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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cytokines / metabolism
  • Dogs
  • Drug Compounding
  • Drug Evaluation, Preclinical
  • Drug Liberation
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Immunologic Factors / pharmacology*
  • Mice
  • Mice, Inbred C3H
  • Rabbits
  • Suspensions
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 8 / agonists*


  • Antineoplastic Agents
  • Cytokines
  • Imidazoles
  • Immunologic Factors
  • Suspensions
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • resiquimod