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. 2022 Nov 18:13:1045976.
doi: 10.3389/fphar.2022.1045976. eCollection 2022.

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

Yu Wang  1 , Rui Wang  1 , Lixin Chen  1 , Lili Chen  1 , Yi Zheng  1 , Yuanrong Xin  2 , Xiqiu Zhou  1 , Xiaoyun Song  1 , Jinzhou Zheng  1
Affiliations

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

Yu Wang et al. Front Pharmacol. .

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.

Keywords: enhanced tumor penetration; magnetic hyperthermia; magnetic targeting; magnetothermal-responsive drug release; thermosensitive polymer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic illustration of the doxorubicin (DOX)-loaded magnetothermally-sensitive micelle modified by Cy7 (DOX–MTM–Cy7) and its effect on enhancing DOX penetration under assistances of magnetic targeting and magnetic hyperthermia.
FIGURE 2
FIGURE 2
Thermo-sensitivity and structure of PCL-b-p(N-co-D): (A) temperature-dependent transmittance curve and diameter variation of PCL-b-p(N-co-D), low critical solution temperature (LCST): 42.3°C; (B) 1H NMR spectrum of PCL-b-poly(N-co-D), marking all characteristic peaks.
FIGURE 3
FIGURE 3
Structure characteristics of PCL-b-poly(N-co-D)–Cy7: (A) 1H NMR spectrum of PCL-b-poly(N-co-D)-Cy7, marking all characteristic peaks; (B) UV–Vis spectra of PCL-b-p(N-co-D), Cy7, and PCL-b-p(N-co-D)–Cy7.
FIGURE 4
FIGURE 4
Morphologies (TEM) and particle size distributions (DLS) of DOX–MT and DOX–MTM: TEM result of (A) DOX–MTs and (B) DOX–MTMs; (C) DLS results of DOX–MT and DOX–MTM.
FIGURE 5
FIGURE 5
Magnetic property and magnetocaloric effect of DOX–MTM: (A) magnetization curves of MnFe2O4 and DOX–MTM at 300 K; (B) time-dependent temperature curve of DOX–MTM in AMF (frequency and strength as 114 kHz and 63.6 kA/m respectively) and corresponding SAR value.
FIGURE 6
FIGURE 6
Drug release profiles of DOX–MTM at 37°C, 43°C and AMF (f = 114 kHz and H applied = 63.6 kA/m): (A) long-term (48 h) and (B) short-term (10 min) drug release profiles of DOX–MTMs under corresponding conditions.
FIGURE 7
FIGURE 7
The cytotoxicity of 4T1 and cellular DOX uptake under different formulas: (A) cytotoxicity of 4T1 after treating with DOX·HCl, DOX–MTM, and DOX–MTM + MH (MH duration: 10 min, 114 kHz, and 15.9 kA/m); (B) cellular DOX uptake after DOX–MTM treatment for 2 h; (C) the cellular DOX–MTM + MH uptake (the same MH condition as cytotoxicity study) for 2 h.
FIGURE 8
FIGURE 8
Near-infrared (NIR) in vivo imaging of tumor-bearing mice after injection of doxorubicin-loaded magnetothermally-sensitive micelle modified by Cy7 (DOX–MTM–Cy7) and DOX distribution in tumor after magnetic hyperthermia (MH) of 20 min: (A) Distribution of DOX–MTM–Cy7 in tumor-bearing mice after different targeting strategies (EPR or EPR + MT) 4 and 20 h post-injection; (B) the intra-tumoral DOX distribution of different targeting approaches after MH (20 min, 114 kHz and 15.9 kA/m) at 20 h post-injection, with cell nuclei staining (DAPI, blue), tumor vessels staining (FITC, green).
FIGURE 9
FIGURE 9
In vivo anti-tumor activities of different treatments: (A) the tumor volume curves after different treatments with the extension of curative time from 1 to 16 d (*p < 0.05; **p < 0.01); (B) the body weight curves after corresponding treatments with the extension of curative time from 1 to 16 d.
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