ABSTRACT
Advanced drug delivery systems often employ nanomaterials as carriers to deliver drugs to desirable disease sites for enhanced efficacy. However, most systems have low drug loading capacity and cause safety concerns. Therefore, many anticancer therapeutics have recently been assembled to NPs form without using any additional nanocarrier to achieve high drug loading. However, carrier-free nanomedicines are often constrained by limitations such as inadequate stability and lack of control in drug release. Therefore, we synthesize carrier-free drug NPs containing cis-aconitic anhydride-modified doxorubicin and paclitaxel (CAD-PTX) and coating with crosslinked (CL) surfactant based on hyaluronic acid (HA) segment. With this design, the pure drug NPs possess pH and redox dual responsive release characteristic and could target CD44 overexpressed cancer cells. Our studies demonstrate that these CAD-PTX-CLHA NPs display high stability, excellent active targeting effect and controllable intracellular drug release, and ultimately achieve significantly better anti-cancer efficiency than individual doxorubicin and paclitaxel.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Carriers/chemistry , Drug Delivery Systems , Nanoparticles/chemistry , Aconitic Acid/analogs & derivatives , Aconitic Acid/chemical synthesis , Aconitic Acid/chemistry , Animals , Cell Line, Tumor , Cross-Linking Reagents/chemistry , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Endocytosis , Humans , Hyaluronic Acid/chemical synthesis , Hyaluronic Acid/chemistry , Hydrogen-Ion Concentration , Mice, Inbred BALB C , Nanoparticles/ultrastructure , Oxidation-Reduction , PaclitaxelABSTRACT
Thirteen structural analogs of two initial intermediates of the L-α-aminoadipate pathway of L-lysine biosynthesis in fungi have been designed and synthesized, including fluoro- and epoxy-derivatives of homoaconitate and homoisocitrate. Some of the obtained compounds exhibited at milimolar range moderate enzyme inhibitory properties against homoaconitase and/or homoisocitrate dehydrogenase of Candida albicans. The structural basis for homoisocitrate dehydrogenase inhibition was revealed by molecular modeling of the enzyme-inhibitor complex. On the other hand, the trimethyl ester forms of some of the novel compounds exhibited antifungal effects. The highest antifungal activity was found for trimethyl trans-homoaconitate, which inhibited growth of some human pathogenic yeasts with minimal inhibitory concentration (MIC) values of 16-32 mg/mL.
