Systemic Immunotherapy with Micellar Resiquimod–Polymer Conjugates Triggers a Robust Antitumor Response in a Breast Cancer Model

Abstract

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.

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

“…In the present study, we utilized 4 mg/kg R848 NE and 2 mg/kg SD-101 individually or in combination to show a synergized antitumor efficacy through intraperitoneal administration. The moderate antitumor efficacies by R848 NE and SD-101 individual treatments were observed (Figure 5C,D,F) compared with saline control (Figure 5B), which correspond with the previous studies for R848 and SD-101 [58,59]. Although individual treatments of R848 NE or SD-101 showed significant tumor growth inhibition (TGI) (50.72% ± 16.83% and 65.65% ± 12.88%), R848 NE/SD-101 combination treatment reached approximately 84.62% ± 28.05% total tumor growth inhibition at the end of the study (Table 1) with the median tumor growth inhibition of 98.05% (Table S3), suggesting the synergistic antitumor efficacy carried out by R848 NE/SD-101 combination treatment.…”

“…In the present study, we utilized 4 mg/kg R848 NE and 2 mg/kg SD-101 individually or in combination to show a synergized antitumor efficacy through intraperitoneal administration. The moderate antitumor efficacies by R848 NE and SD-101 individual treatments were observed (Figure 5C,D,F) compared with saline control (Figure 5B), which correspond with the previous studies for R848 and SD-101 [58,59]. Several reports indicated that both TLR7/8 and TLR9 stimulate IL-6 production, which acts as both a pro-inflammatory and anti-inflammatory cytokine [44][45][46][47].…”

Biodegradable nanomaterials for diagnosis and therapy of tumors

“…13a). 136 Resiquimod was covalently bound to a biodegradable polymer via hydrolytically degradable ester links between the agonist and the polymer, and the size of the NPs was modulated to less than 20 nm which could greatly enhance the permeation and accumulation in the lymphatic system where APCs are present in large quantities and the metastasis usually occurs. After being accepted by cells, the ester links were cleaved quickly probably due to the enzymatic activity and acid condition, releasing resiquimod (Fig.…”

Combined Biomimetic MOF-RVG15 Nanoformulation Efficient Over BBB for Effective Anti-Glioblastoma in Mice Model

“…Several advanced therapeutic drugs, including immune-activating, small molecule targeted, and antibody drugs, have been successful in other malignant tumors. [7][8][9] Unfortunately, the blood-brain barrier (BBB) and blood-brain-tumor barrier (BBTB) restrict the current drugs from entering the brain for effective GBM treatment. 10 Therefore, many therapeutic agents that are effective against glioma cells in vitro exhibit lower response in vivo.…”