Force-controlled release of small molecules with a rotaxane actuator

Abstract

Force-controlled release of small molecules offers great promise for the delivery of drugs and the release of healing or reporting agents in a medical or materials context^1-3. In polymer mechanochemistry, polymers are used as actuators to stretch mechanosensitive molecules (mechanophores)⁴. This technique has enabled the release of molecular cargo by rearrangement, as a direct^5,6 or indirect^7-10 consequence of bond scission in a mechanophore, or by dissociation of cage¹¹, supramolecular¹² or metal complexes^13,14, and even by 'flex activation'^15,16. However, the systems described so far are limited in the diversity and/or quantity of the molecules released per stretching event^1,2. This is due to the difficulty in iteratively activating scissile mechanophores, as the actuating polymers will dissociate after the first activation. Physical encapsulation strategies can be used to deliver a larger cargo load, but these are often subject to non-specific (that is, non-mechanical) release³. Here we show that a rotaxane (an interlocked molecule in which a macrocycle is trapped on a stoppered axle) acts as an efficient actuator to trigger the release of cargo molecules appended to its axle. The release of up to five cargo molecules per rotaxane actuator was demonstrated in solution, by ultrasonication, and in bulk, by compression, achieving a release efficiency of up to 71% and 30%, respectively, which places this rotaxane device among the most efficient release systems achieved so far¹. We also demonstrate the release of three representative functional molecules (a drug, a fluorescent tag and an organocatalyst), and we anticipate that a large variety of cargo molecules could be released with this device. This rotaxane actuator provides a versatile platform for various force-controlled release applications.

Fig. 1. Elongation of the rotaxane actuator leads to the sequential release of the cargo units placed on the axle as they are pushed by the macrocycle.

a, Design of rotaxane actuator 1, able to release up to five cargo units per chain. The rotaxane is built around a pillar[5]arene macrocycle, which can trigger the release of N-triphenylmethyl maleimide (2) by promoting a mechanical retrocycloaddition when entering into contact with the furan/maleimide Diels–Alder adduct. b, Synthesis of cargo-bearing rotaxanes via a stopper exchange mechanism. Conditions: (i) BTBSCl, Et₃N, CHCl₃, −15 °C, 2 h, yield: 11%; (ii) K₂CO₃, 18-crown-6, acetone, room temperature, 16 h, yield: see Supplementary Information; (iii) methyl acrylate, Cu wire, CuBr₂, Me₆TREN, DMSO. Red arrows indicate the direction of the force.

Fig. 2. Mechanical activation of various geometrical isomers of model rotaxane 9.

a, Mechanical activation of cis and trans isomers of model rotaxane 9 bearing endo or exo mechanophores. Conditions: (i) ultrasound (20 kHz, 13 W cm⁻², 1 s on/1 s off), CH₃CN, 5−10 °C, 300 min. b, Partial ¹H NMR (400 MHz, acetone-d₆) spectra of rotaxane 9_trans/exo before (i) and after (ii) sonication, along with reference compound S3 (iii), indicate activation of the Diels–Alder adduct and release of the maleimide cargo. c, Partial ¹H NMR (400 MHz, acetone-d₆) spectra of the post-sonication MeOH extract (i), along with a reference compound 2 (ii).

Fig. 3. Force-controlled release of functional cargo molecules via retrocycloaddition and heterolytic cleavage.

Conditions: ultrasound (20 kHz, 13 W cm⁻², 1 s on/1 s off), 5−10 °C and (i) CH₃CN, 90 min or (ii) 1-dodecane thiol (50 equiv.), CH₃CN/H₂O: 9/1, 90 min or (iii) THF/H₂O: 75/1, 120 min.

Fig. 4. Activation of multicargo rotaxanes in solution and bulk.

a, Mechanical activation of multicargo rotaxanes can lead to partial or complete release of the cargo load. Unselective scission can occur if the rotaxane breaks in the axle or in one of the PMA chains. b, Partial ¹H NMR (400 MHz, acetone-d₆) spectra of rotaxane 1_5-215 before (i) and after (ii) sonication, along with reference compound S22 (iii), indicate the activation of internal and terminal Diels–Alder adducts. c, Structural and activation parameters for representative one-, three- and five-cargo rotaxanes. Percentage of unselective scission combines PMA and axle scissions. Relative error of unselective scission and cargo release, 17–51%, see Supplementary Section 8.7 for full data and calculation details. d, Activation by compression in bulk leads to cargo release in an entangled network. Condition: (i) manual press (0.74 GPa, less than 60 min per cycle, 10–45 cycles).

Extended Data Fig. 1. Cartoon depiction of the force-controlled release of cargo molecules by a rotaxane actuator.

Upon elongation of the rotaxane, by the intermediary of the polymer chains (thin grey strands), the macrocycle (light brown) is pulled along the cargo compartment until it reaches the first cargo molecule (blue ball), which acts as a barrier as the macrocycle is unable to pass this steric obstacle without its detachment. Pulling the macrocycle further eventually triggers the release of the first cargo unit. This process is repeated as the macrocycle is pulled along the cargo compartment, leading to the release of all the cargo molecules and the escape of the macrocycle.