ABSTRACT
Fumaramic acid derivatives can be converted into their cis isomer maleamic acid derivatives under UV illumination, and these maleamic acid derivatives show pH-responsive degradability at acidic pH only after the preceding photoisomerization. The rate of the tandem photoisomerization-degradation of fumaramic acid derivatives can be finely controlled by changing the substituents on the double bond. Photoisomerization-based unlocking of the pH-responsive degradability of fumaramic acid derivatives has strong potential for the development of multisignal-responsive smart materials in biomedical applications.
Subject(s)
Acids/chemistry , Fumarates/chemistry , Hydrogen-Ion Concentration , Drug Delivery Systems , Isomerism , Nitrobenzenes/chemistry , Photochemical Processes , Succinates/chemistryABSTRACT
We developed a new pH-sensitive drug delivery carrier based on ß-cyclodextrin (ß-CD) and 1-methyl-2-(2'-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of ß-CD were successfully attached to MCM residues to produce a medusa-like ß-CD-MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency ( > 90%). More importantly, ß-CD-MCM-CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5 h at pH 5.5. In addition, the inclusion complex between ß-CD-MCM-CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, ß-CD-MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Cephradine/administration & dosage , Drug Carriers/chemical synthesis , Maleic Anhydrides/chemistry , beta-Cyclodextrins/chemistry , Adamantane/chemistry , Animals , Anti-Bacterial Agents/toxicity , Cell Survival/drug effects , Cephradine/toxicity , Drug Carriers/chemistry , Drug Carriers/toxicity , Drug Liberation , Hydrogen-Ion Concentration , Mice , Molecular Structure , NIH 3T3 Cells , beta-Cyclodextrins/toxicityABSTRACT
We synthesized five maleic acid amide derivatives (maleic, citraconic, cis-aconitic, 2-(2'-carboxyethyl) maleic, 1-methyl-2-(2'-carboxyethyl) maleic acid amide), and compared their degradability for the future development of pH-sensitive biomaterials with tailored kinetics of the release of drugs, the change of charge density, and the degradation of scaffolds. The degradation kinetics was highly dependent upon the substituents on the cis-double bond. Among the maleic acid amide derivatives, 2-(2'-carboxyethyl) maleic acid amide with one carboxyethyl and one hydrogen substituent showed appropriate degradability at weakly acidic pH, and the additional carboxyl group can be used as a pH-sensitive linker.
