Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart

Purpose HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. Methods and Results A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. Conclusion Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.

The Radiolabeling of a Gly-Sar Dipeptide Derivative with Flourine-18 and Its Use as a Potential Peptide Transporter PET Imaging Agent

We have developed a novel fluorine-18 radiotracer, dipeptide 1, radiolabeled in two steps from mesylate 3. The initial radiolabeling is achieved in a short reaction time (10 min) and purified through solid-phase extraction (SPE) with modest radiochemical yields (rcy = 10 ± 2%, n = 5) in excellent radiochemical purity (rcp > 99%, n = 5). The de-protection of the tert-butyloxycarbonyl (Boc) and trityl group was achieved with mild heating under acidic conditions to provide 18F-tagged dipeptide 1. Preliminary analysis of 18F-dipeptide 1 was performed to confirm uptake by peptide transporters (PepTs) in human pancreatic carcinoma cell lines Panc1, BxPC3, and ASpc1, which are reported to express the peptide transporter 1 (PepT1). Furthermore, we confirmed in vivo uptake of 18F-dipeptide tracer 1 using microPET/CT in mice harboring subcutaneous flank Panc1, BxPC3, and Aspc1 tumors. In conclusion, we have established the radiolabeling of dipeptide 1 with fluoride-18, and demonstrated its potential as an imaging agent which may have clinical applications for the diagnosis of pancreatic carcinomas.

Intranasal delivery of Paclitaxel encapsulated nanoparticles for brain injury due to Glioblastoma

Brain injury is a common cause for physical and emotional effects to the large number of populations. Moreover, glioblastoma is the tumor in brain with no possible treatment leading to death. The blood–brain barrier’s makes the treatment more difficult by preventing the drugs to reach central nervous system. Paclitaxel (PTX) encapsulated Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), PTX-PLGA-NPs were developed using emulsification method. The PTX-PLGA-NPs were characterized using Malvern Zetasizer and Scanning Electron Microscopy and were evaluated for their cytotoxicity in U87MG cells. PTX-PLGA-NPs were prepared using single emulsion method having size of 154 ± 22.19 nm with zeta potential of –23.7 mV. The PTX-PLGA-NPs were spherical in shape and have dose dependent cytotoxicity on U87MG cells. The PTX was released from the particles with initial burst release followed by sustained release pattern. The biodistribution was studied in mice with glioblastoma model using 125I radiolabeled PTX-PLGA-NPs and anti-glioblastoma was studied with PTX-PLGA-NPs. The biodistribution studies revealed PTX-PLGA-NPs after intranasal administration resulted in higher in vivo uptake with high anti-glioblastoma efficacy. The results suggest that PTX-PLGA-NPs administered through intranasal route have potential in the treatment of glioblastoma.