Boosting Interleukin‐12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR‐Tagged Nanogold

다국어 초록 (Multilingual Abstract)

The clinical use of interleukin‐12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor‐homing peptide containing isoDGR, an αvβ3‐integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head‐to‐tail cyclized‐peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvβ3 and IL12‐receptor recognition. Low‐dose Iso1/Au/IL12, equivalent to 18–75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low‐dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T‐cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR‐tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T‐cell therapy.
Gold nanospheres can be functionalized with interleukin‐12 (IL12), a potent anticancer and immunostimulatory cytokine, and a cyclic peptide containing the isoDGR motif (Iso1) that, after coupling to albumin (Iso1‐HSA), recognizes the αvβ3 integrin overexpressed in tumor vessels and on different tumor cell types. Bifunctional nanospheres (Iso1/Au/IL12) increase the infiltration of immune cells and inhibit tumor growth in preclinical tumor models.