pH-Responsive Oxygen Nanobubbles for Spontaneous Oxygen Delivery in Hypoxic Tumors

Abstract

Tumor hypoxia is a significant factor leading to the resistance of tumors to treatment, especially for photodynamic therapy and radiotherapy where oxygen is needed to kill cancer cells. Oxygen delivery agents such as oxygen-saturated perfluorocarbon nanoemulsions and lipid oxygen microbubbles have been employed to supply oxygen to hypoxic tumors with ultrasound activation. Such oxygen delivery systems are still associated with several drawbacks, including premature oxygen release and the dependence of external stimuli. To address these limitations, we developed oxygen nanobubbles that were enclosed by the acetalated dextran polymer shells for spontaneous oxygeneration in response to a minor pH drop in the tumor microenvironment. The acetalated dextran polymer shell serves as a robust barrier against gas dissolution in the circulating blood to retain the majority of the oxygen payload, and its pH-responsive property enables an abrupt burst release of oxygen in the mild acidic tumor microenvironment. The acetalated dextran oxygen nanobubbles exhibited excellent stability and biocompatibility. In vitro and in vivo experiments were conducted to investigate the pH-responsive oxygen release. The external stimuli-free supply of oxygen by the acetalated dextran oxygen nanobubbles was evaluated on CNE2 tumor-bearing mice, and the intratumoral oxygen level increased by 6-fold after the administration of the oxygen nanobubbles, manifesting that our pH-responsive oxygen nanobubbles hold great potential as a potent oxygen delivery agent to overcome the hypoxia-induced resistance.

Acetalated dextran based nano- and microparticles: synthesis, fabrication, and therapeutic applications

“…Another innovative application of Ac-DEX NPs, is to delivery oxygen for alleviation of tumour hypoxia, which is one of the main causes of cancer resistance to photodynamic therapy and radiotherapy. [106][107][108] Song et al 109 prepared oxygen nanobubbles and enclosed them within pH-responsive Ac-DEX shells for the spontaneous generation of oxygen in response to a minor pH drop in the tumour microenvironment (Fig. 9c).…”

“…Compared with well-known oxygen delivery agents, such as perfluorocarbon nanoemulsions, Ac-DEX oxygen delivery system avoids the premature oxygen release and the requirement of external stimuli (ultrasound activation). 109,110…”

Oxygen‐Enriched Metal‐Phenolic X‐Ray Nanoprocessor for Cancer Radio‐Radiodynamic Therapy in Combination with Checkpoint Blockade Immunotherapy

“…As immunosuppressive TME is to do with hypoxia stress, oxygen enrichment in tumor would relieve the hypoxia environment and radioresistance to enhance RT efficacy. [ 31 ] Herein, Hb@Hf‐Ce6 NPs can also be employed as an oxygen transporter, which directly delivers abundant oxygen into the tumor site. Oxygen perfusion by Hb@Hf‐Ce6 NPs exhibits these following advantages: 1) alleviating tumor hypoxia state; 2) greatly enhancing the RT effectiveness and overcoming radioresistance; and 3) acting as an oxygen donor for achievement of RDT by Ce6.…”

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities, challenges, and future development

“…Tumor hypoxia refers to the zone of solid tumors with an oxygen pressure of less than 10 mm Hg, which is significantly lower than normal tissues (40–60 mm Hg). In addition, radiation therapy is resistant when the oxygen concentration is less than 20 mm Hg 42 . However, the differences in photosensitizers, light doses, and the type of tumors could affect the oxygen demand during PDT.…”