Henrik Torjusen

• Vogelaar, Thomas Daniel; Torjusen, Henrik; Narayanan, Theyencheri & Lund, Reidar (2025). The Kinetic Pathways for the Formation of Complex Coacervate Micelles of Antimicrobial Peptides and Block Copolymers. Macromolecules. ISSN 0024-9297. 58(1), p. 158–168. doi: 10.1021/acs.macromol.4c02077. Full text in Research Archive Show summary

  The conceptual application of complex coacervate core micelles (C3Ms) as drug delivery vehicles has obtained significant interest over the past several decades. Although C3Ms show promise in targeting specific body areas and improving drug circulation times, their low reproducibility and limited stability have hindered their progression to clinical trials and commercial viability. One of the major obstacles is the lack of understanding of the formation and growth kinetics of C3Ms. Since their structure is often controlled kinetically rather than thermodynamically, this insight is essential for achieving good reproducibility and stability of C3M drug delivery vehicles. Time-resolved small-angle X-ray scattering (TR-SAXS) offers excellent insights by resolving spatiotemporal kinetic processes on nanometer/millisecond scales. Here, we investigate the formation kinetics of C3Ms comprised of the antimicrobial peptide, colistin, and poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA). Using TR-SAXS coupled to stopped-flow mixing, we have identified three distinct steps in the mechanism of this complex coacervation system: nucleation, fusion, and single chain/ion-pair insertion. Nucleation cannot be experimentally resolved as it is completed during the mixing process. The fusion kinetics proceed as a first-order reaction with relaxation times of approximately 50–85 ms. The driving force for fusion is larger at increased concentrations. Chain/pair insertion occurs at relaxation times of 15–25 s, where larger remaining size mismatches (higher dispersity) drive the final equilibration process. As expected, the structural formation is concentration-dependent, providing a handle to acquire control over the size and dispersity of these kinetically trapped C3Ms. These findings contribute to a deeper understanding of C3M formation and stability, potentially advancing the development of C3M-based drug delivery systems.

• Vogelaar, Thomas Daniel; Torjusen, Henrik & Lund, Reidar (2024). Size-controlled antimicrobial peptide drug delivery vehicles through complex coacervation. Soft Matter. ISSN 1744-683X. doi: 10.1039/d4sm01157k. Full text in Research Archive Show summary

  Due to the escalating threat of the pathogens’ capability of quick adaptation to antibiotics, finding new alternatives is crucial. Although antimicrobial peptides (AMPs) are highly potent and effective, their therapeutic use is limited‚ as they are prone to enzymatic degradation, are cytotoxic and have low retention. To overcome these challenges, we investigate the complexation of the cationic AMP colistin with diblock copolymers poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA) forming colistin–complex coacervate core micelles (colistin–C3Ms). We present long-term stable kinetically controlled colistin–C3Ms that can be prepared from several block lengths of PEO-b-PMAA polymers, where the polymerisation degree governs the overall micellar size. To achieve precise control over size and polydispersity, which are crucial for drug delivery applications, we investigate the hybridisation of PEO-b-PMAA polymers with varying chain lengths or PMAA homopolymers in ternary complex coacervation systems with colistin. This results in size-tunable colistin–C3Ms, ranging, depending on the mixing ratios, from micellar sizes of 26 nm to 100 nm. With size tunability at rather narrow size distributions and high stability, ternary colistin–C3Ms offer potential advancements in C3M drug delivery, paving the way for more effective and targeted treatments for bacterial infections in precision medicine.

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