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Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials.

 

The structure and composition of the crystal growth unit are of huge fundamental and practical consequence. We propose a method to identify the solute species that incorporates into the growth site on crystal surfaces, the kinks, which rests on the kinetics of the elementary reaction at the kinks. We use as model crystals olanzapine, an antipsychotic medication, and etioporphyrin I, a field‐effect transistor. We combine time‐resolvedin situatomic force microscopy with Raman and absorption spectroscopies, complemented by density functional theory and all‐atom molecular dynamics modeling of the solutions. We show that the structure of the growth unit cannot be deduced neither from the solute oligomers nor from the crystal structure. Chemical kinetics analyses reveal that if the dominant solute species is the one that incorporates into the crystal growth sites, then the kinetics of layer growth complies with a monomolecular rate law. By contrast, if the crystal growth unit assembles from two units of the dominant solute form, a bimolecular rate law ensues. Solutions of both olanzapine and etioporphyrin I are dominated by solute monomers, which exist in equilibrium with a minority of dimers. Whereas numerous olanzapine crystal structures incorporate dimer motifs, etioporphyrin I crystals organize as stacks of monomers. Olanzapine crystal grow by incorporation of dimers. One of the studied face of etioporphyrin I grows by incorporation of the majority monomers, whereas the other one selects the minority dimers as a growth unit. The results highlight the power of the crystallization kinetics analyses to identify the growth unit and illuminate one of the most challenging issues of crystal growth.

 

Abstract The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete tumor resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 50–75%. Advanced real‐time imaging methods that improve the detection of tumor margins can help improve success rates,overall safety, and reduce the cost. Fluorescence imaging in the second near‐infrared (NIR‐II) window has the potential to revolutionize the field due to its high spatial resolution, low background signal, and deep tissue penetration properties, but NIR‐II dyes with adequate in vivo performance and safety profiles are scarce. A novel NIR‐II fluorophore, XW‐03‐66, with a fluorescence quantum yield (QY) of 6.0% in aqueous media is reported. XW‐03‐66 self‐assembles into nanoparticles (≈80 nm) and has a systemic circulation half‐life ( t 1/2 ) of 11.3 h. In mouse models of human papillomavirus (HPV)+ and HPV‐ OSCC, XW‐03‐66 outperformed indocyanine green (ICG), a clinically available NIR dye, and enabled intraoperative NIR‐II image‐guided resection of the tumor and adjacent draining lymph node with negative margins. In vitro and in vivo toxicity assessments revealed minimal safety concerns for in vivo applications.