Research Dr. Ulrich Lächelt

The high therapeutic potential of biomacromolecules (nucleic acids, peptides, proteins) is generally opposed by a rather low ‘drug-likeness’ and unfavorable pharmacokinetic properties, in particular poor distribution to the intracellular target site.

Our research focusses on the synthesis, characterization and application of nanopharmaceuticals for controlled delivery of drugs and biomacromolecules. For this, we use solid-phase synthesis derived oligomers and metal-organic hybrid materials.

Sequence-defined oligomers

Solid-phase synthesis derived oligomers based on artificial building blocks combine advantages of polymeric delivery systems with the chemical precision of peptides. Molecular assembly on solid-phase provides high structural flexibility for the chemical design of carriers with intended properties and implementated functions.

Selected publications

• Kuhn J., Lin Y., Krhac Levacic A., Al Danaf N., Peng L., Höhn M., Lamb D.C., Wagner E., Lächelt U.*, Delivery of Cas9/sgRNA Ribonucleoprotein Complexes via Hydroxystearyl Oligoamino Amides, Bioconj. Chem., 2020. https://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.9b00853
• Kuhn J., Klein P.M., Al Danaf N., Nordin J.Z., Reinhard S., Loy D.M., Höhn M., El Andaloussi S., Lamb D.C., Wagner E., Aoki Y., Lehto T., Lächelt U.*, Supramolecular Assembly of Aminoethylene-Lipopeptide PMO Conjugates into RNA Splice-Switching Nanomicelles, Adv. Funct. Mater., 2019. https://doi.org/10.1002/adfm.201906432
• Truebenbach I., Gorges J., Kuhn J., Kern S., Baratti E., Kazmaier U., Wagner E., Lächelt U.*, Sequence-Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy, Macromol. Biosci., 2017, 17(10). https://doi.org/10.1002/mabi.201600520
• Liu X., Zhang P., He D., Rödl W., Preiß T., Rädler J.O., Wagner E., Lächelt U.*, pH-Reversible Cationic RNase A Conjugates for Enhanced Cellular Delivery and Tumor Cell Killing, Biomacromolecules, 2016, 17, 173-182. https://doi.org/10.1021/acs.biomac.5b01289
• Lächelt U.*, Wittmann V., Müller K., Edinger D., Kos P., Höhn M., Wagner E., Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes, Mol. Pharm., 2014, 11, 2631-2639. https://doi.org/10.1021/mp500017u
• Lächelt U., Kos P., Mickler F.M., Herrmann A., Salcher E.E., Rödl W., Badgujar N., Bräuchle C., Wagner E.*, Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes, Nanomedicine (N. Y., NY, U. S.), 2014, 10, 35-44. https://doi.org/10.1016/j.nano.2013.07.008

Metal-organic nanopharmaceuticals

The combination of organic building units with Lewis base function and inorganic metal ions or metal oxide clusters creates a diverse chemical space of hybrid materials. Metal-organic frameworks (MOFs) are highly attractive for drug delivery since their size and porosity can be tuned and metal sites on the surface provide the possibility for coordinative binding of therapeutics.

Drug molecules with Lewis base funcions in their molecular structure can serve as organic linkers in coordination polymers themselves and enable the formation of drug-metal nanopharmaceuticals with very high drug loading capacity.

Selected publications

• Steinborn B., Lächelt U.*, Metal-Organic Nanopharmaceuticals, Pharmaceutical Nanotechnoogy, 2020. https://doi.org/10.2174/2211738508666200421113215
• Ploetz E.*, Engelke H.*, Lächelt U.*, Wuttke S.*, The Chemistry of Reticular Framework Nanoparticles: MOF, ZIF, and COF Materials, Adv. Funct. Mater., 2020. https://doi.org/10.1002/adfm.201909062
• Steinborn B., Hirschle P., Höhn M., Bauer T., Barz M., Wuttke S., Wagner E., Lächelt U.*, Core-Shell Functionalized Zirconium-Pemetrexed Coordination Nanoparticles as Carriers with a High Drug Content, Adv. Therap., 2019. https://doi.org/10.1002/adtp.201900120
• Zimpel A., Danaf N., Steinborn B., Kuhn J., Höhn M., Bauer T., Hirschle P., Schrimpf W., Engelke H., Wagner E., Barz M., Lamb D.C., Lächelt U.*, Wuttke S.*, Coordinative Binding of Polymers to Metal–Organic Framework Nanoparticles for Control of Interactions at the Biointerface, ACS Nano, 2019, 13(4), 3884-3895. https://doi.org/10.1021/acsnano.8b06287
• Röder R., Preiß T., Hirschle P., Steinborn B., Zimpel A., Höhn M., Rädler J.O., Bein T., Wagner E., Wuttke S.*, Lächelt U.*, Multifunctional nanoparticles by coordinative self-assembly of His-tagged units with metal-organic frameworks, J. Am. Chem. Soc., 2017, 139(6), 2359–2368. https://doi.org/10.1021/jacs.6b11934
• Zimpel A., Preiß T., Röder R., Engelke H., Ingrisch M., Peller M., Rädler J.O., Wagner E., Bein T., Lächelt U.*, Wuttke S.*, Imparting Functionality to MOF Nanoparticles by External Surface Selective Covalent Attachment of Polymers, Chem. Mater., 2016, 28, 3318-3326. https://doi.org/10.1021/acs.chemmater.6b0018