*Article* **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 <sup>1</sup> , Miao Sun <sup>1</sup> , Tian Zhao <sup>3</sup> , Xuanlei Zhu <sup>1</sup> , Xiaoli Deng <sup>1</sup> , Man Zhang <sup>1</sup> , Ying Xu 1,\* and Hongfei Liu 1,4,\***


**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 Mn0.6Zn0.4Fe2O<sup>4</sup> via simple self-assembly. Due to the high content of Mn0.6Zn0.4Fe2O<sup>4</sup> (41.7% *w*/*w*), the theranostic nanocomplex showed high saturation magnetization (103.1 emu g−<sup>1</sup> ) and excellent magnetocaloric effect (404 W g−<sup>1</sup> ), 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:** polymeric prodrug; theranostic nanocomplex; pH-triggering releasing; magnetic targeting; magnetic hyperthermia; magnetic resonance imaging
