Transdermal Delivery of Antigenic Protein Using Ionic Liquid-Based Nanocarriers for Tumor Immunotherapy

Abstract

Transdermal drug delivery systems (TDDSs) may be useful for preventing various diseases including cancer. However, the stratum corneum (SC) inhibits the permeation of foreign particles into the skin. To obtain an effective TDDS, we developed a protein-containing nanocarrier (PCNC) comprising an antigenic protein (ovalbumin/OVA) stabilized by a combination of surfactants, i.e., a lipid-based surface-active ionic liquid and Tween-80. The PCNC was lyophilized to remove water and cyclohexane and then dispersed in isopropyl myristate. It is biocompatible both in vitro and in vivo, and is suitable for use in a therapeutic TDDS. The skin permeability of the PCNC was significantly (p < 0.0001) enhanced, and the transdermal distribution and transdermal flux of the OVA delivery system were 25 and 28 times greater, respectively, than those of its aqueous formulation. The PCNC disrupted the order of lipid orientation in the skin’s SC and increased intercellular protein delivery. It demonstrated effective antitumor activity, drastically (p < 0.001) suppressed tumor growth, increased mouse survival rates, and significantly (p < 0.001) stimulated the OVA-specific tumor immune response. The PCNC also increased the number of cytotoxic T cells expressing CD8 antibodies on their surfaces (CD8 + T-cells) in the tumor microenvironment. These findings suggest that PCNCs may be promising biocompatible carriers for transdermal antigenic protein delivery in tumor immunotherapy.

The Impact of Water on Choline‐2‐Octenoic Ionic Liquid‐Facilitated Transdermal Transport

“…The role of water was first evaluated in ionic liquid-facilitated transdermal transport of drug-like molecules. Informed by recent transdermal permeation work that employed diluted ILs with a range of solvents [22,23] (including water [24][25][26][27][28][29][30] ), the nanoscale origins of these effects were investigated.…”

Research progress of physical transdermal enhancement techniques in tumor therapy

“…[1][2][3][4][5][6][7][8][9] The skin has a strong immune system, including dendritic cells, macrophages, Langerhans cells, lymphocytes, T cells, and natural killer cells, which provide the foundation for tumor immunotherapy. [10][11][12][13] Therefore, TDD has attracted wide attention in tumor therapy since its discovery.…”

Modification with Conventional Surfactants to Improve a Lipid-Based Ionic-Liquid-Associated Transcutaneous Anticancer Vaccine

“…Vaccination is the most successful immunotherapeutic approach in modern medical sciences, as it prevents 3.5–5 million deaths annually, whereas 1.5 million each year people die of diseases that can be prevented by immunization (WHO-2022) [ 1 , 2 , 3 ]. Transcutaneous vaccination is a patient-friendly, effective, and target-specific alternative vaccination/immunization approach because skin contains numerous immunoresponsive antigen-presenting cells (APCs), which are highly efficacious for immunoresponsive diseases such as cancer, anemia, HIV, and diabetes [ 4 , 5 ]. However, the lipidic arrangement of the stratum corneum (SC) hinders the permeation of large and hydrophilic molecules (proteins, peptides, and nucleic acids), which must be transported using a hydrophobic, lipophilic, or oil-based nanocarrier [ 6 , 7 , 8 , 9 ].…”

“…These immunomodulators, which can activate APCs in the skin, are employed as adjuvants with antigens or antigenic proteins in vaccine formulations to enhance the immune response [ 19 , 20 , 21 ]. Among them, IMQ is an excellent immunostimulatory adjuvant that has been used in various immunotherapies, but IMQ-based formulations are challenging to use for transdermal drug delivery because of their limited solubility and low permeability [ 4 , 22 , 23 , 24 , 25 ]. LBIL-associated formulations might represent a promising TDDS approach to overcome these challenges through the generation of nanocarriers in isopropyl myristate (IPM) in the oil phase.…”

“…LBIL-associated formulations might represent a promising TDDS approach to overcome these challenges through the generation of nanocarriers in isopropyl myristate (IPM) in the oil phase. In our previous studies, we found that LBILs significantly increased protein and peptide delivery, whereas surfactants improved formulation quality and drug delivery [ 4 , 26 ]. However, the tests revealed that the immune response to LBIL-based formulations was inferior to that of injectable aqueous formulations.…”