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J Control Release. 2019 Jul 28;306:165-176. doi: 10.1016/j.jconrel.2019.06.003. Epub 2019 Jun 4.

Formulation and preclinical evaluation of a toll-like receptor 7/8 agonist as an anti-tumoral immunomodulator.

Author information

1
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
2
HylaPharm LLC, Lawrence, Kansas, United States of America.
3
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, United States of America; HylaPharm LLC, Lawrence, Kansas, United States of America.
4
HylaPharm LLC, Lawrence, Kansas, United States of America; Division of Dermatology, School of Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States of America.
5
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, United States of America; Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas, United States of America.
6
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, United States of America; HylaPharm LLC, Lawrence, Kansas, United States of America. Electronic address: lforrest@ku.edu.

Abstract

The toll-like receptor 7 and 8 (TLR7/8) agonist Resiquimod (R848) has been recognized as a promising immunostimulator for the treatment of cutaneous cancers in multiple clinical trials. However, systemic administration of R848 often results in strong immune-related toxicities while having limited therapeutic effects to the tumor. In the present study, a prodrug-based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. R848 was conjugated to α-tocopherol to constitute an R848-Toco prodrug, followed by formulating with a tocopherol-modified hyaluronic acid (HA-Toco) as a polymeric nano-suspension. In vitro evaluation showed that the delivery system prolonged the release kinetics while maintaining TLR agonist activities. When administered subcutaneously, the nano-suspension formed a depot at the injection site, inducing localized immune responses without systemic expansion. This formulation also suppressed tumor growth and recruited immune cells to the tumor in a murine model of head and neck cancer. In a preclinical canine study of spontaneous mast cell tumors, the treatment led to a 67% response rate (three partial remissions and one complete remission).

KEYWORDS:

Cancer immunotherapy; Depot effect; Nanotherapeutic formulation; Sustained delivery; Toll-like receptor agonists

PMID:
31173789
PMCID:
PMC6679596
[Available on 2020-07-28]
DOI:
10.1016/j.jconrel.2019.06.003

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