Targeting Tumor Acidosis with pH-Activated Nanoparticles: Enhancing Interleukin-2 Therapy for Solid Cancers

Interleukin-2 (IL-2) has been recognized for its potential in treating metastatic melanoma and renal cell cancers, but its clinical use has been limited due to its immunosuppressive effects and the risk of severe toxicity. A new approach has been taken to enhance the specificity and accumulation of IL-2 at the tumor site by developing a nanoparticle, ONM-400, that encapsulates IL-2 and is activated by the acidic environment of cancerous tissues.

The nanoparticle, ONM-400, is designed to encapsulate IL-2, thereby masking its activity during circulation. The release of IL-2 is triggered by the low pH found in tumor microenvironments, ensuring that the active form of IL-2 is delivered precisely to the tumor site. The development of this nanoparticle involved a proprietary encapsulation method and was characterized for its physical properties. The encapsulated IL-2 was tested for activity in both its inactive state within the nanoparticle and once activated.

In vivo studies using mice with head and neck tumors demonstrated that ONM-400 resulted in higher tumor accumulation and less renal clearance compared to free IL-2. The antitumor effects of ONM-400 were evaluated in mice with MC38 colon cancer and compared to the effects of unencapsulated IL-2. The results showed that ONM-400 induced a strong antitumor response, with 60% of treated animals experiencing complete tumor regression and remaining disease-free for 60 days post-treatment. Additionally, 5 out of 6 animals resisted tumor growth after a secondary challenge.

The study concludes that ONM-400, by leveraging the acidic environment of tumors, provides a concentrated dose of IL-2 within the tumor, leading to a potent antitumor effect. The use of pH-activatable nanoparticles represents an innovative strategy for the targeted delivery of immunomodulators in cancer treatment. All animal studies were conducted with approval from the Pennsylvania State College of Medicine Institutional Animal Care and Use Committee under Animal Protocol Number: 47682.