Amphiphilic Cyclodextrin‐Based Nanoparticulate Vaccines Can Trigger T‐Cell Immune Responses

Abstract

Particulate antigen‐delivery systems are instrumental for therapeutic vaccination, aiming at improving the safety and efficacy of treatments by targeting specialized antigen‐presenting cells (APCs). However, the induction of potent adaptive immune responses, especially cellular immunity, remains a major challenge. Herein, a novel nanoparticulate antigen‐delivery system based on amphiphilic cyclodextrins (CDs) is developed as a platform for therapeutic cancer vaccination. Supramolecular nanosized CD structures are formed in aqueous media and loaded with peptide antigens. The nanoparticle's adjuvant capacity is tested in cell experiments with murine bone marrow‐derived dendritic cells (BMDCs) or macrophages and T cells. Peptide‐loaded nanoparticles cause upregulation of costimulatory molecules on BMDCs and facilitate activation and proliferation of antigen‐specific T‐lymphocytes in vitro. Correct processing for major histocompatibility complex (MHC) class‐I antigen presentation is demonstrated using a capped version of the ovalbumin‐derived peptide SIINFEKL (c‐SFL). After immunization of mice with peptide‐loaded CD nanoparticles, the frequencies of antigen‐specific and cytokine‐producing CD8+ T cells are increased. This work sheds light on the immune‐stimulating properties of amphiphilic CD nanoparticles and reveals their considerable potential as carriers for cancer vaccines.

Engineered Self-Assembly of Amphiphilic Cyclodextrin Conjugates for Drug Encapsulation

“…The thioether derivative heptakis-(6-deoxy-6-hexylthio)-β-cyclodextrin (CDSC 6 , Scheme , 3) was obtained from native β-CD by bromination and subsequent nucleophilic substitution with 1-hexanethiol , with a yield >50%. The 1 H NMR spectrum (Figure C) confirms the conjugation of the alkyl protons H7–19 (δ 0.863–3.327 ppm).…”

“…While hydrophobic molecules can be incorporated in the hydrophobic cavity of the CD structure by forming inclusion complexes, the complexation of hydrophilic compounds is also possible . Further, amphiphilic CD nanoparticles encapsulating small molecules, such as chemotherapeutic agents, ,,− as well as biomacromolecules, such as genes − or peptide antigens, , have been reported.…”

“…Nanocarriers were prepared by nanoprecipitation as previously described. 17 Briefly, amphiphilic CD derivatives were dissolved in the organic solvent and dropped into the aqueous phase under constant stirring at a flow rate of 5 mL min −1 using a syringe pump (Pump 11 Pico Elite Plus, Harvard apparatus, March-Hugstetten, Germany). Purified water was used as the aqueous phase, and the ratio of organic/aqueous phase was 1:2 (v/v), except for the CDOC 12 derivative (1:8 (v/v)).…”

“…Grafting aliphatic chains onto native CDs renders them amphiphilic and enables self-assembly into supramolecular structures such as micelles, vesicles, and nanoparticles. , Amphiphilic CD derivatives with tailor-made physicochemical properties, interfacial behavior, and solubility profiles have been synthesized by aminations, esterifications, or etherifications of the primary and/or secondary hydroxyl groups and explored for the delivery of small molecules, , genes, − as well as peptides. − Such delivery systems have the potential to protect drugs from biodegradation, to improve their solubility, and to control their release. Further, they may also be designed to overcome biological barriers in the human body, like epithelia, or to target specific cells and tissues to enhance the drug’s therapeutic efficacy.…”

Cyclodextrin in Vaccines: Enhancing Efficacy and Stability

“…It was reported that mice immunized with peptide-loaded CD nanoparticles have higher frequencies of antigen-specific and cytokine-producing CD8+ T cells. Contrary to peptide-loaded CD nanoparticles, the blank CD nanoparticles did not cause changes in the CD80 or CD86 levels, and based on this result, it was stated that amphiphilic CD nanoparticles are safe to use as a carrier system in vaccines [86].…”