Improved Access to Potent Anticancer Tubulysins and Linker-Functionalized Payloads Via an All-On-Resin Strategy.

Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.

Fluorescent spherical mesoporous silica nanoparticles loaded with emodin: Synthesis, cellular uptake and anticancer activity.

The natural product emodin (EO) exhibits anti-inflammatory, antiangiogenesis and antineoplastic properties in vitro and in vivo. Due to its biological properties as well as its fluorescence, EO can be useful in pharmacology and pharmacokinetics. To enhance its selectivity to cancer cells, EO was loaded into non-fluorescent and novel fluorescent spherical mesoporous nanoparticles bearing N-methyl isatoic anhydride (SNM~M) or lissamine rhodamine B sulfonyl moieties (SNM~L). The propylamine functionalized mesoporous silica nanomaterial (SNM) were characterized by powder X-ray diffraction (XRD), nitrogen gas sorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), fluorescence spectroscopy, thermogravimetric analysis (TGA) and UV spectroscopy. The cytotoxicity of EO-loaded nanoparticles was tested against the human colon carcinoma cell line HT-29. Non-loaded SNM did not affect cell proliferation, whereas those loaded with EO were at least as efficient as EO alone. It could be shown by fluorescence microscopy that the uptake of silica nanomaterial by the tumor cells occurred within 2 h and the release of EO occurred within 48 h of treatment. Flow cytometry and Western blot analysis showed that SNM containing EO induced apoptosis in HT-29 cells.