A Biocompatible Free Radical Nanogenerator with Real‐Time Monitoring Capability for High Performance Sequential Hypoxic Tumor Therapy

Abstract

Hypoxic microenvironment severely reduces therapeutic efficacy of oxygendependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen-independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near-infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5-8%). Additionally, the aggregation-quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real-time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin-based nanoplatform is promising for high-performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.

A Mitochondrion‐Localized Two‐Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors

“…[17] 5,5-dimethyl-1-pyrroline N-oxide (DMPO) is aw idely used nitrone spin trap,w hich can trap carboncentred radicals.I tc an react with carbon radical to form DMPO-carbon radical adduct giving ac haracteristic quartet of peaks (1:2:2:1) in ESR. [10,11,18] As expected, aq uartet was observed when Ir4-red was mixed with DMPO and irradiated Figure 1B). On the contrary,n oE SR peaks were observed for Ir4 upon irradiation, indicating that pre-reduction of Ir4 with reductase and NADH to obtain Ir4-red is ar equisite to observe the radical ( Figure S21).…”

“…Photo-induced ROSgeneration was confirmed by DCFH-DA staining. [11] As expected, the fluorescence of DCF was only observed for Ir4 after two-photon (l ex = 730 nm) irradiation ( Figure 3C). As ROS generation by mitochondrial photosensitizers can readily cause mitochondrial membrane potential (MMP) loss, [29] change in MMP was assessed by JC-1s taining.A 549 cells treated with Ir4 demonstrated significant MMP reduction in comparison with the controls,w hile Ir1-3 showed no obvious change ( Figure S30-S33).…”

“…[10] Wane ta la lso developed an AIPH and albumin-based theranostic nanoplatform, with outstanding properties. [11] Aside from these few studies which focus only on AIPH, the area remains underexplored.…”

Application of nanotechnology for enhancing photodynamic therapy via ameliorating, neglecting, or exploiting tumor hypoxia

“…Finally, the superior synergistic photo‐therapeutic efficacy of BIA NPs has been demonstrated in the A549 tumor‐bearing mice model (Figure 7E,F). 92 …”

“…(E and F) The in vivo antitumor effect in A549 tumor‐bearing mice. Reproduced with permission 92 . Copyright 2019, Wiley.…”