia counts against body cell mitosis as well as tumor cells, but hypoxia could promote epithelial-mesenchymal transition (EMT) which can accelerate tumor metastasis.…”

“…The mechanisms of photosensitizer generating ROS can be divided two types: (1) Photosensitizer transfers light energy to either tissue substrate and produce superoxide anion radicals (such as O 2 − and HO 2 ), which is called as Type I reaction; (2) Photosensitizer directly converts O 2 molecules into singlet oxygen ( 1 O 2 ), which is Type II reaction (Aniogo et al., 2019 ). The ROS productions don’t only destroys tumor tissues but also decreases the HIF-1α expression (Pramual et al., 2020 ; Zhuang et al., 2021 ). Excessive ROS generated by photosensitizer could induce biomembrane lipid peroxidation and kill of cancer cells.…”

pH-Responsive Amphiphilic Triblock Fluoropolymers as Assemble Oxygen Nanoshuttles for Enhancing PDT against Hypoxic Tumor

“…Photodynamic therapy (PDT) relies on photosensitizers (PSs) to transfer energy to dissolved oxygen (O 2 ) within tumors, − resulting in the generation of cytotoxic 1 O 2 for the treatment of cancer. − Capitalizing on the ability of photodynamics to generate reactive oxygen, Wang et al reported the singlet oxygen-responsive features and corresponding reaction mechanism of a nitroimidazole-containing micelle . Gao et al encapsulated Ce6 with unsaturated fatty acids into polymer micelles, the singlet oxygen produced by Ce6 induces lipid peroxidation, leading to the generation of reactive free radicals and aldehydes .…”