Department of NanoEngineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Center for Nano-ImmunoEngineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Biomacromolecules. 2022 Oct 10;23(10):4379-4387. doi: 10.1021/acs.biomac.2c00831. Epub 2022 Sep 2.
Ovarian cancer is the foremost cause of gynecological cancer and a major cause of cancer death in women. Treatment for advanced stage is surgical debulking followed by chemotherapy; however, most patients relapse with more aggressive and therapy-resistant tumors. There is a need to develop drug delivery approaches to deliver platinum therapies to tumors to increase efficacy while maintaining safety. Toward this goal, we utilized the protein nanotubes from the plant virus, tobacco mosaic virus (TMV), as a drug carrier. Specifically, the nanochannel of TMV was loaded with the active dication form of cisplatin (cisPt), making use of the negatively charged Glu acid side chains that line the interior channel of TMV. We achieved a loading efficiency with ∼2700 cisPt per TMV; formulation stability was established with drug complexes stably loaded into the carrier for 2 months under refrigerated storage. TMV-cisPt maintained its efficacy against ovarian tumor cells with an IC of ∼40 μM. TMV-cisPt exhibited superior efficacy free cisPt in ovarian tumor mouse models using intraperitoneal ID8-Defb29/Vegf-a-Luc (mouse) tumors and subcutaneous A2780 (human) xenografts. TMV-cisPt treatment led to reduced tumor burden and increased survival. Using ID8-Defb29/Vegf-a-Luc-bearing C57BL/6 mice, we also noted reduced tumor growth when animals were treated with TMV alone, which may indicate antitumor immunity induced by the immunomodulatory nature of the plant virus nanoparticle. Biodistribution studies supported the efficacy data, showing increased cisPt accumulation within tumors when delivered the TMV carrier free cisPt administration. Finally, good safety profiles were noted. The study highlights the potential of TMV as a drug carrier against cancer and points to the opportunity to explore plant viruses as chemo-immuno combination cancer therapeutics.
卵巢癌是妇科癌症的首要病因，也是女性癌症死亡的主要原因。晚期治疗是手术去瘤后进行化疗；然而，大多数患者会复发，肿瘤更具侵袭性且对治疗耐药。因此，需要开发药物输送方法，将铂类疗法递送到肿瘤部位，以提高疗效，同时保持安全性。为了实现这一目标，我们利用来自植物病毒烟草花叶病毒 (TMV) 的蛋白质纳米管作为药物载体。具体来说，TMV 的纳米通道装载了顺铂（cisPt）的活性二价形式，利用排列在 TMV 内部通道的带负电荷的 Glu 酸侧链。我们实现了约 2700 个 cisPt 每 TMV 的负载效率；药物复合物稳定负载到载体中，在冷藏储存下 2 个月内保持制剂稳定。TMV-cisPt 对卵巢肿瘤细胞的疗效保持不变，IC 约为 40 μM。在卵巢肿瘤小鼠模型中，TMV-cisPt 表现出优于游离 cisPt 的疗效，使用腹腔内 ID8-Defb29/Vegf-a-Luc（小鼠）肿瘤和皮下 A2780（人）异种移植物。TMV-cisPt 治疗导致肿瘤负担减少和存活率提高。使用携带 ID8-Defb29/Vegf-a-Luc 的 C57BL/6 小鼠，我们还注意到单独用 TMV 治疗时肿瘤生长减少，这可能表明植物病毒纳米颗粒的免疫调节性质诱导了抗肿瘤免疫。生物分布研究支持疗效数据，表明当使用 TMV 载体递送时，cisPt 在肿瘤内的积累增加游离 cisPt 给药。最后，注意到良好的安全性。该研究强调了 TMV 作为抗癌药物载体的潜力，并指出了探索植物病毒作为化疗免疫联合癌症治疗的机会。
