Lipid-Polymer Bilaminar Oxygen Nanobubbles for Enhanced Photodynamic Therapy of Cancer

Abstract

Hypoxia in solid tumors may be a hindrance to effective treatments of tumors in achieving their therapeutic potential, especially for photodynamic therapy (PDT) which requires oxygen as the supplement substrate. Oxygen delivery using perfluorocarbon emulsions or lipid oxygen microbubbles has been developed as the agents to supply endogenous oxygen to fuel singlet oxygen generation in PDT. However, such methods suffer from premature oxygen release and storage issues. To address these limitations, we designed lipid-polymer bilaminar oxygen nanobubbles with chlorin e6 (Ce6) conjugated to the polymer shell as a novel oxygen self-supplement agent for PDT. The resultant nanobubbles possessed excellent stability to reduce the risk of premature oxygen release and were stored as freeze-dried powders to avoid shelf storage issues. In vitro and in vivo experimental results demonstrated that the nanobubbles exhibited much higher cellular uptake rates and tumor targeting efficiency compared to free Ce6. Using the oxygen nanobubbles for PDT, a significant enhancement of therapeutic efficacy and survival rates was achieved on a C6 glioma-bearing mice model with no noticeable side effects, owing to the greatly enhanced singlet oxygen generation powered by oxygen encapsulated nanobubbles.

Fighting Hypoxia to Improve PDT

“…In 2018, Song et al [68] developed nanocapsules composed of a decane core and a polymer shell linked to Ce6, surrounded by lipid molecules conjugated to a hydrophilic polymer PEG (263.2±10.3 nm with a thickness of about 20 nm for the shell). The O 2 nanobubbles (NBs-O 2 ) were finally obtained by O 2 infusion in the nanocapsules.…”

“…Moreover, immunohistochemistry (IHC) staining of tumour sections confirmed the successful cellular transport of the therapeutic payloads to tumour hypoxia and the pronounced antitumour effect elicited by combined hyperthermia/PDT along with the additional O2 supply. In 2018, Song et al [68] developed nanocapsules composed of a decane core and a polymer shell linked to Ce6, surrounded by lipid molecules conjugated to a hydrophilic polymer PEG (263.2±10.3 nm with a thickness of about 20 nm for the shell). The O2 nanobubbles (NBs-O2) were finally obtained by O2 infusion in the nanocapsules.…”

A Bacteriochlorin‐Based Metal–Organic Framework Nanosheet Superoxide Radical Generator for Photoacoustic Imaging‐Guided Highly Efficient Photodynamic Therapy

“…[1][2][3] Photodynamic therapy (PDT) utilizes a photosensitizer (PS) excited by an appropriate light irradiation to generate reactive oxygen species (ROS); in most of cases, it involves a process that the ground triplet-state molecular oxygen ( 3 O 2 ) is transformed to the reactive singlet oxygen ( 1 O 2 ) via the type II mechanism extremely dependent on the concentration of oxygen (O 2 ). [8,9] To address this issue, various innovative strategies have been developed, such as O 2 -replenishing nanosystem to deliver O 2 (e.g., hemoglobin and perfluorocarbon) [10][11][12][13][14] or oxygen self-supplement nanomaterials to generate O 2 (e.g., MnO 2 , Pt, CaO 2 , and catalase) [15][16][17][18][19] in the tumor microenvironment to elevate the tumor O 2 concentration and enhance the PDT efficacy. [8,9] To address this issue, various innovative strategies have been developed, such as O 2 -replenishing nanosystem to deliver O 2 (e.g., hemoglobin and perfluorocarbon) [10][11][12][13][14] or oxygen self-supplement nanomaterials to generate O 2 (e.g., MnO 2 , Pt, CaO 2 , and catalase) [15][16][17][18][19] in the tumor microenvironment to elevate the tumor O 2 concentration and enhance the PDT efficacy.…”

Insight into the efficiency of oxygen introduced photodynamic therapy (PDT) and deep PDT against cancers with various assembled nanocarriers

“…Schematic illustration of preparation of lipid‐polymer bilaminar oxygen nanobubbles conjugated with Ce6 and the PDT process. (Reprinted with permission from Song, Hu, et al (). Copyright 2016, American Chemical Society)…”

“…in vivo test reveals that the O 2 nanobubbles have good tumor targeting capability and long F I G U R E 6 Schematic illustration of preparation of lipid-polymer bilaminar oxygen nanobubbles conjugated with Ce6 and the PDT process. (Reprinted with permission from Song, Hu, et al (2018). Copyright 2016, American Chemical Society) retention time in tumors.…”