Trojan Horse for Light-Triggered Bifurcated Production of Singlet Oxygen and Fenton-Reactive Iron within Cancer Cells

Abstract

Traditional photodynamic therapy for cancer relies on dye-photosensitized generation of singlet oxygen. However, therapeutically effective singlet oxygen generation requires well-oxygenated tissues, whereas many tumor environments tend to be hypoxic. We describe a platform for targeted enhancement of photodynamic therapy that produces singlet oxygen in oxygenated environments and hydroxyl radical, which is typically regarded as the most toxic reactive oxygen species, in hypoxic environments. The 24-subunit iron storage protein bacterioferritin (Bfr) has the unique property of binding 12 heme groups in its protein shell. We inserted the isostructural photosensitizer, zinc(II) protoporphyrin IX (ZnP), in place of the hemes and extended the surface-exposed N-terminal ends of the Bfr subunits with a peptide targeting a receptor that is hyperexpressed on the cell surface of many tumors and tumor vasculature. We then loaded the inner cavity with ∼2500 irons as a ferric oxyhydroxide polymer and finally conjugated 2 kDa polyethylene glycol to the outer surface. We showed that the inserted ZnP photosensitizes generation of both singlet oxygen and the hydroxyl radical, the latter via the reaction of photoreleased ferrous iron with hydrogen peroxide. This targeted iron-loaded ZnP-Bfr construct was endocytosed by C32 melanoma cells and localized to lysosomes. Irradiating the treated cells with light at wavelengths overlapping the ZnP Soret absorption band induced photosensitized intracellular Fe release and substantial lowering of cell viability. This targeted, light-triggered production of intracellular singlet oxygen and Fenton-reactive iron could potentially be developed into a phototherapeutic adjunct for many types of cancers.

Chemodynamic Therapy: Tumour Microenvironment‐Mediated Fenton and Fenton‐like Reactions

“…[29] Fori nstance,o ur group synthesized amorphous Fe 0 nanoparticles (AFeNPs) (Figure 1a), [25] which were rapidly ionized in an acidic TME to release more Fe 2+ ions than Fe 0 nanocrystals (FeNCs) for CDT because it had the reactive nature of metallic glasses.A sp resented in Figure 1b,c, the release rate of ferrous ions from the AFeNPs reached 57 %at ap Ho f6 .5 and 100 %a tapH of 5.4 within 6h,w hich were much higher than those observed for the FeNCs.M oreover, both AFeNPs and FeNCs tended to slowly release ferrous ions at aneutral pH. These results confirmed the capacity of AFeNPs for selective ferrous ion release,t hus ensuring the efficiency of CDT.I na ddition, many other iron-based nanomaterials,i ncluding Fe oxides, [30][31][32] [FeO(OH) n ], [33] and M(Sn,Mn)Fe 2 O 4 [34,35] have also been introduced as CDT agents,b ut none have focused on increasing the release of the catalytic Fe 2+ ions.…”

Chemodynamic Therapy: Tumour Microenvironment‐Mediated Fenton and Fenton‐like Reactions

“…These results confirmed the capacity of AFeNPs for selective ferrous ion release, thus ensuring the efficiency of CDT. In addition, many other iron‐based nanomaterials, including Fe oxides, [FeO(OH) n ], and M(Sn,Mn)Fe 2 O 4 have also been introduced as CDT agents, but none have focused on increasing the release of the catalytic Fe 2+ ions.…”

Self‐Supply of O2 and H2O2 by a Nanocatalytic Medicine to Enhance Combined Chemo/Chemodynamic Therapy

“…In addition, to improve the antitumor effect, more and more therapeutic modalities, such as chemotherapy, starvation therapy, gas therapy, photothermal therapy, and PDT, have been used in combination with CDT to address different targets. The anthracycline class antibiotic doxorubicin (DOX) has been widely used for the treatment of a range of cancers .…”