A Harmless–Harmful Switchable and Uninterrupted Laccase‐Instructed Killer for Activatable Chemodynamic Therapy

Abstract

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H2O2) into hydroxyl radicals (OH•). Although many studies on H2O2 supplementation have been conducted to improve the therapeutic effect of CDT, few studies have focused on the application of superoxide radical (O2−•) in CDT, which may result in better efficacy. A major concern about O2−•‐mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O2−• scavenger. Here, a harmless‐harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is constructed, which is the first CDT agent accelerated by LAC‐instructed O2−• generation and possesses a harmless‐harmful switchable effect because of the photodegradation of the O2−• scavenger iron‐chlorin e6 (FeCe6). LAC‐instructed substrate oxidation effectively catalyzes O2−• production with the help of intracellular reduction, thereby promoting the conversion of Fe3+ to Fe2+, accelerating the generation of OH•, and inducing tumor cell apoptosis and necrosis. The introduced O2−• scavenger FeCe6 is quickly photodegraded during irradiation, while LAC‐instructed O2−• generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC‐instructed O2−• generation but also presents new insight into activatable CDT.

pH-Sensitive Twin Liposomes Containing Quercetin and Laccase for Tumor Therapy

“…Figure presents the UV/Vis spectra of the QER/LAC-containing liposomes according to the pH of the solution. It is known that QER is oxidized by the enzymatic reaction of LAC, activated to a tumor-toxic molecule (Figure a). , Importantly, the reduction of the UV absorption band at 375 nm indicates the generation of oxidized QER (Figure S9). At pH 7.4, the QER/LAC@GDEAP–TLs exhibit a negligible change at 375 nm, similar to that of the free QER in a native state (Figure S10).…”

“…In this study, we report pH-sensitive twin liposomes (TLs) containing quercetin (QER, as a model prodrug) − and laccase (LAC, as a bioactive catalyst for generating toxic QER via catalytic oxidation) , in each individual compartment. First, we generated transient holes (∼35 nm in diameter) on the liposome surface using our liposome magnetoporation method. − The opened pores enabled passive encapsulation of QER or LAC, producing single liposomes (SLs) encapsulating QER or LAC, respectively.…”

“…Subsequently, the transient holes on the liposomes were physically plugged by pH-sensitive/biodegradable glycol chitosan grafted with 3-diethylaminopropylamine (GDEAP, p K b of 6.8) − and avidin (or biotin) . Next, the high-affinity interaction of the biotin–GDEAP (plugged to the SLs containing QER) − and avidin–GDEAP (plugged to the SLs containing LAC) , resulted in the production of TLs, as shown in Figure a. We hypothesized that pH-sensitive GDEAP anchored to the liposome (QER/LAC@GDEAP–TLs) would mediate the rapid release of QER and LAC at the tumor extracellular pH (pH 6.8) because of the ionization of the DEAP moieties and followed by liposomal destabilization, further promoting the LAC-mediated oxidization of QER.…”

Strategies for enhancing cancer chemodynamic therapy performance

“…AFeNPs@CAI CDT MDA-MB-231 [35] FePt@FeOx@TAM-PEG CDT 4T1 [43] UCNP@PVP@MIL88B CDT U87MG [44] H 2 O 2 generation PTCG (EGCG, Pt-OH, PEG-b-PPOH) CDT/Chemotherapy HepG2 [17] Copper hexacyanoferrate CDT 4T1 [40] Den-DOX-Fe 3+ -TA CDT/Chemotherapy U14 [45] PGC-DOX (PEG-GOx, CaCuP, DOX) CDT/Chemotherapy 4T1 [46] ACC@DOX•Fe 2+ -CaSi-PAMAM-FA/mPEG CDT/Chemotherapy A375, 4T1 [47] (MSNs@CaO 2 -ICG)@LA CDT/PDT MCF-7 [48] PZIF67-AT CDT 4T1 [49] Copper peroxide nanodots CDT U87MG [50] GSH depletion FA-Pyrite CDT CT26 [34] MMDM (microphage, MCN, DOX, MnO 2 ) CDT/Chemotherapy 4T1 [51] A@P/uLDHs (artemisinin, PEG, MgFe-LDH) CDT HeLa [52] CCMZ (Cu, CuMoO x , ZP) CDT 4T1 [53] JNP Ve (Au-MnO JNPs, IR1061) CDT/Radiotherapy MCF-7 [54] DMON@Fe 0 /AT CDT 4T1 [55] CMBP (CuO/MnO x @BSA, Pt(IV) prodrug) CDT/Chemotherapy 4T1 [56] Zn x Mn 1−x S/PDA CDT/PTT 4T1 [57] PtCu 3 nanocage CDT/SDT 4T1 [58] External stimuli Light DGU:Fe/Dox CDT/Chemotherapy 4T1 [59] LET-6 (tPy-Cy-Fe, DSPE-PEG) CDT/PTT U87MG [60] GNR@SiO 2 @MnO 2 CDT/PTT U87MG [61] SnFe 2 O 4 nanozyme CDT/PTT/PDT 4T1 [62] MoSe 2 /CoSe 2 @PEG CDT/PTT H-22 [63] HULK (liposome, laccase, MOHQ, FeCe6) CDT 4T1 [64] Cu-OCNP/Lap CDT/PTT HeLa [65] AuPd@Fe x O y CDT/PTT A549 [66] Fe-doped MoO x nanowires CDT/PTT HeLa [67] Hollow magnetite nanoclusters CDT/PTT HeLa [68] ICG@Mn/Cu/Zn-MOF@MnO 2 CDT/PTT/PDT U87 [69] Wesselsite (SrCuSi 4 O 10 ) nanosheets CDT/PTT/Starvation therapy 4T1 [70] MoP 2 nanorods CDT/PTT CAL27 [71] X-ray Cu 2 (OH)PO 4 @PAAS CDT/Radiotherapy HeLa [72] CoFe 2 O 4 nanoparticles CDT/Radiotherapy MCF-7…”

Intelligent Nanoplatform with Multi Therapeutic Modalities for Synergistic Cancer Therapy

“…Reactive oxygen species (ROS), especially highly toxic hydroxyl radicals (•OH) − and superoxide radicals (O 2 –• ) ,, have emerged as a thriving strategy for more effective tumor treatment. In recent years, many in-site ROS generation-based strategies such as photodynamic therapy (PDT), − sonodynamic therapy (SDT), − and chemodynamic therapy (CDT) ,− have been extensively developed for precise and efficient cancer treatment.…”