Intramolecular cyclization assistance for fast degradation of ornithine‐based poly(ester amide)s

Abstract

Inspired by the spontaneous cyclization of ornithine in peptides, polyesters containing protected ornithine (Orn) side chains along the backbone were synthesized and shown to degrade rapidly upon deprotection through intramolecular cyclization. A new ornithine-based poly(ester amide) PEA 1 and a lysine-based control PEA 2, both bearing the light-sensitive protecting group o-nitrobenzyl alcohol (ONB), were synthesized. Tert-butyl carbamate (Boc)-protected versions 1-Boc and 2-Boc were also synthesized for proof of concept. GPC confirmed that 1-Boc degrades over 40 times faster than 2-Boc following deprotection into the designed intramolecular cyclization products. Finally, TEM visualization of particles made from 1 encapsulating iron oxide nanoparticles reveals complete disruption of nanoparticles and release of payload within a day upon UV irradiation.

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

“…25,69,70 The proposed 1,6-O/N acyl shi is analogous to that reported by Almutairi and coworkers for 6-and 7-membered acyl shis in PAEs featuring side chain nucleophiles. 23,26,27,30 However, the rapid and highly selective sequence of alternating 1,5-and 1,6-cyclizations to generate diketopiperazine 5 is a novel and characteristic feature for the degradation of the poly(a-amino esters) such as P1 + . As diketopiperazines are common elimination products in the degradation of peptides, 71 the structure-activity relationships described herein for O/N acyl shis may provide insights on related chemistries of biopolymers (i.e.…”

“…The potential toxicity of the (aza)quinone methide byproducts 15 has stimulated research into alternative chemistries for stimuli-sensitive degradation processes, 16 including disuldebased self-immolative systems that degrade upon reduction, 17,18 acid-labile polymers, [19][20][21][22] or amine-functionalized polyesters and polycarbonates that degrade either through intramolecular nucleophilic attack or by hydrolysis. 11,[23][24][25][26][27][28][29][30][31] Cationic poly(aminoester)s are an attractive class of materials due to the tunable lability of the ester linkage 32 and the functional cationic ammonium repeat units that can bind appropriate polyanionic cargoes and then become neutral, enabling cargo release. Several classes of cationic poly(aminoester)s have been shown to undergo pHsensitive degradation resulting from deprotonation of embedded ammonium groups, which leads to nucleophilic attack on the ester backbone.…”

Amplified responses in materials using linear polymers that depolymerize from end‐to‐end when exposed to specific stimuli

“…This nomenclature also differentiates this new class of linear depolymerizable polymers from polymers that continuously depolymerize when the backbone cleaves in response to a non‐specific signal (e.g., hydrolysis) (these polymers are termed CD b polymers) . It further differentiates this class of polymers from those that degrade via fragmentation depolymerization reactions (FD polymers) in which reaction with one stimulus cleaves the polymer into two shorter polymers, but where additional reactions between the stimulus and the polymer are required to complete the degradation process (these polymers do not provide amplified responses) …”

UV-responsive degradable polymers derived from 1-(4-aminophenyl) ethane-1,2-diol

“…Substantial effort has been devoted to developing degradable polymers with stimuli‐responsive groups incorporated into the polymer backbones to control their degradation. Recently, there is growing interest in designing polymers whose degradation is controlled by the terminal or side‐chain trigger‐responsive groups . Representative examples include the self‐immolative polymers developed by Shabat and coworkers that can be degraded through removal of the terminal trigger‐responsive protecting group and the polymers developed by the Almutairi and Gillies groups with trigger‐responsive domains placed on the side groups which control the polymer degradation.…”

“…Recently, there is growing interest in designing polymers whose degradation is controlled by the terminal or side-chain trigger-responsive groups. [16][17][18][19][20][21][22][23][24] Representative examples include the selfimmolative polymers developed by Shabat and coworkers that can be degraded through removal of the terminal trigger-responsive protecting group 25,26 and the polymers developed by the Almutairi 24,[27][28][29][30] and Gillies groups 17,31,32 with trigger-responsive domains placed on the side groups which control the polymer degradation. Inspired by these works, we recently designed 2,6-bis(hydroxymethyl)aniline (BHA), an analog of the key block of the self-immolative polymers ((4-aminophenyl)methanol), and used it to develop chain-shattering-polymers (CSPs) 33 and chain-shattering polymeric therapeutics.…”