ATP-responsive codelivery of doxorubicin and nucleic acids for the synergistic cancer therapy

Abstract

Polymer vesicles have wide applications in drug delivery, antibacterial and water remediation, etc. Theranostic polymer vesicles that can simultaneously deliver diagnostic and therapeutic agents, have been developed for more accurate diagnosis and more efficient cancer chemotherapy. Magnetic resonance imaging (MRI) is one of the most powerful and non-invasive clinical imaging modalities with high spatial resolution. Traditional T1 MRI contrast agents such as diethylene triamine pentacetatic acid (DTPA) chelated gadolinium [Gd(III)] have poor sensitivity, leading to a risk of accumulated toxicity in vivo. To significantly improve the sensitivity of a T1 MRI contrast agent and to enhance the efficacy of cancer chemotherapy, herein for the first time we report a noncytotoxic asymmetrical cancer targeting polymer vesicle based on R-poly(l-glutamic acid)-block-poly(caprolactone) [R is folic acid (FA) or DTPA]. Such asymmetrical vesicles have a cancer-targeting outer corona and a Gd(III)-chelating and drug-loading-enhancing inner corona, exhibiting an extremely high T1 relaxivity (42.39 mM −1 s, 8-fold better than DTPA-Gd) and anticancer drug loading efficiency (52.6% for doxorubicin hydrochloride, DOX · HCl). Moreover, the DOX-loaded vesicles exhibited excellent antitumor activity (two-fold better than free DOX). This “chelatingjust-inside” strategy for synthesizing asymmetrical polymer vesicles provided promising potential theranostic applications in magnetic resonance imaging and cancer-targeted drug delivery.