Methacrylic-based nanogels for the pH-sensitive delivery of 5-Fluorouracil in the colon

N Ashwanikumar,1,* Nisha Asok Kumar,2,* S Asha Nair,2 GS Vinod Kumar11Chemical Biology, 2Cancer Research Programme, Rajiv Gandhi Center for Biotechnology, Poojappura, Thiruvananthapuram, Kerala, India *These authors contributed equally to this workAbstract: Methacrylic-based copolymers in drug-delivery systems demonstrate a pH-sensitive drug-releasing behavior in the colon. In this study, copolymers of methacrylic acid and 2-ethyl hexyl acrylate were prepared using a microemulsion polymerization technique. The purified copolymer was characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. 5-Fluorouracil (5-FU) was entrapped within methacrylic-based copolymers by a solvent evaporation method. The size of the nanogels formed was characterized by transmission electron microscopy and atomic force microscopy. In vitro drug-release studies using phosphate-buffered saline at different pH levels demonstrated the sustained release of 5-FU and its pH dependence. Cell proliferation assay of a human colon tumor colon cancer cell line (HCT-116) was performed and showed that the nanogels containing 5-FU exhibited considerable cytotoxicity in comparison with free 5-FU. Cell uptake of the nanogels was also monitored using confocal microscopy. Western blot analysis and flow cytometry studies confirmed that the nanogels could be successfully used as an efficient vector for pH-sensitive and controlled delivery of drugs specifically targeted to the colon.Keywords: 5-FU, methacrylic polymer, colon cancer, nanoge

Peptide decorated glycolipid nanomicelles for drug delivery across the blood–brain barrier (BBB)

Schematic summary of the development of peptide decorated glycolipid nanomicelles for brain delivery by crossing Blood Brain Barrier (BBB).</p

Binding energy analysis and molecular dynamic simulation studies of the designed orally active, non-toxic GABARAP modulators

Epilepsy is a severe neurological disorder that occurs when the communication between the neurons is disturbed. Gamma-amino butyric acid-associated protein (GABARAP) plays a key role in balancing Gamma-aminobutyric acid-A (GABA(A)) receptor functions of inhibiting the neurotransmission and controlling the seizure. In this study, we introduce the derivatives of the selected anti-epileptic drugs, namely Felbamate and Clobazam, by substituting different hydrophilic and hydrophobic groups at the specified positions. Molecular docking studies between the derivatives and GABARAP were carried out using PyRx software. The interacting residues were identified from LigPlot+. Drug-likeness, drug-related properties, and toxic endpoints of each derivative were analyzed using the SwissADME, Osiris property explorer, and ProTox-II servers. After analyzing the binding energy, drug-properties, and toxicity, the best five derivatives of Felbamate and Clobazam were selected. Molecular Dynamic simulation studies involving the target-ligand interaction were carried out for 100 nanoseconds using GROMACS 2018. The root mean square deviation, root mean square fluctuation, radius of gyration, Solvent accessible area, Energy plots and trajectories of the ten GABARAP complexes of the derivatives, and two GABARAP complexes of parent drugs were compared and critically analyzed. Among the five Felbamate derivatives, F7 formed the most stable complex with GABARAP. Among the five Clobazam derivatives, C27, C33 and C32 showed stable GABARAP interaction. In light of the above systematic computational analysis, we propose F7, C27, C33, and C32 as the potential anti-epileptic drug candidates for developing novel therapeutics. The substitution of hydrophobic groups at para position on benzene ring has promoted strong binding to GABARAP. Communicated by Ramaswamy H. Sarma</p