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When synthetic polyamines, such poly(allylamine hydrochloride) (PAH), are mixed with crosslink-forming multivalent anions, they can undergo complex coacervation. This phenomenon has recently been exploited in various applications, ranging from inorganic material synthesis, to underwater adhesion, to multiple-month release of small, water-soluble molecules. Here, using ibuprofen as a model drug molecule, we show that these coacervates may be especially effective in the long-term release of weakly amphiphilic anionic drugs. Colloidal amphiphile/polyelectrolyte complex dispersions are first prepared by mixing the amphiphilic drug (ibuprofen) with PAH. Pentavalent tripolyphosphate (TPP) ions are then added to these dispersions to form ibuprofen-loaded PAH/TPP coacervates (where the strongly-binding TPP displaces the weaker-bound ibuprofen from the PAH amine groups). The initial ibuprofen/PAH binding leads to extremely high drug loading capacities (LC-values), where the ibuprofen comprises up to roughly 30% of the coacervate mass. Conversely, the dense ionic crosslinking of PAH by TPP results in very slow release rates, where the release of ibuprofen (a small, water-soluble drug) is extended over timescales that exceed 6 months. When ibuprofen is replaced with strong anionic amphiphiles, however ( i.e. , sodium dodecyl sulfate and sodium dodecylbenzenesulfonate), the stronger amphiphile/polyelectrolyte binding disrupts PAH/TPP association and sharply increases the coacervate solute permeability. These findings suggest that: (1) as sustained release vehicles, PAH/TPP coacervates might be very attractive for the encapsulation and multiple-month release of weakly amphiphilic anionic payloads; and (2) strong amphiphile incorporation could be useful for tailoring PAH/TPP coacervate properties.
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Polyphenol-stabilized coacervates for enzyme-triggered drug delivery
Abstract Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Here we report a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, we develop size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. We discover a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery.
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- Award ID(s):
- 2242375
- PAR ID:
- 10535694
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 15
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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