Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy.

The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

Tanshinol suppresses osteosarcoma by specifically inducing apoptosis of U2-OS cells through p53-mediated mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Salviae miltiorrhizae (also called Danshen in traditional Chinese medicine) is a famous herbal medicine, which has been frequently used to treat blood stasis syndrome including osteosarcoma (OS) in traditional Chinese medicine. Main components of Danshen have been assumed to exhibit anti-OS capacity. Nevertheless, tanshinol (TS, main component of Danshen)'s efficacy and mechanism in OS hasn't been clearly described ever since. This drew our attention, since OS is the most frequent primary bone carcinomas in children and adolescents, with a high incidence and fatality rate. Unfortunately, chemotherapy for OS has faced many clinical challenges due to the increasing chemoresistance and recurrence. This study was then designed to deeply explore TS's role in OS therapy. AIM OF THE STUDY: To explore the anti-OS efficacy and mechanism of TS, we conducted in vivo and in vitro experiments by using a zebrafish xenograft model and U2-OS cells. MATERIALS AND METHODS: CCK-8 assay, DAPI and γ-H2A.X immunofluorescence staining, and flow cytometry (apoptosis verification) were employed to determine the anti-proliferative and pro-apoptotic effects of TS. qPCR and Western blot were used to examine TS's molecular actions and mechanism on apoptosis of U2-OS cells. RESULTS: The in vivo data showed that TS significantly inhibited U2-OS tumor growth in larval zebrafish from 2 to 20 ng/mL. In vitro data indicated that TS exerted significant anti-proliferative and pro-apoptotic effects on U2-OS cells in a dose-dependent manner. Moreover, TS has no inhibitory effect on bMSCs, suggesting its safety on normal bone-forming cells. Molecular data illustrated that TS obviously activated the p53 signaling-related proteins (p-p53, Bax, CASP3, CASP9) and its upstream JNK (p-JNK, p-c-JUN) and ATM (p-ATM) signaling molecules through phosphorylation and cleavage, followed by up-regulation of the pro-apoptotic genes, NOXA, PUMA, TP53, BAX, and BIM, and down-regulation of Bcl-2 protein. CONCLUSION: In sum, TS specifically induced apoptosis of U2-OS cells by activating p53 signaling pathways, indicating TS as a promising candidate for OS treatment.

Nanostructured lipid carrier-based pH and temperature dual-responsive hydrogel composed of carboxymethyl chitosan and poloxamer for drug delivery.

The aim of this study was to develop a novel nanostructured lipid carrier (NLC) based dual-responsive hydrogel for ocular drug delivery of quercetin (QN). NLC loaded with quercetin (QN-NLC) was prepared using melt-emulsification combined with ultra-sonication technique. A three-factor five-level central composite design (CCD) was employed to optimize the formulation of QN-NLC. The optimized QN-NLC presented a particle size of 75.54nm with narrow size distribution and high encapsulation efficiency (97.14%).QN-NLC was characterized by TEM and DSC. In addition, a pH and temperature dual-responsive hydrogel composed of carboxymethyl chitosan (CMCS) and poloxamer 407(F127) was constructed by a cross-linking reaction with a naturally occurring nontoxic crosslinking agent genipin (GP). FT-IR was employed to demonstrate that F127/CMCS hydrogel was successfully synthesized. The results of SEM analysis and swelling experiments indicated that F127/CMCS hydrogel was both temperature-responsive and pH-responsive. From the results of In vitro release studies, dual temperature and pH responsiveness of the hydrogel was demonstrated, and 80.52% of total quercetin was released from the QN-NLC based hydrogel (QN-NLC-Gel) within 3days, revealing QN-NLC-Gel released drug sustainably. Taken together, the developed NLC-based hydrogel is a promising drug delivery system for the ophthalmic application.

Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate.

The aim of this study was to develop and characterize a novel colloidal system, namely, timolol maleate chitosan coated liposomes (TM-CHL) to enhance the ocular permeation, precorneal residence time and bioavailability. The resulting TM-CHL was the most promising formulation with a mean particle size of 150.7nm and an EE% of 75.83±1.61%. In vitro release of the TM-CHL showed an extended drug release profile. The TM-CHL exhibited significant mucin adhesion and compared with commercial eye drops, TM-CHL produced a 3.18-fold increase in the apparent permeability coefficient (Papp), resulting in a significant enhancement of corneal permeation. In addition, the gamma scintigraphic study and the pharmacokinetic study showed that TM-CHL could be retained at the corneal surface for longer time compared with eye drops. The ocular irritation study indicated that the developed liposomes produced no significant irritant effects. Furthermore, pharmacodynamics results showed that the maximum intraocular pressure(IOP) produced by TM-CHL was (19.67±1.14) mmHg compared with the (23.80±1.49) mmHg for TM eye drops, revealing that TM-CHL was more effective in reducing the IOP. These results demonstrate that CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM.