Pyridoclax-loaded nanoemulsion for enhanced anticancer effect on ovarian cancer.

BACKGROUND: Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant ovarian cancers. To correct the unfavorable intrinsic physico-chemical properties of this BCS II drug, a formulation strategy was implied in the drug discovery step. Pyridoclax-loaded nanoemulsions (NEs) were developed to permit its preclinical evaluation. RESULTS: The resulting nanoemulsions displayed a mean size of about 100 nm and a high encapsulation efficiency (>95%) at a drug loading of 2 wt%, enabling a 1,000-fold increase of the Pyridoclax apparent solubility. NEs have enabled a sustained release of the drug as assayed by a dialysis bag method. In addition, anti-tumor effects of the Pyridoclax-loaded nanoemulsions (PNEs) showed a 2.5-fold higher activity on chemoresistant ovarian cancer cells than free Pyridoclax. This effect was confirmed by a drastic increase of caspase 3/7 activation from 10 µM PNEs, as newly objectified by real time apoptose imaging. The Pyridoclax bioavailability was kept unchanged after encapsulation in nanoemulsions as determined in a mice model after oral administration. CONCLUSION: Thus, NEs should permit valuable Pyridoclax oral administration, and valorization of this promising anticancer drug by maintaining its original anticancer activity, and by reducing the Pyridoclax therapeutic concentration.

Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy, docking and molecular dynamics approaches.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15 µM in combination with anti-Bcl-xL strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1. Communicated by Ramaswamy H. Sarma.

Comparison of 2 strategies to enhance pyridoclax solubility: Nanoemulsion delivery system versus salt synthesis.

Pyridoclax is an original oligopyridine lead, very promising in treatment of chemoresistant cancers. However, from solubility measurement and permeability evaluation, it appeared that this compound can be considered as a BCS II drug, with a poor water solubility. To overcome this unfavorable property, two strategies were proposed and compared: pyridoclax di-hydrochloride salt synthesis and formulation of pyridoclax-loaded nanoemulsions (PNEs) efficiently performed by transposing the spontaneous emulsification process previously developed by our team. Whereas the salt improved the thermodynamic solubility of the drug by a factor 4, the apparent solubility of the encapsulated pyridoclax was 1000-fold higher. Their stability was assessed upon dilution in various complex biomimetic media relevant for oral administration (SGF, FaSSIF-V2, FeSSIF-V2) or for the intravenous route (PBS). The solubility of the salt was affected by the nature of the medium, indicating that it could precipitate after administration, negatively impacting its bioavailability and its efficiency in vivo. On the contrary, in all media, PNEs remained stable in terms of granulometric properties (determined by DLS), ζ-potential and encapsulation efficiency (measured by HPLC). Thus, such nanomedicines appear as a valuable option to perform preclinical studies on the promising pyridoclax.

Targeting the BH3 domain of Bcl-2 family proteins. A brief history from natural products to foldamers as promising cancer therapeutic avenues.

For many years the spotlight in drug discovery has been on a relatively small number of validated therapeutic target classes, such as G-protein coupled receptors and enzymes such as protein kinases, with well characterized enzymatic and cellular activities. However, with recent progress in genomics and proteomics, protein-protein interactions (PPIs) provide new way of finding novel bioactive molecules acting on their interfaces. This review addresses the current case studies and state of the art in the development of small chemical modulators controlling interactions of proteins that have pathological implications in various human diseases and in particular in cancer. The attention is focused on Bcl-2 family protein modulators ranging from natural products to synthetic ones with particular interest in foldamers as BH3 alpha helix mimetics.