198P - Polarization of tumor-associated macrophages enhanced by 2-HP-_-cyclodextrin modified PLGA nanoparticles

Background

Immunotherapy for cancer is closely related to the tumor immunosuppressive microenvironment (TIME). Resiquimod (a mixed TLR7/8 agonist also known as R848) has been shown to mediate promising immunostimulatory activity in a variety of preclinical models. Poly(D, L-lactic-co-glycolic acid) (PLGA) is one of the most commonly used biodegradable polymer.

Methods

The nanoparticles loaded with R848 (CD@R848@NP) were prepared by improved emulsion-solvent evaporation method, and the drug loading rate and entrapment efficiency were calculated. Its physical and chemical properties and drug release stability were measured, and its polarization effect on macrophages was evaluated in vitro. After labeling with IR780 fluorescent dye, the localization of the nanoparticles in vivo and in vitro was analyzed. CD@R848@NP was used to treat MC38 colon cancer mice by tail vein injection combined with intraperitoneal injection of TNFR2 antibody.

Results

(1) The prepared CD@R848@NP nanoparticles have strong stability, no obvious cytotoxicity, sustained release effect and increased release under acidic conditions. The load content (LC) and entrapment efficiency (EE) of R848 were (3.11 ±0.61)% and (65.36 ±3)%. (2) In vitro experiments showed that HP-β-CD modified nanoparticles could be better absorbed by macrophages, and in vivo localization experiments confirmed that they could be better located in tumor tissues. (3) CD@R848@NP combined with Anti-TNFR2 could eliminate MC38 tumor in mice, and there was no significant change in body weight. Hue results showed that the nanoparticles had no obvious toxicity to all organs. After 24 hours of administration, the secretion of IL-12 factor in blood of mice was significantly higher than that of other groups. The results of tumor histochemistry showed that the secretion of TNF α and IL-6 factors in CD@R848@NP was significantly higher than that in other groups.

Conclusions

PLGA nanoparticles encapsulated with R848 can effectively deliver drugs to tumor tissue and induce tumor-associated macrophages to polarize into M1 macrophages. On the other hand, TNFR2 antibodies can inhibit the activation of Treg cells, reduce immunosuppression in tumor microenvironment and eliminate tumor.

Legal entity responsible for the study

The authors.

Funding

The National Natural Science Foundation of China (82060308), Guizhou Immunotherapy Research Talent Base (RCJD2018-11).

Disclosure

All authors have declared no conflicts of interest.