Although nanomedicine has the potential to enhance cancer immunotherapy, its ability to obtain antitumor immunity with high specificity and without hampering immune tolerance remains unexplored. An article published recently in the journal Nature Communications discussed a semiconducting polymer-based cancer sono-immunotherapy activated in deep tissues.
Study: Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles. Image Credit: Kateryna Kon/Shutterstock.com
The semiconducting polymer prepared in this study generated singlet oxygen (1O2) that acted as a linker for two conjugating immunomodulators onto the polymer. This conjugation resulted in semiconducting polymer immunomodulatory nanoparticles with inhibited immunotherapeutic actions.
The 1O2 generated by semiconducting polymer immunomodulatory nanoparticles under ultrasound (US) irradiation had two roles. Firstly, to reprogram the tumor microenvironment by debulking tumors to enhance tumor immunogenicity. Secondly, to release the immunomodulators remotely, specifically at the tumor site.
Thus, sono-immunotherapy eliminated tumors and prevented their reoccurrence in a mouse model suffering from pancreatic tumors. Additionally, semiconducting polymer immunomodulatory nanoparticles showed antitumor activity in a rabbit tumor model. Furthermore, the semiconducting polymer immunomodulatory nanoparticle’s sonodynamic activation restricted the immunotherapeutic action on tumors, reducing the immune-related side effects.
Nanomedicines Towards Cancer Therapy
Cancer immunotherapy plays a vital role as an effective anticancer therapy that targets the host immune system. The immunotherapy based on checkpoint blockade interferes in inhibitory pathways of adaptive immunity, thereby improving the patient survival rate across various cancer types.
The therapeutic index of immunotherapy depends on pre-existing immunity conditions. Moreover, the non-immunogenic or cold tumors with low tumor-infiltrating lymphocytes have a poor response to immune checkpoint immunotherapy. Hence, other therapeutic models with the ability to obtain immunogenic cell death (ICD) can be integrated into checkpoint blockade immunotherapy.
Thus, the above integration can convert the cold tumors into their hot phenotypes and enhance the susceptibility of tumors to immunotherapy. However, combinational immunotherapies result in immune-related adverse events (irAEs) due to lower homeostatic immune tolerance toward monotherapy.
To this end, nanomedicines can enhance immunotherapy and reduce irAEs. Hydrogel-based nanomedicines allow sustained release of cytokines of immune checkpoint blockers or immune cells in the tumor microenvironment. This induces regional responses, which are difficult to treat due to their invisibility and inaccessibility. Moreover, the administration of immunotherapeutic agent-based nanoparticles results in the release of the active agents (immunotherapeutic agents) in response to tumor biomarkers for controlled immunotherapy at tumor sites.
Despite developing near-infrared (NIR) stimulated immunotherapeutic nanoagents, their application is hindered due to the NIR's shallow tissue penetration. Contrastingly, the US can penetrate deep tissues and induce the reactive oxygen species (ROS) generation from sonosensitizers for cancer therapy. However, integrating the sonodynamic process as an exogenous stimulant for nanomedicines remains unexplored.
Sono-immunotherapy Using Deep-tissue Activatable Semiconducting Polymer Immunomodulatory Nanoparticles
In the present study, the developed semiconducting polymer nanoparticles (SPNs) were used in cancer sono-immunotherapy at the deep tissue level. A library of agents screened for sono-immunotherapy revealed that ideal semiconducting immunomodulatory nanoparticles should have high efficiency toward sonodynamic 1O2 generation.
The developed SPNs were used to construct semiconducting polymer immunomodulatory nanoparticles by conjugating immunomodulators to SPN’s backbone via a 1O2-cleavable linker. Moreover, the semiconducting polymer immunomodulatory nanoparticles were tested against pancreatic tumors in mouse and rabbit models.
The administration of the semiconducting polymer immunomodulatory nanoparticles into mouse and rabbit models revealed that they could accumulate effectively in mouse and rabbit models' subcutaneous and orthotopic pancreatic tumors.
The semiconducting polymer immunomodulatory nanoparticles generated 1O2 on subjected to US irradiation. Moreover, the generated 1O2 debulked tumor tissues, reprogramed the tumor microenvironment, and scissored the 1O2 linkers that were cleavable to release the immunomodulators remotely.
The sonodynamic activation of nanomedicines facilitated the tumor-specific immunotherapeutic action. Hence, the sono-immunotherapy mediated by semiconducting polymer immunomodulatory nanoparticles showed high antitumor activity against primary and metastatic pancreatic tumors, preventing their reoccurrence, and reducing the irAEs probability. The pancreatic tumor’s deep-tissue therapy mediated by semiconducting polymer immunomodulatory nanoparticles covered 5-centimeter tissues alongside rabbit orthotopic pancreatic tumors that are deep-seated.
Conclusion
To summarize, SPNs were used to develop sono-immunotherapeutic nanoagents, activated at the deep tissue level, and their anticancer activity was tested in the pancreatic tumor mouse model. The sono-immunotherapy mediated by semiconducting polymer immunomodulatory nanoparticles depended on SPN’s sonodynamic properties. This sono-immunotherapy eradicated the tumors noninvasively and enhanced the pancreatic tumor’s immunogenicity via ICD induction.
Furthermore, semiconducting polymer immunomodulatory nanoparticles could achieve deep-tissue therapy on subcutaneous and orthotopic pancreatic tumors in mouse and rabbits, respectively. With the help of the present work, semiconducting polymer immunomodulatory nanoparticles were represented as immunotherapeutic agents. These agents exhibited high antitumor immunity without hampering systemic immune tolerance.
Moreover, the flexibility for structural modification in semiconducting polymer immunomodulatory nanoparticles allowed the generalization of the sonodynamic activation approach by conjugating nanoparticles with other immunotherapeutic molecules. Thus, the sonodynamic activation approach worked beyond checkpoint blockade immunotherapy.
Reference
Li, J., Luo, Y., Zeng, Z., Cui, D., Huang, J., Xu, C., Li, L et al. (2022). Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles. Nature Communication. https://www.nature.com/articles/s41467-022-31551-6
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