Cupric-ion-promoted fabrication of oxygen-replenishing nanotherapeutics for synergistic chemo and photodynamic therapy against tumor hypoxia

摘要

Mixing a glutathione (GSH)-responsive carboxy zinc(II) phthalocyanine ( ZnPc center dot) and CuSO 4 center dot 5H 2 O in water with or without the presence of the anticancer drug SN38 resulted in the formation of selfassembled nanotherapeutics labeled as ZnPc center dot/Cu/SN38@NP and ZnPc center dot/Cu@NP , respectively. The Cu 2 + ions not only promoted the self-assembly of the carboxy phthalocyanine through metal complexation, but also catalyzed the transformation of H 2 O 2 to oxygen via a catalase-like reaction, rendering an oxygenreplenishing property to the nanosystems. Both nanosystems exhibited high stability in aqueous media, but the nanoparticles disassembled gradually in an acidic or GSH-enriched environment and inside human colorectal adenocarcinoma HT29 cells, releasing the encapsulated therapeutic components. The disassembly process together with the activation by the intracellular GSH led to relaxation of the intrinsic quenching of the nanophotosensitizers and restoration of the photoactivities of ZnPc center dot. Under a hypoxic condition, ZnPc center dot/Cu/SN38@NP could attenuate the intracellular hypoxia level and maintain the photodynamic activity due to its Cu 2 + -promoted oxygen-replenishing ability. The photodynamic effect of ZnPc center dot and the anticancer effect of SN38 worked cooperatively, causing substantial apoptotic cell death. The dual therapeutic actions could also effectively inhibit the tumor growth in HT29 tumor-bearing nude mice without initiating notable adverse effects to the mice.

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