CLR-2100 (Cellectar Biosciences/Onconova Therapeutics)

Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.

The conversion of lignin can produce biomass-derived aromatic compounds such as 2-pyrone-4,6-dicarboxylic acid (PDC), which is a potential sustainable precursor of bioplastics. PDC is a pseudoaromatic dicarboxylic acid that can aggregate in aqueous solution. Aggregation depends upon PDC-PDC, PDC-water, and PDC-ion interactions that are representative of interactions in similar charged, aromatic compounds. These interactions both dictate PDC aggregation and the likelihood that PDC aggregates exhibit parallel stacking configurations that may promote PDC crystallization, which can be leveraged to separate PDC from solution. However, the interplay of interactions that drive aggregation and structure formation, and how these depend upon the charge of PDC and ionic species present in solution, remains unclear. In this work, we investigate PDC aggregation in diverse ionic solutions using all-atom molecular dynamics simulations and molecular clustering analysis. We consider ion-induced dipole interactions by using a modified Lennard-Jones nonbonded model for divalent ions in solutions. From molecular clustering analysis, we derive characteristic parameters to quantify aggregate sizes and parallel stacking configurations. We show that acid dissociation facilitates PDC aggregation in ionic solutions via ion-mediated interactions, and different ionic solutions influence both the likelihood of aggregation and the formation of parallel aggregates. In particular, we find that parallel stacking is primarily found in solutions with monovalent ions, whereas divalent ions promote larger, but less structured, aggregates. These results provide molecular-scale insight into the effects of specific ions on the aggregation of like-charged PDC molecules to inform understanding of related separation processes.