Release of Molecular Cargo from Polymer Systems by Mechanochemistry

Abstract

The design and manipulation of (multi)functional materials at the nanoscale holds the promise of fuelling tomorrow's major technological advances. In the realm of macromolecular nanosystems, the incorporation of force-responsive groups, so called mechanophores, has resulted in unprecedented access to responsive behaviours and enabled sophisticated functions of the resulting structures and advanced materials. Among the diverse force-activated motifs, the on-demand release or activation of compounds, such as catalysts, drugs, or monomers for self-healing, are sought-after since they enable triggering pristine small molecule function from macromolecular frameworks. Here, we highlight examples of molecular cargo release systems from polymer-based architectures in solution by means of sonochemical activation by ultrasound (ultrasound-induced mechanochemistry). Important design concepts of these advanced materials are discussed, as well as their syntheses and applications.

Keywords: drug release; mechanochemistry; polymers; sonochemistry; ultrasound.

Figure 1

Force‐induced bond scission occurs at the incorporated mechanophore (orange and blue) in a polymer backbone (red). Depending on the functional groups and the surrounding environment, different levels of energy are needed for stretching or structural distortion of the polymer backbone to overcome attractive intermolecular interactions, depicted by the unwinding of the polymer coil.

Figure 2

Different approaches for force‐induced acid generation. a) gDCC from indene (1) rearranged to 2‐chloronaphthalene (2), while formally releasing HCl; b) oxime sulfonate mechanophores produce trifluoromethyl ketone moieties and an acid, which is thought to be an aryl sulfonic acid;^[13] c) alkoxy substituted MeO‐gDCCs released either HCl or MeCl, with 0.58 equiv. of HCl released per mechanophore activation and 67 protons released per chain scission event.

Figure 3

Oxanorbornadiene‐based mechanophore 7 embedded in a network formed by polymerization with methyl acrylate. a) Mechanophore activation led to a cycloelimination of the [4+2] adduct, ultimately releasing the benzyl furfuryl ether 8 b; b) PMA was exchanged for a polyurethane (PU) network 10 to reduce macroscopic failure.

Figure 4

Carbene release 12 a–b from an N‐heterocyclic carbene‐carbodiimide adduct in a PMA network 11 a–b.

Figure 5

In a PDMS network (red), the Diels‐Alder adduct of anthracene and phenyltriazolinedione was used as a cross‐linker. Tension accelerated the flex‐activated retro Diels‐Alder reaction, resulting in dienophile release accompanied by turn‐on of the anthracene fluorescence.

Figure 6

Organic peroxide mechanophores can be incorporated into a polymer network to release fluorescent 18 and have potential for application in designing stress‐responsive materials.

Figure 7

Furan‐maleimide Diels‐Alder adducts are potent mechanophores for cargo release. a) Fluorogenic coumarin was released after a cascade reaction, allowing for tracking of the reaction progress by using fluorescence spectroscopy in addition to commonly employed NMR spectroscopy; b) a wide range of cargo scope, such as alcohol, alkylamine, arylamine, carboxylic acid, and sulfonic acid.

Figure 8

Substituent effects on the reactivity of 2‐furylcarbinol derivatives. Corresponding activation energies for fragmentation of the α‐C−O bond calculated at the M06‐2X/6‐311+G** level of density functional theory. Reproduced from Ref. [37] with permission. Copyright 2021, American Chemical Society.

Figure 9

The force‐induced intermolecular release of drugs using disulfide mechanophores. First, the disulfide was cleaved and protonated, after which the resulting thiol underwent Michael‐addition to the oxanorbornene structure, upon which elimination of the furan‐bearing drug proceeded.

Figure 10

The force‐induced intramolecular release of drugs from β‐carbonate disulfide mechanophores. The generated thiols underwent intramolecular 5‐exo‐trig cyclisation, releasing the cargo and greatly accelerating the process compared to intermolecular systems.

Figure 11

Polyaptamers were prepared by an RCT process bearing multiple cargo binding sites in their backbone. Ultrasonication stretches and fragments the polyaptamers, releasing the drug cargo.

Figure 12

Polymer‐substituted NHC ligands 31 a–b & 33 a–c for reaction catalysis by mechanochemical activation of latent catalysts. a) Activation of Ag‐NHC complexes 31 a–b enabled transesterification reactions catalysed by free carbenes and Ag⁺ b) polymer‐bound, Grubbs‐like Ru‐catalysts 33 a–c activated mechanochemically allowed for substrate coordination and subsequent ring‐closing metathesis (RCM) reactions.

Figure 13

Intramolecular cross‐linking by Rh‐π bonds led to controlled unfolding of the polymer under stress in solution, showing that mechanical stress can be removed from the polymer backbone and successfully transferred onto the weaker intrachain cross‐links. Linear polybutadiene was functionalized by cycloaddition of dichlorocarbene to the double bonds, giving gDCC mechanophores in the backbone. Base quantities were tuned to provide a conversion of 45 % with butadiene units remaining unreacted for subsequent rhodium coordination.

Figure 14

Metallocenes are unique mechanophores undergoing several intramolecular changes. This depends on the magnitude of force exerted on the system. ^[2c]

Figure 15

Fc‐containing bifunctional initiator bearing methyl α‐bromoisobutyrate was used to prepare 38 and a reference polymer (not depicted) with M _n of 133 and 119 kDa, respectively, and a narrow Đ_M of 1.1. Scission of the Fc mechanophore in a PMA backbone is at least 10× more favoured than non‐specific cleavage and leads to Fe³⁺ release.

Figure 16

Representative synthetic scheme for Fc‐containing polymers used in the study of Craig, Tang and co‐workers, exemplarily showing gDCC.

Figure 17

CoGEF‐computed potential (top) and force (bottom) as a function of the stretching distance for Fc (orange dots) and Rc (turquoise dots). Reproduced from Ref. [58] with permission. Copyright 2021, Royal Society of Chemistry.

Figure 18

a) Force‐induced bond scission of a metallocenes following a peeling mechanism; b) conformational restrictions in ansa‐type metallocenes lead to a shearing mechanism.

Figure 19

Three different ansa‐bridged Fc‐based mechanophores. Cis ‐42₃ , trans ‐42₃ and cis ‐42₅ (f. l. t. r.), with cis ‐42₅ having the lowest ring‐strain. Cis ‐42₃ shows a dissociation rate constant increase of several orders of magnitude due to the ansa‐bridge.

Figure 20

The exo PEG‐functionalized octahedral cage 43 has an X _n of 220 repetitive ethylene glycol units connected to each vertex, resulting in a total M _n of 60 kDa. When activated by ultrasound in aqueous solution, the cage fragmented, releasing the non‐covalently bound, preloaded cargo from its hydrophobic cavity.