Dimeric Drug Polymeric Micelles with Acid-Active Tumor Targeting and FRET-indicated Drug Release

Trans-activating transcriptional activator (TAT), a cell-penetrating peptide, has been extensively used for facilitating cellular uptake and nuclear targeting of drug delivery systems. However, the positively charged TAT peptide usually strongly interacts with serum components and undergoes substantial phagocytosis by the reticuloendothelial system, causing a short blood circulation in vivo. In this work, an acid-active tumor targeting nanoplatform DA-TAT-PECL was developed to effectively inhibit the nonspecific interactions of TAT in the bloodstream. 2,3-dimethylmaleic anhydride (DA) was first used to convert the TAT's amines to carboxylic acid, the resulting DA-TAT was further conjugated to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL, PECL) to get DA-TAT-PECL. After self-assembly into polymeric micelles, they were capable of circulating in the physiological condition for a long time and promoting cell penetration upon accumulation at the tumor site and de-shielding the DA group. Moreover, camptothecin (CPT) was used as the anticancer drug and modified into a dimer (CPT)₂-ss-Mal, in which two CPT molecules were connected by a reduction-labile maleimide thioether bond. The Förster resonance energy transfer (FRET) signal between CPT and maleimide thioether bond was monitored to visualize the drug release process and effective targeted delivery of antitumor drugs was demonstrated. This pH/reduction dual-responsive micelle system provides a new platform for high fidelity cancer therapy.