TY - JOUR
T1 - Dendrimer-Mediated Targeted Delivery of Rapamycin to Tumor-Associated Macrophages Improves Systemic Treatment of Glioblastoma
AU - Sharma, Anjali
AU - Liaw, Kevin
AU - Sharma, Rishi
AU - Spriggs, Talis
AU - Appiani La Rosa, Santiago
AU - Kannan, Sujatha
AU - Kannan, Rangaramanujam M.
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/12/14
Y1 - 2020/12/14
N2 - Glioblastoma exhibits high mortality rates due to challenges with drug delivery to the brain and into solid tumors. This two-pronged barrier necessitates high doses of systemic therapies, resulting in significant off-target toxicities. Recently, dendrimer-nanomedicines (without ligands) have shown promise for targeting specific cells in brain tumors from systemic circulation, for improved efficacy and amelioration of systemic toxicities. A dendrimer-rapamycin conjugate (D-Rapa) is presented here that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration. D-Rapa improves suppression of pro-tumor expression in activated TAMs and antiproliferative properties of rapamycin in glioma cells in vitro. In vivo, D-Rapa localizes specifically within TAMs, acting as depots to release rapamycin into the tumor microenvironment. This targeted delivery strategy yields improved reduction in tumor burden and systemic toxicities in a challenging, clinically relevant orthotopic syngeneic model of glioblastoma, demonstrating the significant potential of dendrimers as targeted immunotherapies for improving glioblastoma treatment, still an unmet need.
AB - Glioblastoma exhibits high mortality rates due to challenges with drug delivery to the brain and into solid tumors. This two-pronged barrier necessitates high doses of systemic therapies, resulting in significant off-target toxicities. Recently, dendrimer-nanomedicines (without ligands) have shown promise for targeting specific cells in brain tumors from systemic circulation, for improved efficacy and amelioration of systemic toxicities. A dendrimer-rapamycin conjugate (D-Rapa) is presented here that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration. D-Rapa improves suppression of pro-tumor expression in activated TAMs and antiproliferative properties of rapamycin in glioma cells in vitro. In vivo, D-Rapa localizes specifically within TAMs, acting as depots to release rapamycin into the tumor microenvironment. This targeted delivery strategy yields improved reduction in tumor burden and systemic toxicities in a challenging, clinically relevant orthotopic syngeneic model of glioblastoma, demonstrating the significant potential of dendrimers as targeted immunotherapies for improving glioblastoma treatment, still an unmet need.
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U2 - 10.1021/acs.biomac.0c01270
DO - 10.1021/acs.biomac.0c01270
M3 - Article
C2 - 33112134
AN - SCOPUS:85095856098
SN - 1525-7797
VL - 21
SP - 5148
EP - 5161
JO - Biomacromolecules
JF - Biomacromolecules
IS - 12
ER -