Walter, Melanie and Baumann, Felix and Schorr, Kathrin and Goepferich, Achim (2023) Ectoenzymes as promising cell identification structures for the high avidity targeting of polymeric nanoparticles. INTERNATIONAL JOURNAL OF PHARMACEUTICS, 647: 123453. ISSN 0378-5173, 1873-3476
Full text not available from this repository. (Request a copy)Abstract
Pharmacotherapy is often limited by undesired side effects while insufficient drug reaches the site of action. Active-targeted nanotherapy should provide a solution for this problem, by using ligands in the nanoparticle corona for the identification of receptors on the target-cell surface. However, since receptor binding is directly associated with pharmacological responses, today's targeting concepts must be critically evaluated. We hypothesized that addressing ectoenzymes would help to overcome this problem, but it was not clear if particles would show sufficiently high avidity to provide us with a viable alternative to classical ligand-receptor concepts. We scrutinized this aspect by immobilizing the highly selective angiotensin-converting enzyme 2 (ACE2) inhibitor MLN-4760 in the corona of block-copolymer nanoparticles and investigated enzyme binding via microscale thermophoresis and flow cytometry. Excellent avidities with Kd values as low as 243 pM for soluble ACE2 and 306 pM for ACE2-positive cells were obtained. In addition, the inhibitory activity had an IC50 value of 2.88 nM. Reliable target cell identification could be proven in coculture experiments. High avidity is the basis for minimizing material loss to off-target sites and paves the way for a paradigm shift in nanoparticle targeting which does not trigger unintended side effects following target cell identification.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSFERRIN RECEPTOR; BINDING; ADHESION; INTEGRINS; CANCER; GPCR; Adverse nanoparticle effects; Target cell anchoring; PLA-PEG; Enzyme-responsive; Targeting efficiency; Cell identification |
| Subjects: | 600 Technology > 600 Technology (Applied sciences) 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 06:43 |
| Last Modified: | 30 Jan 2024 06:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59165 |
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