Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF’s anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate–copper complex (CuET).

The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the “Seed and Soil” theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions to block TAM recruitment, eliminate TAMs, reprogram M2 TAMs, or bolster their phagocytic capabilities via specific pathways. Nanomaterials including inorganic materials, organic materials for small molecules and large molecules stand at the forefront, presenting significant opportunities for precise targeting and modulation of TAMs to enhance therapeutic efficacy in cancer treatment. This review provides an overview of the progress in designing nanoparticles for interacting with and influencing the TAMs as a significant strategy in cancer therapy. This comprehensive review presents the role of TAMs in the TME and various targeting strategies as a promising frontier in the ever-evolving field of cancer therapy. The current trends and challenges associated with TAM-based therapy in cancer are presented.

Classical mechanical simulation of molecular models at constant pH is an advanced technique for studying conformational dynamics in the presence of proton titration which is critical to pharmaceutical design. The algorithms presented previously have been limited to fixed charge force fields. This work introduces the first constant pH molecular dynamics (CpHMD) algorithm compatible with multipolar electrostatics and polarizability. Additionally, our implementation in the open-source Force Field X software has the unique ability to handle titration state changes in crystalline systems, including flexible support for all 230 space groups. Evaluation of the constant pH AMOEBA model was performed on 11 crystal peptide systems that span the titrating amino acids Asp, Glu, His, Lys, and Cys. Accurate titration state predictions for these crystals, including for the coordination of Zn+2 by cysteines, demonstrates the promise of the method for constant pH molecular dynamics simulations of proteins in the context of pKa predictions, assessment of protein conformational ensembles, and for the calculation of protein-ligand binding affinity.

Pharmaceutical cocrystals offer a promising strategy to improve the performance of solubility-limited drug candidates, but determining the total equilibrium cocrystal solubility (SCC,T) remains challenging for highly soluble and potentially highly desirable cocrystals prone to solution-mediated phase transformations. This work establishes a material-efficient approach to access eutectic compositions and to determine SCC,T across cocrystals with a broad range of coformer solubilities, using only drug and coformer solubility information and targeted experiments, avoiding resource-intensive trial-and-error experiments. Ten naringenin cocrystals, spanning a wide range of coformer-to-drug solubility ratios (SCF,T/SD,T), were evaluated in biorelevant media. For five highly soluble and kinetically unstable cocrystals (SCF,T/SD,T > 5000), eutectic compositions were successfully achieved using a predissolving coformer strategy, enabling the determination of key cocrystal solution parameters, mainly the apparent solubility product, cocrystal solubility, and solution stability. The coformer concentration required to reach the eutectic point was cocrystal-dependent and strongly correlated with SCF,T/SD,T (R2 = 0.955), enabling an a priori estimation of the eutectic point and minimizing the experimental burden and API consumption. Across the resulting broad range in SCC,T, only a modest log−log correlation with SCF,T/SD,T was observed, indicating coformer solubility alone is an insufficient predictor of cocrystal solubility. Exploratory multivariate analyses showed coformer solubility, lattice energetics, coformer lipophilicity, and drug-coformer intermolecular interactions collectively provided improved descriptive performance over coformer solubility alone. Overall, this work provides a practical and efficient approach for rationally accessing eutectic conditions and determining cocrystal solubility with limited material across cocrystals with diverse solubilities. This study lays the groundwork to expand the SCC,T database and better establish coformer−cocrystal performance relationships to anticipate cocrystal solution performance and support the rational selection of coformers for pharmaceutical cocrystal design.