Mitochondria-Targetable Lysine-Based Biodegradable Nanogels Through Hydrophobic-Hydrophilic Conversion

For several decades, to maximize the therapeutic efficacy of drugs, various drug delivery systems that target various cells or subcellular organelles (e.g., nucleus, mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, etc.) have been developed. However, most targeted drug delivery systems use methods to directly conjugate the targeting moiety to the drug or to decorate the nanoparticle surface.<br/>In this study, an ε-poly(_L-lysine)-based mitochondrial targeted drug delivery system (i.e., REPL-NG) was developed by introducing hydrophobic and biodegradable disulfide bonds into a hydrophilic polymer without a mitochondrial targeting moiety. REPL exists in the form of nanogels in aqueous solution due to hydrophilic primary amines on the surface and hydrophobic disulfide bonds inside the core. Thus, hydrophobic drugs such as doxorubicin could be encapsulated into REPL-NG (i.e., DOX@REPL-NG) by hydrophobic interactions.<br/>In HCT116 cell line, a human colorectal cancer cell line, DOX@REPL-NG was internalized by endocytosis and was able to escape the endo/lysosomes by the proton-buffering effect of the primary amine of REPL-NG. After internalization, DOX@REPL-NG favored mitochondria over the nucleus, and as a result, a greater amount of DOX was uptaken into mitochondria rather than the nucleus. In addition, in HCT116-xenografted nude mice, DOX@REPL-NG exhibited superior antitumor effect than free DOX-HCl by tumor accumulation and retention of DOX. In conclusion, DOX@REPL-NG could target mitochondria by modulating the hydrophobicity of lysine-based polymers without commonly used mitochondrial targeting moiety.