α/ß-Peptides as Nanomolar Triggers of Lipid Raft-Mediated Endocytosis through GM1 Ganglioside Recognition.

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/ß-peptide tags with high affinity to the lipid raft-associated ganglioside GM1. These sequences induce effective internalization of the attached immunoglobulin cargo. The structural requirements of the GM1-peptide interaction are presented, and the importance of the membrane components are shown. The results contribute to the development of a receptor-based cell delivery platform.

Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization.

The negative membrane potential of bacterial cells influences crucial cellular processes. Inspired by the molecular scaffold of the antimicrobial peptide PGLa, we have developed antimicrobial foldamers with a computer-guided design strategy. The novel PGLa analogues induce sustained membrane hyperpolarization. When co-administered as an adjuvant, the resulting compounds - PGLb1 and PGLb2 - have substantially reduced the level of antibiotic resistance of multi-drug resistant Escherichia coli, Klebsiella pneumoniae and Shigella flexneri clinical isolates. The observed antibiotic potentiation was mediated by hyperpolarization of the bacterial membrane caused by the alteration of cellular ion transport. Specifically, PGLb1 and PGLb2 are selective ionophores that enhance the Goldman-Hodgkin-Katz potential across the bacterial membrane. These findings indicate that manipulating bacterial membrane electrophysiology could be a valuable tool to overcome antimicrobial resistance.

Mechanisms of the effectiveness of lipid nanoparticle formulations loaded with anti-tubercular drugs combinations toward overcoming drug bioavailability in tuberculosis.

Dual-drug-loaded lipid nanoparticle formulations (LNFs) namely solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (are also solid lipid nanoparticles- a new generation of traditional SLNs) were developed and delivered to differentiated THP-1 cells. Developed LNFs have smooth and spherical surface morphology and nano range in size. In vitro drugs release profiles from these LNFs were slow and sustained. Particles were well co-localised in a different compartment (lysosome and endosome) of polarised macrophage by using suitable pH-dependent and antibody-mediated trafficking probe. Majority of the LNFs were also capable of existing in phago-lysosomal complex and able to effectively co-localise with the different cellular compartment of THP-1. The journey of the lipid carrier started through the formation of coated vesicle on differentiated macrophage surface, will further followed to idetify the efficient delivery of nano carrierat lysosomal and endosomal compartment in a sub cellular level of specific cell population. Comparative oral in vivo pharmacokinetic study revealed that nanostructured lipid carrier enhanced the pharmacokinetic profile compared to solid lipid nanoparticles and overall inclined the relative bioavailability by many folds. Cumulative results suggest that nanostructured lipid carrier could be an effective, alternative and promising lipid-mediated oral drug delivery approach than solid lipid nanoparticles.