https://orcid.org/0009-0004-0658-9466
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Abstract
Purpose
This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD).
Methods
R848-loaded PLGA nanoparticles modified with 2-HP-β-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo.
Results
The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-β-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival.
Conclusion
The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.
Keywords:
Abbreviations
PLGA, poly (lactic-co-glycolic acid); CRC, Colorectal cancer; TEM, Transmission Electron Microscope; TLR, Toll-like receptor; TAM, tumor-associated macrophage; TIME, tumor immune microenvironment; Tregs, CD4+Foxp3+ regulatory T cells; A-T, anti-TNFR2; CD, β-cyclodextrin; R848, Resiquimod; NPs, bare PLGA nanoparticles; CD@NPs, PLGA nanocapsules modified with 2-HP-β-CD; R848@NPs, R848 coated with PLGA nanoparticles; CD@R848@NP, drug R848-loaded PLGA nanoparticles modified by 2-HP-β-CD; CD@R848@NP+A-T, CD@R848@NP+anti-TNFR2; R848+A-T, R848+anti-TNFR2; IR-780-R848@NPs, the drug R848 and IR-780 dye loaded with PLGA nanoparticles; IR-780-CD@R848@NPs, the drug R848 and IR-780 dye loaded with PLGA nanoparticles modified with 2-HP-β-CD.
Ethics Approval
All animal-related procedures were carried out based on an approved protocol from the institutional animal care and treatment committee (license number for laboratory animals: EAE-GZU-2022-7088). Protocol for animals study were approved by Institutional Animal Care Committee of Guizhou University.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.