PH-responsive intramolecular FRET-based self-tracking polymer prodrug nanoparticles for real-time tumor intracellular drug release monitoring and imaging.

Abstract

An intramolecular fluorescence resonance energy transfer (FRET)-based macromolecular theranostic prodrug was designed by directly conjugating Doxorubicin (DOX) as the FRET acceptor onto the naphthalimide side groups in the fluorescent copolymer PPEGMA20-PNAP8 as the FRET energy donor via an acid-labile imine bond, without a fluorogenic linker. The proposed PPEGMA20-PNAP8-DOX theranostic prodrug showed a high DOX content of 24.3% owing to a conjugation efficiency of>93% under mild conjugation conditions. It could easily self-assemble into unique theranostic nanoparticles with a Dh of 71nm. The theranostic nanoparticles showed excellent pH-triggered DOX release performance with very low premature drug leakage of 6.3% in normal physiological medium over 129h, while>91% of the conjugated DOX was released in the acidic tumor intracellular microenvironment. MTT assays indicated the enhanced antitumor efficacy of the proposed theranostic nanoparticles compared with free DOX. Furthermore, because drug release was triggered by pH, orange fluorescence was restored to the blue fluorescence of the backbone copolymer. Such self-tracking pH-responsive colorful fluorescence variations during intracellular drug delivery and release are expected to allow real-time tumor intracellular drug release monitoring and imaging diagnosis.