H<sub>2</sub>O<sub>2</sub>‑Activatable and
O<sub>2</sub>‑Evolving Nanoparticles for Highly Efficient and
Selective Photodynamic Therapy against Hypoxic Tumor Cells
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Abstract
The low selectivity of currently
available photosensitizers, which
causes the treatment-related toxicity and side effects on adjacent
normal tissues, is a major limitation for clinical photodynamic therapy
(PDT) against cancer. Moreover, since PDT process is strongly oxygen
dependent, its therapeutic effect is seriously hindered in hypoxic
tumor cells. To overcome these problems, a cell-specific, H<sub>2</sub>O<sub>2</sub>-activatable, and O<sub>2</sub>-evolving PDT nanoparticle
(HAOP NP) is developed for highly selective and efficient cancer treatment.
The nanoparticle is composed of photosensitizer and catalase in the
aqueous core, black hole quencher in the polymeric shell, and functionalized
with a tumor targeting ligand c(RGDfK). Once HAOP NP is selectively
taken up by α<sub>v</sub>β<sub>3</sub> integrin-rich tumor
cells, the intracellular H<sub>2</sub>O<sub>2</sub> penetrates the
shell into the core and is catalyzed by catalase to generate O<sub>2</sub>, leading to the shell rupture and release of photosensitizer.
Under irradiation, the released photosensitizer induces the formation
of cytotoxic singlet oxygen (<sup>1</sup>O<sub>2</sub>) in the presence
of O<sub>2</sub> to kill cancer cells. The cell-specific and H<sub>2</sub>O<sub>2</sub>-activatable generation of <sup>1</sup>O<sub>2</sub> selectively destroys cancer cells and prevents the damage
to normal cells. More significantly, HAOP NP continuously generates
O<sub>2</sub> in PDT process, which greatly improves the PDT efficacy
in hypoxic tumor. Therefore, this work presents a new paradigm for
H<sub>2</sub>O<sub>2</sub>-triggered PDT against cancer cells and
provides a new avenue for overcoming hypoxia to achieve effective
treatment of solid tumors