Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0021, United States.
Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0021, United States.
Biomacromolecules. 2022 Dec 12;23(12):5127-5136. doi: 10.1021/acs.biomac.2c00873. Epub 2022 Nov 14.
Peritoneal metastases (PMs) occur due to the metastasis of gynecological and gastrointestinal cancers such as ovarian, colon, pancreatic, or gastric tumors. PM outgrowth is often fatal, and patients with PMs have a median survival of 6 months. Cowpea mosaic virus (CPMV) has been shown, when injected intratumorally, to act as an immunomodulator reversing the immunosuppressive tumor microenvironment, therefore turning cold tumors hot and priming systemic antitumor immunity. However, not all tumors are injectable, and PMs especially will require targeted treatments to direct CPMV toward the disseminated tumor nodules. Toward this goal, we designed and tested a CPMV nanoparticle targeted to S100A9, a key immune mediator for many cancer types indicated in cancer growth, invasiveness, and metastasis. Here, we chose to use an intraperitoneal (IP) colon cancer model, and analysis of IP gavage fluid demonstrates that S100A9 is upregulated following IP challenge. S100A9-targeted CPMV particles displaying peptide ligands specific for S100A9 homed to IP-disseminated tumors, and treatment led to improved survival and decreased tumor burden. Targeting CPMV to S100A9 improves preclinical outcomes and harbors the potential of utilizing CPMV for the treatment of IP-disseminated diseases.
腹膜转移（PMs）是由于卵巢、结肠、胰腺或胃等肿瘤的妇科和胃肠道癌症转移而发生的。PM 的生长通常是致命的，PM 患者的中位生存期为 6 个月。已证明，当将香豆花病毒（CPMV）瘤内注射时，它可以作为免疫调节剂，逆转免疫抑制性肿瘤微环境，从而使冷肿瘤变热，并启动全身抗肿瘤免疫。然而，并非所有肿瘤都可注射，特别是 PM 需要靶向治疗将 CPMV 靶向播散的肿瘤结节。为此，我们设计并测试了一种针对 S100A9 的 CPMV 纳米颗粒，S100A9 是许多癌症类型中表明在癌症生长、侵袭和转移中起关键免疫介质作用的蛋白质。在这里，我们选择使用腹腔（IP）结肠癌模型，对 IP 灌胃液的分析表明，IP 挑战后 S100A9 上调。显示针对 S100A9 的肽配体的 S100A9 靶向 CPMV 颗粒归巢到 IP 播散的肿瘤，并且治疗导致生存率提高和肿瘤负担减少。将 CPMV 靶向 S100A9 可改善临床前结果，并具有利用 CPMV 治疗 IP 播散性疾病的潜力。
