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. 2022 Apr 14;15(4):480.
doi: 10.3390/ph15040480.

A Theranostic Nanocomplex Combining with Magnetic Hyperthermia for Enhanced Accumulation and Efficacy of pH-Triggering Polymeric Cisplatin(IV) Prodrugs

Yang Qu  1   2 , Zhiqi Wang  1 , Miao Sun  1 , Tian Zhao  3 , Xuanlei Zhu  1 , Xiaoli Deng  1 , Man Zhang  1 , Ying Xu  1 , Hongfei Liu  1   4
Affiliations

A Theranostic Nanocomplex Combining with Magnetic Hyperthermia for Enhanced Accumulation and Efficacy of pH-Triggering Polymeric Cisplatin(IV) Prodrugs

Yang Qu et al. Pharmaceuticals (Basel). .

Abstract

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric prodrug micelle, we synthesized amphiphilic polymeric Pt(IV) with high Pt content (22.5%), then developed a theranostic nanocomplex by integrating polymeric Pt(IV) with superparamagnetic Mn0.6Zn0.4Fe2O4 via simple self-assembly. Due to the high content of Mn0.6Zn0.4Fe2O4 (41.7% w/w), the theranostic nanocomplex showed high saturation magnetization (103.1 emu g-1) and excellent magnetocaloric effect (404 W g-1), both of them indicating its advantages in efficient magnetic targeting (MT), magnetic hyperthermia (MH), and magnetic resonance imaging (MRI). In vitro, in combination with MH, the theranostic nanocomplex showed as high cytotoxicity as cisplatin because of a significant increase in platinum of cellular uptake. In vivo, the accumulation of theranostic nanocomplex in tumors was increased by MT and confirmed by MRI. Furthermore, MH improved penetration of theranostic nanocomplex in tumors as expanding blackened area in tumors was observed by MRI. Based on these properties, the theranostic nanocomplex, under the assistance of MT and MH, showed the highest tumor growth inhibition rate (88.38%) after different treatments, while the body weight of mice increased slightly, indicating low side effects compared to those of cisplatin. The study provided an advanced theranostic nanocomplex with low toxicity and high efficacy, indicating a great clinical potential of polymeric Pt(IV).

Keywords: magnetic hyperthermia; magnetic resonance imaging; magnetic targeting; pH-triggering releasing; polymeric prodrug; theranostic nanocomplex.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the theranostic nanocomplex formation and its cascading effects on diagnosis and therapy of tumors, including efficient magnetic targeting firstly, following magnetic resonance imaging, subsequent magnetic hyperthermia to promote penetration of nanocomplex, and enhanced antitumor efficiency of polymeric Pt(IV) finally.
Figure 2
Figure 2
1H NMR spectra of mPEG-b-pHEMA and polymeric Pt(IV) in DMSO-d6.
Figure 3
Figure 3
Morphologies (TEM) and particle size distributions (DLS) of PPM, MTN, and SPIO: (A) TEM result of PPMs; (B) TEM result of MTNs, inset: TEM result of SPIOs; (C) DLS results of PPM, MTN, and SPIO.
Figure 4
Figure 4
Magnetic property and magnetocaloric effect of MTNs: (A) magnetization curve of the MTN at 300 K; inset: photograph of MTN solution and its response to an external magnet at 1 h; (B) time-dependent temperature curve of MTN in AMF (corresponding parameters as 114 kHz of frequency and 63.6 kA m−1 of strength) and corresponding SAR value.
Figure 5
Figure 5
Drug release profiles of MTN under different conditions: (A) Pt release profiles of MTN under intracellular environment (pH = 5.0 + 1 mM GSH), physiological condition (pH = 7.4 + 5 μM GSH), pure acid environment (pH = 5.0), and pure reductive environment (1 mM GSH); (B) the influence of MH on Pt release under intracellular environment.
Figure 6
Figure 6
The cytotoxicity of 4T1 treated with cisplatin, PPM, MTN, and MTN + MH (duration time of MH: 20 min per 24 h) for 24 h (A) and 48 h (B).
Figure 7
Figure 7
The intracellular Pt contents by treating with cisplatin, PPM, MTN, and MTN + MH for 1 h and 4 h. The MH was operated for the initial 20 min of the study. (* p < 0.05; ** p < 0.01).
Figure 8
Figure 8
T2-weighted MRI results of orthotopic breast tumor before and after i.v. administration of MTN with corresponding treatments: MTN (A1–A3) and MTN + MT (B1–B3). Before intravenous injection of MTN, orthotopic breast tumors were scanned by MRI as control (A1,B1). After injection, the duration time of MT was 4 h, and the tumors were scanned again at 20 h (A2,B2). After MH of 20 min, the third MRI results (A3,B3) were obtained at 22 h after intravenous injection of MTN.
Figure 9
Figure 9
Tissue slices of main organs and tumors after treatments by MTN or MTN + MT. The duration time of MT was 4 h, and those tissues were obtained at 22 h after intravenous injection of MTN. These tissue slices were stained by nuclear fast red and Prussian blue simultaneously.
Figure 10
Figure 10
In vivo antitumor activities of different treatments: (A) the tumor volume curves after different treatments with the extension of curative time from 0 to 15 d; (B) the body weight curves after corresponding treatments with the extension of curative time from 0 to 15 d.
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