Apoptosis and Paraptosis Induced by Disulfiram-Loaded Ca²⁺/Cu²⁺ Dual-Ions Nano Trap for Breast Cancer Treatment

Abstract

Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca 2+ /Cu 2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu 2+ -tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca 2+ /Cu 2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca 2+ , Cu 2+ , and DSF releasing simultaneously. The released Ca 2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H 2 O 2 ) overexpression. Meanwhile, Ca 2+ /reactive oxygen speciesassociated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)−copper complexes formed by the Cu 2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu 2+ will be reduced by intracellular glutathione to generate Cu + , which can catalyze the H 2 O 2 to produce a toxic hydroxyl radical by a Cu + -mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.

A Nanorobotics-Based Approach of Breast Cancer in the Nanotechnology Era

“…designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative pathways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”

“…In 1907, Paul Ehrlich, whose work was related to the development of chemotherapy and specific targeted treatment concepts [54], introduced the term "magic bullet" as a drug specifically targeting a particular pathogen, without affecting the normal cells of the host, anticipating the era of the development of site-specific therapies for cancer treatment [55,56]. Today, the use of nanomedicine and nano(bio)technology in the BC field involves handling modern and challenging variants of Ehrlich s "magic bullet", which can be considered as nano-"magic bullets" that are able to perform multiple and targeted functions and tasks, such as different types of nanorobots/nanobots/nanovehicles/nanomachines/nanomotors/nanodevices or nanosubmarines/nanosubs [21,57], nanotrains [58], nanostars [59], enzymatic, magnetic or DNAzyme based nanoflowers/nanoclusters [60][61][62], urchin-head/hollow tail nanorobots with sharp nanospikes [12], nanospheres [63], nanocubes [64], nanorods [65], nanoneedles [66], nanotubes [67], worm-like nanocrystal micelles [68], nanoshells [43], nanosponges and nanokillers [47], nanoknives [69], nanoballons [70], nanozymes [71], nano-snowflakes [25], nanobubbles [72,73], nanoemulsions [74], nanobodies [75], nanobiosensors [76], nanopores [77], nanocages [33], nanotraps [34],or nanogenerators [78] (Figure 1). Undoubtedly, the use of nanoparticulate-based platforms has provide more and more advantages to the BC field including great biocompatibility and biodistibution, multifunctionality, the ability to overcome biological barriers and bioaccumulate in multiple tumor sites, even in the nucleus and specific organel...…”

“…Functionally, this SCCI nano-modulator, or SA/Cur@CaCO 3− ICG, induces large amounts of ROS, followed by tumor cell apoptosis, or directly kills tumor cells, reducing the mitochondrial membrane potential and downregulating ATP production by accumulating large amounts of Ca 2+ and having an acidic pH [42]. Furthermore, Guo et al (2024) designed and fabricated a Ca 2+ /Cu 2+ dual-ion nanotrap to avoid cell apoptosis evasion by synchronously inducing both apoptosis and paraptosis, an alternative cell death pathway characterized by endoplasmic reticulum and/or mitochondrial swelling and cytoplasmic vacuolization [130] for BC treatment [34]. Thus, these authors used a Cu 2+ -tannic acid metal phenolic network that was embedded onto the amorphous calcium carbonate NP's surface, followed by mDSPE-PEG/lipid capping to form the disulfiram (DSF)-loaded Ca 2+ /Cu 2+ dual-ion nanotrap.…”

“…In this review, readers will be able to deepen their knowledge of the structure, behavior and role of nanorobots, among other nanomaterials, in BC theranostic. We have summarized here the characteristics of several functionalized nanodevices that have been designed to counteract the main neoplastic hallmark features of BC by sustaining proliferative path-ways [31,32], evading growth suppressors/evasion of anti-growth signaling [12], resisting programmed cell death [33][34][35][36][37][38][39][40][41][42], inducing angiogenesis (neovascularization) [43][44][45][46], activating invasion and metastasis [47][48][49], preventing genomic instability, mutation, mitosis/cell cycle deregulation [50], evading/avoiding immune destruction [51] and deregulating autophagy [52,53].…”

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis

“…Tumoral apoptosis or programmed cell death has been considered an essential homeostatic mechanism that maintains cell generation with cell death. However, apoptotic resistance, like defects in the apoptotic pathway, has become an urgent clinical problem, which greatly limits the therapeutic efficacy because conventional chemotherapy and irradiation work primarily by inducing apoptosis. − Based on this, much attention has been focused on the explorations against apoptotic resistance. , However, the resulting apoptotic defects in tumors are various and complex, including overexpression of antiapoptotic proteins, mutations of proapoptotic proteins, loss of caspase, or overexpression of drug transporters. − Therefore, it always remains a great challenge to reverse the resistance of apoptosis via a simple one-pathway intervention. Luckily, necroptosis, another form of regulated cell death, has become a probable and intrinsic pathway of tumors against apoptotic resistance. − …”