Miriplatin-loaded liposome, as a novel mitophagy inducer, suppresses pancreatic cancer proliferation through blocking POLG and TFAM-mediated mtDNA replication

Pancreatic cancer is a more aggressive and refractory malignancy. Resistance and toxicity limit drug efficacy. Herein, we report a lower toxic and higher effective miriplatin (MPt)-loaded liposome, LMPt, exhibiting totally different anti-cancer mechanism from previously reported platinum agents. Both in gemcitabine (GEM)-resistant/sensitive (GEM-R/S) pancreatic cancer cells, LMPt exhibits prominent anti-cancer activity, led by faster cellular entry-induced larger accumulation of MPt. The level of caveolin-1 (Cav-1) determines entry rate and switch of entry pathways of LMPt, indicating a novel role of Cav-1 in nanoparticle entry. After endosome-lysosome processing, in unchanged metabolite, MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM, to degrade POLG and TFAM. Then, via PINK1-Parkin axis, mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA (mtDNA) replication blocking. Additionally, POLG and TFAM are identified as novel prognostic markers of pancreatic cancer, and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity. Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA (target of most platinum agents), and totally distinct mechanism of MPt and other formulations of MPt. Self-assembly offers LMPt special efficacy and mechanisms. Prominent action and characteristic mechanism make LMPt a promising cancer candidate.

A Study of Miriplatin and Its Pt-metabolites in Beagle Dog Plasma by Size Exclusion Chromatography-Inductively Coupled Plasma Mass Spectrometry / 分析化学

AstudyofPt-metabolitesfromanewanti-hepatomadrugmiriplatinwasimportanttomiriplatin's pharmacology research. Therefore, a method based on size exclusion chromatography-inductively coupled plasma mass spectrometry ( SEC-ICP-MS) was developed to study miriplatin and its Pt-metabolites in Beagle dog plasma. This method could be used to study total platinum concentration half-quantitatively. Compared with traditional ICP-MS direct determination, data acquired from this SEC-ICP-MS method were almost the same. By using BioSep-s2000 column, 25 mmol/L of pH 7. 2 phosphate buffer as eluent, and Pt-195 as detecting isotope, we discovered miriplatin with its four Pt-metabolites in dog plasma after intra-hepatic artery administration. The main Pt-metabolite was m2 , which associated with plasma proteins. Miriplatin in plasma did not bind with plasma proteins. According to calculation, the ratio of miriplatin/m2 first decreased rapidly, and then slowly increased to its second climax, finally slowly decreased.

Synthesis of miriplatin, a novel platinum-based antitumor-drug / 中国药学杂志

OBJECTIVE: To synthesize the platinum-based anti-tumor drug miriplatin. METHODS: Miriplatin was synthesized from K4PtCl4. K4PtCl4 was reacted with sodium nitrite to give the K4Pt(NO2)4 solution which reacted with(IR, 2R)-1,2-cyclohexane-diamine thus resulting in the key intermediate Pt(C6H14N2) (NO2)2. The key intermediate was subsequently reacted with hydrazine sulfate and sodium myristate in n-butanol to give the target compound. The structure of the target compound was identified by elemental analysis, ESI-MS, FT-IR, H-NMR, thermal analysis and specific optical rotation measurement. RESULTS: The structure of the synthesized compound was consistent with the title compound, and the yield was about 61%. CONCLUSION: This study provides a novel synthesis process for miriplatin.

Transcatheter Arterial Chemotherapy with Miriplatin for Hepatocellular Carcinoma Patients with Chronic Renal Failure: Report of Three Cases

Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure.