TY - JOUR
T1 - Therapeutic inhibitory RNA in head and neck cancer via functional targeted lipid nanoparticles
AU - Kampel, Liyona
AU - Goldsmith, Meir
AU - Ramishetti, Srinivas
AU - Veiga, Nuphar
AU - Rosenblum, Daniel
AU - Gutkin, Anna
AU - Chatterjee, Sushmita
AU - Penn, Moran
AU - Lerman, Galya
AU - Peer, Dan
AU - Muhanna, Nidal
N1 - Funding Information:
This work was supported in part by grants from the Israel Science Foundation (ISF), EU Expert and Lewis Trust awarded to D·P, and by the Kahn Foundation grant awarded to L.K.
Publisher Copyright:
© 2021 Elsevier B.V.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/9/10
Y1 - 2021/9/10
N2 - Currently there are no specific therapies addressing the distinctive biology of human papillomavirus (HPV)-induced cancer approved for clinical use. Short interfering RNA (siRNA) has much potential for therapeutic manipulation of HPV E6/E7 oncoproteins. Lipid-based nanoparticles (LNPs) can be utilized for systemic transportation and delivery of siRNA at target site. We recently developed a recombinant protein linker that enables uniform conjugation of targeting antibodies to the LNPs. Herein, we demonstrate the therapeutic efficacy of anti-E6/E7 siRNA delivered via targeted LNPs (tLNPs) in a xenograft HPV-positive tumor model. We show that anti-epidermal growth factor receptor (EGFR) antibodies, anchored to the LNPs as targeting moieties, facilitate cargo delivery but also mediate anti-tumor activity. Treatment with siE6 via tLNPs resulted in 50% greater reduction of tumor volume compared to treatment with siControl encapsulated in isoLNPs (coated with isotype control antibodies). We demonstrate superior suppression of HPV oncogenes and higher induction of apoptosis by the tLNPs both in vitro and in vivo. Altogether, the coupling of inhibitory siE6 with anti-EGFR antibodies, that further elicited anti-tumor effects, successfully restricted tumor progression. This system that combines potent siRNA and therapeutically functional tLNPs can be modulated against various cancer models.
AB - Currently there are no specific therapies addressing the distinctive biology of human papillomavirus (HPV)-induced cancer approved for clinical use. Short interfering RNA (siRNA) has much potential for therapeutic manipulation of HPV E6/E7 oncoproteins. Lipid-based nanoparticles (LNPs) can be utilized for systemic transportation and delivery of siRNA at target site. We recently developed a recombinant protein linker that enables uniform conjugation of targeting antibodies to the LNPs. Herein, we demonstrate the therapeutic efficacy of anti-E6/E7 siRNA delivered via targeted LNPs (tLNPs) in a xenograft HPV-positive tumor model. We show that anti-epidermal growth factor receptor (EGFR) antibodies, anchored to the LNPs as targeting moieties, facilitate cargo delivery but also mediate anti-tumor activity. Treatment with siE6 via tLNPs resulted in 50% greater reduction of tumor volume compared to treatment with siControl encapsulated in isoLNPs (coated with isotype control antibodies). We demonstrate superior suppression of HPV oncogenes and higher induction of apoptosis by the tLNPs both in vitro and in vivo. Altogether, the coupling of inhibitory siE6 with anti-EGFR antibodies, that further elicited anti-tumor effects, successfully restricted tumor progression. This system that combines potent siRNA and therapeutically functional tLNPs can be modulated against various cancer models.
KW - HPV
KW - Head and neck cancer
KW - Lipid-based nanoparticle
KW - Targeting
KW - siRNA
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U2 - 10.1016/j.jconrel.2021.07.034
DO - 10.1016/j.jconrel.2021.07.034
M3 - Article
C2 - 34303750
AN - SCOPUS:85111305419
SN - 0168-3659
VL - 337
SP - 378
EP - 389
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -