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.

Drug-Loaded Lipid Magnetic Nanoparticles for Combined Local Hyperthermia and Chemotherapy against Glioblastoma Multiforme

“…Lipid-based nanocarriers are among the most promising systems for this purpose because of their high biocompatibility, ability to overcome the BBB, improved encapsulation capacity, and the possibility to modify their surface to improve tumor targeting; , moreover, these systems can be designed to release their cargo when exposed to a specific stimulus (e.g., pH, enzymes, temperature). As a consequence, various multimodal approaches to antitumor drug delivery have been explored, combining conventional therapeutic strategies ( e.g., chemotherapy) with other emerging alternatives such as magnetic hyperthermia (MH), photothermal therapy (PTT), and gene therapy. − Among them, MH is a promising strategy to develop a minimally invasive, localized, and remote antitumor treatment. − Conversely to conventional pharmacological agents used for cancer treatment or other methods of whole-body or regional hyperthermia, the heating in MH remains highly localized, and it depends on the simultaneous presence of magnetic nanoparticles and their excitation under an external alternating magnetic field (AMF) . This contributes to minimize systemic side effects and allows for a better recovery of the neighboring healthy cells or tissues, since the microenvironment of the treated area is not strongly stressed. , …”

“…As a consequence, various multimodal approaches to antitumor drug delivery have been explored, combining conventional therapeutic strategies ( e.g., chemotherapy) with other emerging alternatives such as magnetic hyperthermia (MH), photothermal therapy (PTT), and gene therapy. 17 − 20 Among them, MH is a promising strategy to develop a minimally invasive, localized, and remote antitumor treatment. 21 − 23 Conversely to conventional pharmacological agents used for cancer treatment or other methods of whole-body or regional hyperthermia, the heating in MH remains highly localized, and it depends on the simultaneous presence of magnetic nanoparticles and their excitation under an external alternating magnetic field (AMF).…”