Acid-degradable polymers for drug delivery: a decade of innovation

Abstract

Polymers that start degrading under acidic conditions are increasingly investigated as a pathway to trigger the release of drugs once the drug carrier reached the slightly acidic tumour environment or after the drug carrier has been taken up by cells, resulting in the localization of the polymer in the acidic endosomes and lysosomes. The advances in the design of acid-degradable polymers and drug delivery systems have been summarized and discussed in this review article. Various acid-labile groups such as acetals, orthoester, hydrazones, imines and cis-aconityl, that can undergo cleavage in slightly acidic conditions, have been employed to create polymer architectures or polymer-drug conjugates that can degrade under lysosomal and endosomal conditions, triggering the fast release of drugs or DNA.

pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation

“…Subsequently, the TLR7/8 agonist IMDQ (26) was covalently ligated to the core of the nanoparticles through amide bond formation between the primary amine of IMDQ and the activated PFP esters in the nanoparticle core. Core cross-linking was performed by addition of the bis-amino-ketal 2,2-bis(aminoethoxy)propane, which installs pH-sensitive ketal moieties that render the cross-links susceptible to acid hydrolysis (25,27). Subsequently, the remaining unreacted PFP esters were converted to hydrophilic repeating units by addition of excess 2-aminoethanol.…”

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

“…In case of the galactosylated control nanogel, only the nondegradable cross-linker was used to exclude degradability during experiments. The ketal-containing cross-linker is particularly interesting for biomedical applications [51][52][53] as it readily degrades in response to the acidic pH that is sensed in endosomes upon cellular endocytosis.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…Endolysosomal release pH Endosomes/ lysosomes Acetal/ketal [28][29][30][31][32]36] Linear polymers [33][34][35] Micelles [37,41] Polymersomes [38,40] Nanoparticles [39] Ortho ester [30][31][32] Micelles [42,43] Polymersomes [44] Imine [30][31][32]36] Micelles [45][46][47][48] Oxime [28,31,36] Nanoparticles [49] Micelles [50,51] Maleic acid amide derivatives [29,30,32] Micelles [41,52,54] Nanoparticles [53] Hydrazone [28][29][30][31][32]36] Linear polymers [55][56]…”

“…Both linear poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) as well as poly(amidoamine) (PAMAM) dendrimers modified with hydrazide groups have been used to couple Dox via hydrazone linkers. [32,[55][56][57][58][59][60][61][62][63] HPMA polymers bearing hydrazone linkages have also been explored for the delivery of other anticancer drugs such as paclitaxel and docetaxel. [64] The hydrazone motif has also been used to prepare micelles and nanoparticles that allow pH-dependent release of Figure 1.…”

“…pH-Triggered Release: Acid-labile chemical bonds that are stable in the bloodstream (pH 7.4) but upon endocytic internalization are cleaved in the slightly acidic late endosomal (pH 5-6) and lysosomal (pH 4-5) environments, have been used to promote endolysosomal release. [30][31][32] Among the different pH sensitive linkers, which are available, such as acetal/ketal, [28][29][30][31][32][33][34][35][36][37][38][39][40][41] ortho ester, [30][31][32][42][43][44] imine, [30][31][32]36,[45][46][47][48] oxime, [28,31,36,[49][50][51] and maleic acid amide derivatives, [29,30,32,41,[52][53][54] the hydrazone linker [28][29][30][31]<...>…”