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Abstract Nonionic hydrogels are of particular interest for long‐term therapeutic implantation due to their minimal immunogenicity relative to their charged counterparts. However, in situ formation of nonionic supramolecular hydrogels under physiological conditions has been a challenging task. In this context, we report on our discovery of salt‐triggered hydrogelation of nonionic supramolecular polymers (SPs) formed by self‐assembling prodrug hydrogelators (SAPHs) through the Hofmeister effect. The designed SAPHs consist of two SN‐38 units, which is an active metabolite of the anticancer drug irinotecan, and a short peptide grafted with two or four oligoethylene glycol (OEG) segments. Upon self‐assembly in water, the resultant nonionic SPs can be triggered to gel upon addition of phosphate salts. Our1H NMR studies revealed that the added phosphates led to a change in the chemical shift of the methylene protons, suggestive of a disruption of the water‐ether hydrogen bonds and consequent reorganization of the hydration shell surrounding the SPs. This deshielding effect, commensurate with the amount of salt added, likely promoted associative interactions among the SAPH filaments to percolate into a 3D network. The formed hydrogels exhibited a sustained release profile of SN‐38 hydrogelator that acted potently against cancer cells.
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Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates
Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impact of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug/alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels, as well as their drug release profiles, showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design, with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials.
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- Award ID(s):
- 1944875
- PAR ID:
- 10577910
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- Biomacromolecules
- Volume:
- 25
- Issue:
- 7
- ISSN:
- 1525-7797
- Page Range / eLocation ID:
- 4482 to 4491
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.biomac.4c00519
