Pi‐Stacking Enhances Stability, Scalability of Formation, Control over Flexibility, and Circulation Time of Polymeric Filamentous Nanocarriers

Abstract

Self‐assembling filomicelles (FMs) are of great interest to nanomedicine due to their structural flexibility, extensive systemic circulation time, and amenability to unique “cylinder‐to‐sphere” morphological transitions. However, current fabrication techniques for preparing FMs are highly variable and difficult to scale. Herein, it is demonstrated that tetrablock copolymers composed of poly(ethylene glycol)‐b‐poly(propylene sulfide) (PEG‐b‐PPS) diblocks linked by a pi‐stacking perylene bisimide (PBI) moiety permit rapid, scalable, and facile assembly of FMs via the flash nanoprecipitation (FNP) method. Coassembling the tetrablocks and PEG‐b‐PPS diblocks at different molar ratios resulted in mixed PBI‐containing FMs (mPBI‐FM) with tunable length and flexibility. The flexibility of mPBI‐FM can be optimized to decrease uptake by macrophages in vivo, leading to increased circulation time versus (−)PBI‐FM without PBI tetrablocks after intravenous administration in mice. While PEG‐b‐PPS diblocks form FM within a narrow range of hydrophilic weight fractions, incorporation of pi‐stacking PBI groups expanded this range to increase favorability of FM assembly. Furthermore, the aggregation‐dependent fluorescence of PBI shifted during oxidation‐induced “cylinder‐to‐sphere” transitions of mPBI‐FM into micelles, resulting in a distinct emission wavelength for filamentous versus spherical nanostructures. Thus, incorporation of pi‐stacking allows for rapid, scalable assembly of FMs with tunable flexibility and stability for theranostic and nanomedicine applications.

From Solution to Thin Film: Molecular Assembly of π-Conjugated Systems and Impact on (Opto)electronic Properties

“…394,395 π stacking modulation has also been related to enhanced mechanical properties, 396 thin film morphology and stabilities. 397,398 In addition to the most common modes of π−π interactions, structurally related variations (e.g., cation−π, 399 anion−π, 400 hydrogen bond−π 401 ) derived from π contacts have also been described and exploited in crystal engineering. Further, radical-based π−stacking (i.e., pancake bonding) 402−404 has also been used toward chemical design of novel OSC architectures.…”

Harnessing the Therapeutic Potential of Biomacromolecules through Intracellular Delivery of Nucleic Acids, Peptides, and Proteins

“…Therefore, we and others have explored strategies to improve the in vivo stability of PAMs through micelle core cross‐linking ( Figure A,B), [ 208–210 ] incorporating additional peptide coiled‐coil interactions, PEGylation (Figure 13C), [ 211,212 ] hydrogen bonding (Figure 13D), [ 213,214 ] and π – π stacking. [ 215 ]…”

“…[207] However, it is much more difficult to target other tissues. Therefore, we and others have explored strategies to improve the in vivo stability of PAMs through micelle core cross-linking (Figure 13A,B), [208][209][210] incorporating additional peptide coiled-coil interactions, PEGylation (Figure 13C), [211,212] hydrogen bonding (Figure 13D), [213,214] and 𝜋-𝜋 [215] The morphology of micelle nanoparticles is another important factor that commands consideration during the design process. Worm-like micelles are not ideal for in vivo nanoparticle circulation as they potentially entangle and form local depots.…”

Non-spherical Polymeric Nanocarriers for Therapeutics: The Effect of Shape on Biological Systems and Drug Delivery Properties

“…Nanocarrier flexibility also affect cellular uptake, as stiffer particles typically showed increased internalization by immune cells [ 87 ]. Flexible filomicelles based on tetrablock copolymers of PEG-b-PPS linked by a pi-stacking perylene bisimide (PBI) [ 72 ], were optimized to decrease macrophage uptake and increase circulation time after intravenous administration in mice.…”