Enhanced selectivity, cellular uptake, and in vitro activity of an intrinsically fluorescent copper-tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer

In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)2] was synthesized for selective hypoxia-targeted therapy. The nanocomplex revealed a crystalline form, and exhibited higher lipophilicity, compared to TPZ. Furthermore, its stability was confirmed in different media, with minimum dissociation in serum (∼20% up to 72 h). In contrast to other hypoxia-targeted agents, our intrinsically fluorescent nanocomplex offered an invaluable tool to monitor its cellular uptake and intracellular distribution under both normoxia and hypoxia. The conferred higher cellular uptake of the nanocomplex, especially under hypoxia, and its biocompatible reductive potential resulted in superior hypoxia selectivity in two prostate cancer (PC) cell lines. More promisingly, the nanocomplex showed higher potency in three-dimensional tumor spheroids, compared to TPZ, due to its slower metabolism, and probably deeper penetration in tumor spheroids. Interestingly, the nuclear localization of the intact nanocomplex, combined with its higher DNA binding affinity, as evidenced by the DNA binding assay, resulted in significant S-phase cell-cycle arrest, followed by apoptosis in the three-dimensional spheroid model. In conclusion, the presented findings suggested that the Cu(TPZ)2 nanocomplex can be a promising hypoxia-targeted therapeutic, which could potentiate the efficacy of the existing chemo- and radiotherapy in PC

Confinement of carbon dots localizing to the ultrathin layered double hydroxides toward simultaneous triple-mode bioimaging and photothermal therapy

It is a great challenge to develop multifunctional nanocarriers for cancer diagnosis and therapy. Herein, versatile CDs/ICG-uLDHs nanovehicles for triple-modal fluorescence/photoacoustic/two-photon bioimaging and effective photothermal therapy were prepared via a facile self-assembly of red emission carbon dots (CDs), indocyanine green (ICG) with the ultrathin layered double hydroxides (uLDHs). Due to the J-aggregates of ICG constructed in the self-assembly process, CDs/ICG-uLDHs was able to stabilize the photothermal agent ICG and enhanced its photothermal efficiency. Furthermore, the unique confinement effect of uLDHs has extended the fluorescence lifetime of CDs in favor of bioimaging. Considering the excellent in vitro and in vivo phototherapeutics and multimodal imaging effects, this work provides a promising platform for the construction of multifunctional theranostic nanocarrier system for the cancer treatment

Combined <i>In Situ</i> and <i>In Silico</i> Studies of Guest Intercalation into the Layered Double Hydroxide [LiAl₂(OH)₆]X·<i>y</i>H₂O

Phosphonoacetate (PAA), diethyl phosphonoacetate (DPA), and sulfoacetate (SAA) anions have been intercalated into the galleries of the layered double hydroxide (LDH) [LiAl₂(OH)₆·X]·<i>y</i>H₂O (LiAl-X; X = Cl, NO₃). X-ray diffraction (XRD), Fourier transform infrared spectroscopy, and elemental microanalysis confirmed the successful intercalation of the guest ions into the LDH. The guests could also be de-intercalated and recovered from the host intact. <i>In situ</i> XRD was used to probe the mechanisms of the reactions, and the intercalation of PAA proceeded via clear intermediate phases. In contrast, the SAA and DPA reactions did not show any intermediates, but the organic intercalates exhibited changes in their interlayer spacing as the reaction progressed. Molecular dynamics (MD) simulations were used to investigate the interlayer structure of the intercalation compounds. It was found that the intermediates observed <i>in situ</i> correspond to local energy minima in the MD simulations. MD can thus predict the course of an intercalation reaction and allow the <i>a priori</i> identification of intermediate phases. This is the first time that <i>in silico</i> and <i>in situ</i> measurements have been combined to unravel this level of understanding of intercalation reactions