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Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

2012; Nature Portfolio; Volume: 11; Issue: 10 Linguagem: Inglês

10.1038/nmat3355

1476-4660

Jason Y. Park, Stephen H. Wrzesinski, Eric Stern, Michael Look, Jason M. Criscione, Ragy Ragheb, Steven M. Jay, Stacey L. Demento, Atu Agawu, Paula Licona-Limón, Anthony F. Ferrandino, David G. Gonzalez, Ann Habermann, Richard A. Flavell, Tarek M. Fahmy,

Nanoparticle-Based Drug Delivery

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses. The sustained release of both hydrophilic and hydrophobic immunomodulators for metastatic melanoma by nanoscale liposomal polymeric gels administered intratumorally or systemically is demonstrated. It is also shown that such a co-delivery approach delays tumour growth and increases the survival of tumour-bearing mice, and that its efficacy results from the activation of both innate and adaptative immune responses.