Survivin-targeted nanomedicine for increased potency of abiraterone and enzalutamide against prostate cancer.

Prostate cancer is the leading and most aggressive cancer around the world, several therapeutic approaches have emerged but none have achieved the satisfactory result. However, these therapeutic approaches face many challenges related to their delivery to target cells, including their in vivo decay, the limited uptake by target cells, the requirements for nuclear penetration (in some cases), and the damage caused to healthy cells. These barriers can be avoided by effective, targeted, combinatorial approaches, with minimal side effects, which are being investigated for the treatment of cancer. Here, we developed a combinatorial nanomedicine comprising abiraterone and enzalutamide bioconjugated survivin-encapsulated gold nanoparticles (AbEzSvGNPs) for targeted therapy of prostate cancer. AbEzSvGNPs were characterized by different biophysical techniques such as UV visible spectroscopy, dynamic light scattering, zeta potential, transmission electron microscope, and Fourier transform infrared spectroscopy. Interestingly, the effect of abiraterone, enzalutamide and surviving encapsulated gold nanoparticles was found to be synergistic in nature in AbEzSvGNPs against DU 145 (IC50 = 4.21 µM) and PC-3 (IC50 = 5.58 µM) cells and their potential was observed to be greatly enhanced as compared with the combined effect of the drugs (abiraterone and enzalutamide) in their free form. Furthermore, AbEzSvGNPs were found to be highly safe and did not exhibit significant cytotoxicity against normal rat kidney cells. The observed effects of AbEzSvGNPs involved the modulation of different signaling pathways in prostate cancer cells. This delivery system employed non-androgen receptor-dependent delivery of abiraterone and enzalutamide. The anionic AbEzSvGNPs delivered abiraterone and enzalutamide unaltered into the nucleus through caveolae mediated internalization to act nonspecifically on DNA; internalization of the anionic nanoparticles into the cytoplasm was also observed via other routes. AbEzSvGNPs synthesized and evaluated in this study are promising candidates for prostate cancer therapy.

Evaluation of vincamine against Acetylcholinesterase enzyme.

The current article deals with the in-silico along with enzyme kinetics approach to search for a prominent AChE enzyme inhibitor among the known natural compounds. The computational tools were involved for this purpose and eventual vincamine, a monoterpenoid indole alkaloid, was selected based on several parameters, including free energy of binding (-10.77 kcal/mol) and ADME parameter. Computationally, it confirmed the interaction between vincamine and AChE at an indistinguishable locus from that of substrate AChI (-3.94 kcal/mol) but with much higher binding energy. Interestingly, amino acid residues Gly120, Gly121, Gly122, Glu202, Trp86, Tyr133, Ser203, Phe297, and His447 of AChE were found to be common in these interactions. Further, these findings were approved with wet lab tests where detailed kinetics was studied. It was found that vincamine inhibited AChE with the inhibition constant Ki (239 µM). The value of  IC50 (239 µM) and KM (0.598 mM) was determined and further confirmed by Dixon, Lineweaver- Burk reciprocal, Hanes, and Eadie- Hofstee plots, respectively. The mode of interaction of the compound was found to be competitive for AChE. Thus, the present computational and enzyme kinetics studies conclude that vincamine can be a promising inhibitor of AChE for the effective management of AD.

Fruit Derived Potentially Bioactive Bioengineered Silver Nanoparticles.

INTRODUCTION: Protein-derived biogenic syntheses of inorganic nanoparticles have gained immense attention because of their broad spectrum of applications. Proteins offer a reducing environment to enable the synthesis of nanoparticles and encapsulate synthesized nanoparticles and provide them temporal stability in addition to biocompatibility. METHODS: In the present study, Benincasa hispida fruit proteins were used to synthesize silver nanoparticles (AgNPs) at 37 °C over five days of incubation. The synthesis of AgNPs was confirmed by UV-Vis spectroscopy, TEM, zeta potential, and DLS analyses. Further, these NPs depicted antibacterial and antibiofilm effects. Additionally, the anticancer activities of nanoparticles were also tested against the lung cancer cell line (A549) with respect to the normal cell line (NRK) using MTT assay. Further, the estimation of ROS generation through DCFH-DA staining along with a reduction in mitochondrial membrane potential by Mito Tracker Red CMX staining was carried out. Moreover, nuclear degradation in the AgNPs treated cells was cross-checked by DAPI staining. RESULTS: The average size of AgNPs was detected to be 27 ±1 nm by TEM analysis, whereas surface encapsulation by protein was determined by FTIR spectroscopy. These NPs were effective against bacterial pathogens such as Escherichia coli, Staphylococcus aureus, Salmonella enteric, and Staphylococcus epidermis with MICs of 148.12 µg/mL, 165.63 µg/mL, 162.77 µg/mL, and 124.88 µg/mL, respectively. Furthermore, these nanoparticles inhibit the formation of biofilms of E. coli, S. aureus, S. enteric, and S. epidermis by 71.14%, 73.89%, 66.66%, and 64.81%, respectively. Similarly, these nanoparticles were also found to inhibit (IC50 = 57.11 µM) the lung cancer cell line (A549). At the same time, they were non-toxic against NRK cells up to a concentration of 200 µM. DISCUSSION: We successfully synthesized potentially potent antibacterial, antibiofilm and anticancer biogenic AgNPs.