Zhensheng Li

Self-Assembly of Porphyrin–Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape

Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin-paclitaxel conjugates (Py-s-s-PTX) were synthesized by using a disulfide bond as a linker. The Py-s-s-PTX could self-assemble into nanoparticles (Py-s-s-PTX NPs) with a size of about 100u2005nm via disulfide-induced assembly. Py-s-s-PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py-s-s-PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py-s-s-PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide-assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy.

Nanoscale Fluorescent Metal–Organic Framework@Microporous Organic Polymer Composites for Enhanced Intracellular Uptake and Bioimaging

Polymer-modified metal-organic frameworks combine the advantages of both soft polymers and crystalline metal-organic frameworks (MOFs). It is a big challenge to develop simple methods for surface modification of MOFs. In this work, MOF@microporous organic polymer (MOP) hybrid nanoparticles (UNP) have been synthesized by epitaxial growth of luminescent boron-dipyrromethene (BODIPYs)-imine MOPs on the surface of UiO-MOF seeds, which exhibit low cytotoxicity, smaller size distribution, well-retained pore integrity, and available functional sites. After folic acid grafting, the enhanced intracellular uptake and bioimaging was validated.

Small molecular nanomedicines made from a camptothecin dimer containing a disulfide bond.

A small molecular camptothecin (CPT) dimer could self-assemble into stable nanoparticles in aqueous solution, which was characterized by TEM and DLS. These nanomedicines could be internalized by cancer cells as revealed by confocal laser scanning microscopy, and indicated high cellular proliferation inhibition toward HeLa and HepG2 cells with low IC50 values and reduction-responsive cytotoxicity towards HeLa cells. The feasible assembly method and outstanding properties of CPT–NPs provide an alternative approach for exploring new nanomedicines for cancer therapy.

Reduction-responsive fluorescence off–on BODIPY–camptothecin conjugates for self-reporting drug release

A reduction-responsive fluorescence off-on theranostic prodrug with self-reporting drug release was constructed based on boron dipyrromethene (BODIPY) and therapeutic drug camptothecin (CPT) with a long flexible disulfide linker. Treatment with dithiothreitol (DTT) induced cleavage of the disulfide bond, followed by intramolecular cyclization reaction to release free CPT, simultaneously perturbing electronic energy transfer (EET) and resulting in enhanced blue and green fluorescence emissions. The changes of the fluorescence ratio over time provided the opportunity for detection and real-time monitoring of drug release at the cellular levels. In addition, the disulfide-linked dyad composed of hydrophobic molecules could self-assemble into stable nanoparticles in aqueous solution, facilitating drug delivery and cancer therapy in vivo due to the enhanced permeation and retention (EPR) effect. Nanomedicines displayed similar fluorescence enhancement in tumor cells. These findings confirm that this dye-disulfide-drug system (DDD) has a significant potential for thiol-activated cancer theranostic and self-reporting drug release in a clinical setting.

Amphiphilic Cyanine–Platinum Conjugates as Fluorescent Nanodrugs

Two fluorescent nanomedicines based on small molecular cyanine-platinum conjugates have been prepared via a nanoprecipitation method and characterized by transmission electron microscopy (TEM) as well as dynamic light scattering (DLS). The conjugates exhibited an enhanced fluorescence in their nanoparticle formulation compared to that in solution. The nanomedicines could be endocytosed by cancer cells as revealed by confocal laser scanning microscopy (CLSM) and showed high cellular proliferation inhibition. Fluorescent platinum nanomedicines prepared directly from small molecules could be an alternative strategy for developing new drugs with simultaneous cellular imaging and cancer therapy functions.

A glutathione-activatable photodynamic and fluorescent imaging monochromatic photosensitizer

The currently available photodynamic sensitizers usually lead to undesirable side effects, including dark toxicity from heavy-atom effect and nonspecific phototoxicity. To address these issues, we designed and prepared a smart photosensitizer from boron dipyrromethene (BODIPY), and the dark toxicity and phototoxicity were reduced via heavy-atom-free substitution and controllable photosensitization, respectively. Importantly, the photodynamic effect together with fluorescence imaging can be simultaneously switched on through the suppression of intramolecular charge transfer (ICT) and photoinduced electron-transfer (PeT) induced by cancer-related biothiol glutathione (GSH) in a buffer solution. Moreover, the sensitizer exhibits obvious fluorescence enhancement and selective phototoxicity towards cancer cells in a biological system upon irradiation. The present monochromatic photosensitizer, which combines fluorescence imaging and targeted PDT treatment within a single chromophore, possesses great potentials as a new activatable theranostic reagent in cancer therapy.