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Overcoming Biological Barriers: Synthesis and Evaluation of Molecular Transporters


High molecular weight and highly-charged biomolecules are emerging as drugs with high selectivity and efficacy; however, new strategies are needed to improve their efficiency and targeted delivery in biological systems. One potential solution is the conjugation or association of the biologic with a molecular transporter.

Inspired by proteins, such as HIV-Tat, with cellular translocation abilities, numerous guanidinium-rich molecular transporters have been synthesized from a diverse range of nonpeptidic scaffolds. While their repertoire has expanded tremendously in the past two decades, new transporters can provide unique intracellular distributions, targeting effects, or pharmacological properties.

Polymyxin B is a cyclic polypeptide antibiotic containing five primary amines and a hydrophobic tail that has not been exploited as a delivery module. Here, we synthesized functionalized derivatives of polymyxin and its per-guanidinylated derivative and evaluated their cellular uptake in mammalian cells. Both polymyxin and its guanidinylated form effectively enter mammalian cells at nanomolar concentrations and can facilitate the cellular delivery of large biomolecules and liposomal assemblies.

Guanidinoglycosides are a non-oligomeric class of molecular transporters developed in our lab that permeate the cell membrane through heparan sulfate-dependent pathways at low nanomolar concentrations. To further advance guanidinoglycosides as transporters, guanidinylated neomycin (GNeo) derivatives containing different fatty acids were synthesized and incorporated into liposomes. A small molecule dye or a lysosomal enzyme were encapsulated in the liposomes and delivered to Chinese hamster ovary cells or human fibroblasts, respectively. Incorporation of stearyl- or di-oleyl-GNeo lipids into liposomes resulted in the greatest enhancement of uptake. The delivery of α-L-iduronidase, a lysosomal enzyme, was able to restore enzyme function in fibroblasts lacking endogenous enzyme. As an alternative approach to enhance GNeo as a molecular transporter, oligomers of GNeo were synthesized using ring-opening metathesis polymerization. The synthesis of the reactive monomer, formation of GNeo oligomers, and preliminary cellular uptake studies are presented. In addition to using GNeo for new delivery systems, we also sought to explore the effect the linker connecting the cargo to the carrier has on conjugation and uptake. Varying the length and hydrophobic properties of the linker joining GNeo to biotin resulted in diverse conjugation efficiencies to streptavidin and differences in cellular uptake, highlighting the importance of the linker when designing and studying new molecular transporters.

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