iRGD Modified Chemo‐immunotherapeutic Nanoparticles for Enhanced Immunotherapy against Glioblastoma

Abstract

Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8+ T lymphocytes and inhibit CD4+ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.

Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy

“…Furthermore, both PCP-Mn-DTA@1-MT and PCP-Mn-DTA@GOx@1-MT inhibited the downregulation of IDO expression more significantly as compared to free 1-MT ( p < 0.01, Fig. 6b ), suggesting that the IDO activity suppression was benefited by the advanced delivery efficiency of the nanosystem 10 .

Fig.

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Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy

“…Furthermore, both PCP-Mn-DTA@1-MT and PCP-Mn-DTA@GOx@1-MT inhibited the downregulation of IDO expression more significantly as compared to free 1-MT ( p < 0.01, Fig. 6b ), suggesting that the IDO activity suppression was benefited by the advanced delivery efficiency of the nanosystem 10 .

Fig.

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Enhanced Penetrability of a Tetrahedral Framework Nucleic Acid by Modification with iRGD for DOX-Targeted Delivery to Triple-Negative Breast Cancer

“…Previous studies − have demonstrated that αvβ3 and αvβ5 integrins were overexpressed on 4T1 and the RGD motif could bind to αv integrin specifically. In Figure A, compared to the Cy5-S1 group, the results suggested that Cy5–tFNA was capable of distinguishing membrane permeability than ssDNA, which was consistent with the results reported in our previous studies. − Moreover, Cy5–tFNA@iRGD showed greatest intracellular accumulation, indicating the decisive factor of iRGD in helping the internalization of the tFNA delivery system.…”

Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help?

“…If the DOX-loaded PEGylated liposomes are decorated with the CB5005 peptide, similar results are obtained with remarkable cell and nucleus permeabilities, resulting in a significant increase of the survival times [138]. Finally, different examples of NPs combining DOX with a curcumin-loaded dual-layer pH-sensitive NPs [139], 1-methyltryptophan (immune checkpoint inhibitor) in mesoporous silica [140], or hydroxychloroquine-loaded legumain-responsive gold nanoparticles [141] have been reported and substantiated their efficiency to overcome BBB, while enhancing synergistic effects.…”

Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy

“…Furthermore, both PCP-Mn-DTA@1-MT and PCP-Mn-DTA@GOx@1-MT inhibited the downregulation of IDO expression more significantly as compared to free 1-MT ( p < 0.01, Fig. 6b ), suggesting that the IDO activity suppression was benefited by the advanced delivery efficiency of the nanosystem 10 .

Fig.

…”

Enhanced Penetrability of a Tetrahedral Framework Nucleic Acid by Modification with iRGD for DOX-Targeted Delivery to Triple-Negative Breast Cancer

“…Previous studies − have demonstrated that αvβ3 and αvβ5 integrins were overexpressed on 4T1 and the RGD motif could bind to αv integrin specifically. In Figure A, compared to the Cy5-S1 group, the results suggested that Cy5–tFNA was capable of distinguishing membrane permeability than ssDNA, which was consistent with the results reported in our previous studies. − Moreover, Cy5–tFNA@iRGD showed greatest intracellular accumulation, indicating the decisive factor of iRGD in helping the internalization of the tFNA delivery system.…”

Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help?

“…If the DOX-loaded PEGylated liposomes are decorated with the CB5005 peptide, similar results are obtained with remarkable cell and nucleus permeabilities, resulting in a significant increase of the survival times [138]. Finally, different examples of NPs combining DOX with a curcumin-loaded dual-layer pH-sensitive NPs [139], 1-methyltryptophan (immune checkpoint inhibitor) in mesoporous silica [140], or hydroxychloroquine-loaded legumain-responsive gold nanoparticles [141] have been reported and substantiated their efficiency to overcome BBB, while enhancing synergistic effects.…”

Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy

“…Furthermore, both PCP-Mn-DTA@1-MT and PCP-Mn-DTA@GOx@1-MT inhibited the downregulation of IDO expression more significantly as compared to free 1-MT ( p < 0.01, Fig. 6b ), suggesting that the IDO activity suppression was benefited by the advanced delivery efficiency of the nanosystem 10 .

Fig.

…”

Enhanced Penetrability of a Tetrahedral Framework Nucleic Acid by Modification with iRGD for DOX-Targeted Delivery to Triple-Negative Breast Cancer

“…Previous studies − have demonstrated that αvβ3 and αvβ5 integrins were overexpressed on 4T1 and the RGD motif could bind to αv integrin specifically. In Figure A, compared to the Cy5-S1 group, the results suggested that Cy5–tFNA was capable of distinguishing membrane permeability than ssDNA, which was consistent with the results reported in our previous studies. − Moreover, Cy5–tFNA@iRGD showed greatest intracellular accumulation, indicating the decisive factor of iRGD in helping the internalization of the tFNA delivery system.…”

Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help?

“…If the DOX-loaded PEGylated liposomes are decorated with the CB5005 peptide, similar results are obtained with remarkable cell and nucleus permeabilities, resulting in a significant increase of the survival times [138]. Finally, different examples of NPs combining DOX with a curcumin-loaded dual-layer pH-sensitive NPs [139], 1-methyltryptophan (immune checkpoint inhibitor) in mesoporous silica [140], or hydroxychloroquine-loaded legumain-responsive gold nanoparticles [141] have been reported and substantiated their efficiency to overcome BBB, while enhancing synergistic effects.…”