Enhanced tumor penetration for efficient chemotherapy by a magnetothermally sensitive micelle combined with magnetic targeting and magnetic hyperthermia.

ABSTRACT

The high accumulation and poor penetration of nanocarriers in tumor is a contradiction of nanomedicine, which reduces the efficacy of chemotherapy. Due to the positive effect of hyperthermia on in vivo drug diffusion, we designed a magnetothermally sensitive micelle (MTM) by integrating magnetic targeting (MT), magnetic hyperthermia (MH), and magnetothermally responsive drug release to facilitate simultaneous drug accumulation and penetration in tumor. Accordingly, we synthesized a cyanine7-modified thermosensitive polymer with phase transition at 42.3°C, and utilized it to prepare drug-loaded MTMs by encapsulating superparamagnetic MnFe2O4 nanoparticles and doxorubicin (DOX). The obtained DOX-MTM had not only high contents of DOX (9.1%) and MnFe2O4 (38.7%), but also some advantages such as superparamagnetism, high saturation magnetization, excellent magnetocaloric effect, and magnetothermal-dependent drug release. Therefore, DOX-MTM improved in vitro DOX cytotoxicity by enhancing DOX endocytosis under the assistance of MH. Furthermore, MT and MH enhanced in vivo DOX-MTM accumulation and DOX penetration in tumor, respectively, substantially inhibiting tumor growth (84%) with excellent biosafety. These results indicate the development of an optimized drug delivery system with MH and MH-dependent drug release, introducing a feasible strategy to enhance the application of nanomedicines in tumor chemotherapy.