Alkene–Azide 1,3‐Dipolar Cycloaddition as a Trigger for Ultrashort Peptide Hydrogel Dissolution

Abstract

An alkene–azide 1,3‐dipolar cycloaddition between trans‐cyclooctene (TCO) and an azide‐capped hydrogel that promotes rapid gel dissolution is reported. Using an ultrashort aryl azide‐capped peptide hydrogel (PhePhe), we have demonstrated proof‐of‐concept where upon reaction with TCO, the hydrogel undergoes a gel–sol transition via 1,2,3‐triazoline degradation and 1,6‐self‐immolation of the generated aniline. The potential application of this as a general trigger in sustained drug delivery is demonstrated through release of encapsulated cargo (doxorubicin). Administration of TCO resulted in 87 % of the cargo being released in 10 h, compared to 13–14 % in the control gels. This is the first example of a potential bioorthogonal‐triggered hydrogel dissolution using a traditional click‐type reaction. This type of stimulus could be extended to other aryl azide‐capped hydrogels.

Synthesis and formulation of self‐immolative PEG‐aryl azide block copolymers and click‐to‐release reactivity with trans‐cyclooctene

“…TEM was used to investigate particle formation, and were conducted using our previously reported standard conditions. 30 Polymer-based particle dispersions were prepared (1 mg/ml) and 10 μl of sample was deposited onto plasma-glowed TEM grids (300 mesh, carbon-coated copper grids). Excess sample was carefully removed after 1 min using blotting paper.…”

“…To complement these alkyl azide-based nanoparticles, we designed a block copolymer with an aryl azide self-immolative linker. Similar to our prodrug and hydrogel strategies, [28][29][30][31][32] the reaction of the aryl azide embedded in the block co-polymer with trans-cyclooctene (TCO) would lead to formation of a triazoline/imine, and eventual self-immolation that would alter the properties of the block copolymer (Figure 1(A)).…”

“…fields. [19][20][21][22][23] While the fastest click-to-release reactions are based on the inverse-electron-demand Diels-Alder reaction, [24][25][26][27] our group is interested in the reactivity of aryl azides and their orthogonality in biological systems so that they can be applied to click-to-release type applications, [28][29][30][31][32] and to the best of our knowledge, there has been no examples of stimuli-responsive nanoparticles that are formulated from block copolymers containing the aryl azide self-immolative linker. Thus, we were interested to see if these types of polymers could be prepared, and second, be used in bioorthogonally-activated stimuli-responsive nanoparticles.…”

“…While the structure of the aryl azide dictates its reactivity, [33][34][35] functionalised aryl azides have relatively high biological stability, with selective reactivity for strained alkenes and alkynes ([3+2]-cycloadditions), [35][36][37] triphenylphosphines (Staudinger reaction), 38 or H 2 S. [39][40][41] We have developed the alkene-azide [3+2]-cycloaddition as a bioorthogonal click-to-release reaction for prodrugs 28,29,32 and hydrogels, 30,31 while others have investigated H 2 S; a gaseous transmitter in the body, as an activation mechanism for aryl azide-containing probes, prodrugs, and materials. [39][40][41] Alkyl azides can also be reduced by H 2 S 42 or glutathione, 43 however, aryl azides are considered more responsive to, and selective toward, alkenes and H 2 S, 44 even in the presence of other endogenous thiol/thiolate species (e.g., glutathione).…”

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

“…Since our original description of the flow photoisomerization protocol, it has been employed by a number of groups for trans ‐cyclooctene synthesis with applications that include radiochemistry, cellular imaging, drug delivery and materials science . There have also been a number of modifications to the flow procedure that have been introduced.…”