Leveraging disulfiram to treat cancer: Mechanisms of action, delivery strategies, and treatment regimens

Listening to Drug Delivery and Responses via Photoacoustic Imaging.

Cancer remains a severe threat to human health. To date, although various therapeutic methods, including radiotherapy (RT), chemotherapy, chemodynamic therapy (CDT), phototherapy, starvation therapy, and immunotherapy, have entered a new stage of rapid progress in cancer theranostics, their limited therapeutic effect and significant side effects need to be considered carefully. With the rapid development of nanotechnology, the marriage of nanomaterials and therapeutic methods provides the practical possibility to improve the deficiencies in cancer therapy. Notably, metal-organic frameworks (MOFs) composed of ions/clusters and bridging ligands through coordination bonds have been widely applied in cancer therapy to deal with the drawbacks of different therapeutic methods, such as severe side effects, low stability, and poor efficacy, owing to their controllable morphologies, tailorable diameters, diverse compositions, tunable porosities, high specific surface areas, facile functionalization, and good biocompatibility. This review summarizes the recent advanced developments and achievements of multifunctional MOF-based nanoplatforms for cancer therapy through single therapy methods, including RT, chemotherapy, CDT, phototherapy (photodynamic and photothermal therapy), starvation therapy and immunotherapy, and combination therapy methods. Moreover, the prospects and challenges of MOF-based nanoplatforms used in tumor therapy are also discussed.

Multifunctional metal-organic framework (MOF)-based nanoplatforms for cancer therapy: from single to combination therapy

Abstract Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases. 

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Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Advances in Single-component inorganic nanostructures for photoacoustic imaging guided photothermal therapy.

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein-protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.

Although multimethod therapy has shown great promise for effective cancer treatment, it is still a great challenge to develop simple and effective strategies to construct multifunctional therapeutic reagents. According to the characteristics of the tumor microenvironment, such as a mild acidic environment and overexpression of H2O2, an intelligent therapeutic reagent with photoacoustic (PA) imaging-guided photothermal therapy, chemodynamic therapy, and in situ chemotherapy was constructed by simply loading disulfiram (DSF) in a Cu-based porous metal-organic framework (HKUST-1). The resultant material DFS@HKUST-1 shows near-infrared adsorption around 600-900 nm and effective photoacoustic imaging properties and photothermal conversion efficiency upon 808 nm irradiation. Besides, after DFS@HKUST-1 is enriched in the tumor, the acidic environment of the tumor will slowly trigger the decomposition of HKUST-1, leading to the release of Cu2+ ions to react with DSF and endogenous H2O2 to generate the Cu/DSF complex (CuET) and cytotoxic •OH for chemotherapy and chemodynamic therapy, respectively. Therefore, DFS@HKUST-1 can serve as a promising tumor microenvironment response therapeutic reagent for photoacoustic imaging-guided multimethod therapy.

Tumor Microenvironment-Responsive Reagent DFS@HKUST-1 for Photoacoustic Imaging-Guided Multimethod Therapy

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

Gd(III) chelates are important T1-weighted contrast agents used in clinical magnetic resonance imaging (MRI), but their low longitudinal relaxivity (r1) results in limited imaging efficiency. In this study, we utilize a geometric confinement strategy to restrict a Gd chelate (Gd-DTPA) within the channels of a porous metal-organic framework material (MOF-808) for increasing its r1 relaxivity. Moreover, the Gd-DTPA-grafted MOF-808 nanoparticles were further surface modified with polyaniline (PANI) to construct an MRI-guided photothermal therapy platform. The resulting Gd-DTPA-MOF-808@PANI shows a high r1 relaxivity of 30.1 mM-1 s-1 (0.5 T), which is 5.4 times higher than that of the commercial contrast agent Magnevist. In vivo experiments revealed that Gd-DTPA-MOF-808@PANI has good T1-weighted contrast performance and can effectively guide photothermal ablation of tumors upon 808 nm laser irradiation. This work may shed some light on the design and preparation of high relaxation rate Gd-based contrast agents for theranostic application via utilization of versatile MOF materials.

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy. The dynamic change of SHP2 between closed and open conformations under either physiological or pathological conditions provides opportunities to design SHP2 inhibitors for treating SHP2‐related diseases. To date, several SHP2 allosteric inhibitors have advanced into clinical trials as mono‐ or combined therapy of cancers. In this review, we provide an overview on the structural landscape of SHP2 under physiological and pathological conditions and also comprehensively analyze the binding models of SHP2/inhibitor complexes. Structural features of SHP2 under pathological conditions and co‐crystal structures of SHP2/inhibitor complexes will definitely facilitate structure‐guided design of SHP2 inhibitors. Finally, proteolysis targeting chimeric (PROTAC) based SHP2 degraders have shown therapeutic promise for cancer therapy and are also briefly discussed. We hope this review could provide crystallographic landscape for SHP2 targeted drug discovery.

Xinyu Yang

Papers

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.

Tumor Microenvironment-Responsive Reagent DFS@HKUST-1 for Photoacoustic Imaging-Guided Multimethod Therapy

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery