Ibrutinib (IBR), an irreversible
Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting
tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low
tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a
sialic acid (SA)-
stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted
immunotherapy. Amphiphilic egg
phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the
tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic
cytokines released by TAM and eventually suppressed
tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for
cancer immunotherapy. STATEMENT OF SIGNIFICANCE:
Ibrutinib (IBR), an irreversible
Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting
tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low
tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a
sialic acid (SA)-
stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic
cytokine release, reducing angiogenesis, and suppressing
tumor growth. These results implied that the SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting
immunotherapy with minimal systemic side effects.