Banik Bhabatosh, Ashokan Akash, Choi Joshua H, Surnar Bapurao, Dhar Shanta
NanoTherapeutics Research Laboratory, Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Dalton Trans. 2023 Mar 21;52(12):3575-3585. doi: 10.1039/d2dt03149c.
The success story of cisplatin spans over six decades now and yet it continues to be the key player in most chemotherapeutic regimens. Numerous efforts have been made to improve its efficacy, address its shortcomings, and overcome drug resistance. One such strategy is to develop new platinum(IV)-based prodrugs with functionally active ligands to deliver combination therapeutics. This strategy not only enables the drug candidate to access multiple drug targets but also enhances the kinetic inertness of platinum complexes and thereby ensures greater accumulation of active drugs at the target site. We report the synthesis of Platin-, a platinum(IV)-based cisplatin prodrug tethered to the active component of ancient herbal medicine, curcumin, as one of the axial ligands. This combination complex showed improved chemotherapeutic efficacy in cisplatin resistant A2780/CP70 cell lines compared with the individual components. An amine-terminated biodegradable polymer was suitably functionalized with the triphenylphosphonium (TPP) cation to obtain a mitochondria-directed drug delivery platform. Quantification of Platin- loading into these NPs using complementary techniques employing curcumin optical properties in high-performance liquid chromatography and platinum-based inductively coupled plasma mass spectrometry evidenced efficacious payload incorporation resulting in functional activities of both the components. Stability studies for a period of one week indicated that the NPs remain stable, enabling substantial loading and controlled release of the prodrug. The targeting nanoparticle (NP) platform was utilized to deliver Platin- primarily in the mitochondrial network of cancer cells as monitored using confocal microscopy employing the green fluorescence of the curcumin pendant. Our studies showed that amine terminated NPs were relatively less efficient in their ability to target mitochondria despite being positively charged. This re-validated the importance of lipophilic positively charged TPP surface functionalities to successfully target cellular mitochondria. We validated the capabilities of Platin- and its mitochondria-targeting nanoparticles towards inflicting mitochondria-directed activity in cisplatin-sensitive and cisplatin-resistant cell lines. Furthermore, our studies also demonstrated the effectiveness of Platin- incorporated targeting NPs in attenuating cellular inflammatory markers by utilizing the curcumin component. This study advances our understanding of the cisplatin prodrug approach to combine chemotherapeutic and inflammatory effects in accessing combinatory pathways.
顺铂的成功故事至今已跨越六十多年，然而它仍是大多数化疗方案中的关键药物。人们已做出诸多努力来提高其疗效、解决其缺点并克服耐药性。其中一种策略是开发新型基于铂（IV）的前药，这些前药带有功能活性配体以实现联合治疗。这种策略不仅能使候选药物作用于多个药物靶点，还能增强铂配合物的动力学惰性，从而确保活性药物在靶点部位有更高的积累。我们报告了Platin的合成，它是一种基于铂（IV）的顺铂前药，与古老草药姜黄素的活性成分相连，作为轴向配体之一。与单个成分相比，这种复合配合物在顺铂耐药的A2780/CP70细胞系中显示出更高的化疗疗效。一种胺端基可生物降解聚合物用三苯基膦（TPP）阳离子进行了适当功能化，以获得一个线粒体靶向药物递送平台。利用高效液相色谱中姜黄素光学性质以及基于铂的电感耦合等离子体质谱的互补技术对这些纳米颗粒中Platin的负载量进行定量，证明了有效载荷的掺入，从而使两种成分都具有功能活性。为期一周的稳定性研究表明，纳米颗粒保持稳定，能够大量负载并实现前药的控释。使用共聚焦显微镜监测姜黄素侧链的绿色荧光，靶向纳米颗粒（NP）平台主要用于将Platin递送至癌细胞的线粒体网络中。我们的研究表明，尽管胺端基纳米颗粒带正电荷，但其靶向线粒体的能力相对较低。这再次验证了亲脂性带正电荷的TPP表面功能对于成功靶向细胞线粒体的重要性。我们验证了Platin及其线粒体靶向纳米颗粒在顺铂敏感和耐药细胞系中引发线粒体定向活性的能力。此外，我们的研究还证明了掺入Platin的靶向纳米颗粒通过利用姜黄素成分在减轻细胞炎症标志物方面的有效性。这项研究增进了我们对顺铂前药方法在联合化疗和炎症效应以进入联合途径方面的理解。
