TY - JOUR
T1 - Systemic Immunotherapy with Micellar Resiquimod–Polymer Conjugates Triggers a Robust Antitumor Response in a Breast Cancer Model
AU - Kakwere, Hamilton
AU - Zhang, Hua
AU - Ingham, Elizabeth S.
AU - Nura-Raie, Marina
AU - Tumbale, Spencer K.
AU - Allen, Riley
AU - Tam, Sarah M.
AU - Wu, Bo
AU - Liu, Cheng
AU - Kheirolomoom, Azadeh
AU - Fite, Brett Z.
AU - Ilovitsh, Asaf
AU - Lewis, Jamal S.
AU - Ferrara, Katherine W.
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/5/19
Y1 - 2021/5/19
N2 - Resiquimod is an immunopotent toll-like receptor 7/8 agonist with antitumor activity. Despite being potent against skin cancers, it is poorly tolerated systemically due to toxicity. Integrating resiquimod into nanoparticles presents an avenue to circumvent the toxicity problem. Herein, the preparation of degradable nanoparticles with covalently bound resiquimod and their systemic application in cancer immunotherapy is reported. Dispersion in water of amphiphilic constructs integrating resiquimod covalently bound via degradable amide or ester linkages yields immune-activating nanoparticles. The degradable agonist–nanoparticle bonds allow the release of resiquimod from the carrier nanoparticles. In vitro assays with antigen presenting cells demonstrate that the nanoparticles retain the immunostimulatory activity of resiquimod. Systemic administration of the nanoparticles and checkpoint blockade (aPD-1) to a breast cancer mouse model with multiple established tumors triggers antitumor activity evidenced by suppressed tumor growth and enhanced CD8+ T-cell infiltration. Nanoparticles with ester links, which hydrolyze more readily, yield a stronger immune response with 75% of tumors eliminated when combined with aPD-1. The reduced tumor growth and the presence of activated CD8+ T-cells across multiple tumors suggest the potential for treating metastatic cancer.
AB - Resiquimod is an immunopotent toll-like receptor 7/8 agonist with antitumor activity. Despite being potent against skin cancers, it is poorly tolerated systemically due to toxicity. Integrating resiquimod into nanoparticles presents an avenue to circumvent the toxicity problem. Herein, the preparation of degradable nanoparticles with covalently bound resiquimod and their systemic application in cancer immunotherapy is reported. Dispersion in water of amphiphilic constructs integrating resiquimod covalently bound via degradable amide or ester linkages yields immune-activating nanoparticles. The degradable agonist–nanoparticle bonds allow the release of resiquimod from the carrier nanoparticles. In vitro assays with antigen presenting cells demonstrate that the nanoparticles retain the immunostimulatory activity of resiquimod. Systemic administration of the nanoparticles and checkpoint blockade (aPD-1) to a breast cancer mouse model with multiple established tumors triggers antitumor activity evidenced by suppressed tumor growth and enhanced CD8+ T-cell infiltration. Nanoparticles with ester links, which hydrolyze more readily, yield a stronger immune response with 75% of tumors eliminated when combined with aPD-1. The reduced tumor growth and the presence of activated CD8+ T-cells across multiple tumors suggest the potential for treating metastatic cancer.
KW - immunotherapy
KW - metastatic breast cancer
KW - nanotechnology
KW - resiquimod
KW - toll-like receptor agonist
KW - vaccines
UR - http://www.scopus.com/inward/record.url?scp=85101860568&partnerID=8YFLogxK
U2 - 10.1002/adhm.202100008
DO - 10.1002/adhm.202100008
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C2 - 33646600
AN - SCOPUS:85101860568
SN - 2192-2640
VL - 10
JO - Advanced healthcare materials
JF - Advanced healthcare materials
IS - 10
M1 - 2100008
ER -