| Cisplatin is one of the most widely used antitumor drugs highly effective against a large variety of solid cancers. However, the side-effects and drug resistances limit the application of cisplatin. Pt(Ⅳprodrugs offer a promising alternative to overcome the drawback of Pt(Ⅱ) drugs. Pt(Ⅳ) complexes are more inert in coordination chemistry and exhibit less toxic than Pt(Ⅱ) drugs. Upon entering the cell, the Pt(Ⅳ) prodrugs are reduced by intracellular reducing molecules to generate Pt(Ⅱ) drugs and regain their cytotoxicity. Furthermore, the Pt(Ⅳ) prodrugs possess two additional axial ligands, which offer an unique approach for the drug design to modify the pharmacokinetic effects of prodrugs, including lipophilicity, redox potential and biological activity.Oral administration can maintain an optimum concentration of drugs in a prolonged circulation period, which could decrease the adverse effects and improve the drug efficacy. Pt(Ⅱ) drugs are not orally bioavailable due to their chemical reactivity and severe gastrointestinal side effects. On the other hand, Pt(Ⅳ) complexes exhibit high advantages for the oral administration because they are kinetically more inert in the coordination substitution. However, the undesired reduction of Pt(Ⅳ) complexes could occur during oral administration, which reduces the bioavailability of Pt(Ⅳ) drugs. We rationalize that this challenge could be addressed by using a drug delivery strategy. Generally, nanocarriers can protect the drug molecules from the metabolic degradation within gastrointestinal tract, improve their solubility and promote the controlled drug release and drug targeting.Thus, we do the work from two aspects, designing new Pt(Ⅳ) complexes and developing platinum-based oral delivery systems.In the first part, we ligate aspirin to cisplatin, to generate c,c,t-[PtCl2(NH3)2(OH) (aspirin)] (asplatin). Asplatin exhibits significant cytotoxicity to tumor cells and almost fully overcomes the drug resistance of the cisplatin resistant cells. Asplatin is highly accumulated in cancer cells; upon the reduction with cellular ascorbic acid, asplatin is activated and binds to DNA more efficiently than cisplatin. Mechanistic studies reveal that asplatin promotes the apoptosis via the BCL-2 associated mitochondrial pathway. The down-regulation of BCL-2 along with the up-regulation of BAX and BAK enhances the mitochondrial outer membrane permeability, resulting in cell apoptosis. The in vivo experiment shows that asplatin exerts a significant inhibitory effect on tumor growth with lower systemic toxicity compared with cisplatin. This result offers a novel strategy to enhance sensitivity of platinum drugs by ligation of the anti-inflammation drug aspirin.In the second part, we prepared a self-assembled cholesterol-asplatin-incorporated nanoparticles (SCANs) for oral delivery of the Pt(IV) prodrug in cancer therapy. The conjugation of asplatin to cholesterol allows the self-assembly of the hydrophilic platinum complex to the lipid polymeric nanoparticles. SCANs exhibit high gastrointestinal stability, sustained drug release and enhanced uptake by simulated intestinal Caco-2 cells as well as HepG2 cancer cells. SCANs show prominent cytotoxicity compared with cisplatin in vitro, and are effective to cisplatin-resistant cells. In vivo assays show that the oral treatment of SCANs efficaciously inhibits the tumor growth on the subcutaneous HepG2 hepatocellular carcinoma model. The drug efficacy of the oral treatment of SCANs is comparable to the intravenous injection of cisplatin; nevertheless, SCANs demonstrate significantly lower toxicity with negligible nephrotoxicity and unaffected body weight. On the other hand, the long circulation and sustained release improve the pharmacokinetics of SCANs, resulting in the enhanced oral bio availability of SCANs with ～4.32 fold increase than free asplatin. These results indicate that the SCANs have great potential in oral platinum drugs delivery for cancer treatment. |
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