Poly(2-ethyl-2-oxazoline) Conjugates with Salicylic Acid via Degradable Modular Ester Linkages

Abstract

Conjugation of drugs to polymers is a widely used approach to gain control over the release of therapeutics. In this contribution, salicylic acid, a multipurpose model drug, is conjugated to the biocompatible poly­(2-ethyl-2-oxazoline) (PEtOx). The drug is attached to the side chains of a polymer carrier through a hydrolytically cleavable ester linker, via a sequential postpolymerization modification. The chemical modulation of this ester, i.e., by primary or secondary alcohols, is demonstrated to greatly influence the ester hydrolysis rate. This crucial parameter allows us to tune the in vitro kinetics of the sustained drug release for periods exceeding a month in phosphate-buffered saline (PBS). The synthetic accessibility of the cleavable linker, together with the modularity of the drug release rate offered by this approach, highlights the utility of this class of polymers in the field of long-lasting drug delivery systems for persistent and chronic disease treatment.

Thermoresponsive Polymer–Antibiotic Conjugates Based on Gradient Copolymers of 2-Oxazoline and 2-Oxazine

“…The dynamic phase transition behavior of the polymers used here would be expected to influence the release of the drug due to changes in hydration, thus impacting the rate of hydrolysis of the linker between the polymer and drug. To test this, solutions of the two polymer–drug conjugates, POzi-Et-CZ and POzi- m Bz-CZ were prepared at a concentration of 5 mg/mL and the drug release was studied at 37 °C and pH of 8.5this pH was chosen as an accelerated drug release model compensating for absence of esterases that would be found in human tissues. , Because of the long release times (up to 48 h), some degradation of the cefazolin was observed. Cefazolin is known to be unstable under various conditions, including basic conditions. , By measuring the degradation of cefazolin at pH 8.5 over time (Figure S12), the degraded cefazolin could be compensated for in the release plots by adding the degraded amount to the measured amount (equations can be found in the Supporting Information).…”

“…To test this, solutions of the two polymer−drug conjugates, POzi-Et-CZ and POzi-mBz-CZ were prepared at a concentration of 5 mg/mL and the drug release was studied at 37 °C and pH of 8.5this pH was chosen as an accelerated drug release model compensating for absence of esterases that would be found in human tissues. 22,32 Because of the long release times (up to 48 h), some degradation of the cefazolin was observed. Cefazolin is known to be unstable under various conditions, including basic conditions.…”

“…Two types of ester-containing linkers between the polymer backbone and the cefazolin were compared in this study as it is known that the hydrolytic cleavage of ester linker groups is greatly influenced by the adjacent chemical groups and the stability of the products following cleavage . This has been demonstrated by Bernhard et al using poly­(2-ethyl- co -C 3 MestOx) copolymers with three different ester linkages, obtained by the esterification between the acid functional group in salicylic acid and three hydroxyl groups (primary, secondary, and tertiary alcohols) on the side chain of the polymer, and showed the significant influence of modular ester chemistry on the kinetics of drug release. Furthermore, the release of the drug from the poly­(2-ethyl-2-oxazoline)-rotigotine conjugate is also facilitated by the presence of a beta-triazole ester group.…”

Accelerated Post‐Polymerization Amidation of Polymers with Side‐Chain Ester Groups by Intramolecular Activation

“…We attribute this observation to the intramolecular activation of the pendant esters by the newly formed amides, as illustrated in the brief outline of this work in Figure 1. Finally we demonstrate that this phenomenon can be exploited in the synthesis of various hydrophilic (co)poly(acrylamide) structures, which have demonstrated potential for biomedical applications, such as regenerative medicine, drug or nucleic acid delivery [26–37] …”

“…Finally we demonstrate that this phenomenon can be exploited in the synthesis of various hydrophilic (co)poly(acrylamide) structures, which have demonstrated potential for biomedical applications, such as regenerative medicine, drug or nucleic acid delivery. [26][27][28][29][30][31][32][33][34][35][36][37]…”