Superior Antitumor Efficacy of IFN-α2b-Incorporated Photo-Cross-Linked Hydrogels Combined with T Cell Transfer and Low-Dose Irradiation Against Gastric Cancer.

Abstract

INTRODUCTION:

The exhaustion and poor homing of activated lymphocytes are critical obstacles in adoptive cell immunotherapy for solid tumors. In order to effectively deliver immune cells into tumors, we encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor and utilized low-dose irradiation (LDI) as a tumoral attractor of T cells.

METHODS:

Hydroxypropyl cellulose hydrogels were prepared by irradiation techniques, and the cross-sectional microstructure was characterized by scanning electron microscopy. The synergistic antitumor mechanism of combination of IFN-α2b and CIK cells was evaluated by detecting the expression of activation marker CD69 on CIK cell surface and IFN-γ production by CIK cells. The in vivo antitumor activity of IFN-α2b-incorporated hydroxypropyl cellulose hydrogels combined with CIK and radiation was evaluated in an MKN-45 xenografted nude mice model.

RESULTS:

The bioactivity of IFN-α2b was well maintained in ultraviolet-reactive, rapidly cross-linkable hydroxypropyl cellulose hydrogels. In vitro studies demonstrated IFN-α2b-activated T cells, as evidenced by upregulating early activation marker CD69 and secretion inflammatory cytokine IFN-γ. In vivo real-time image showed our hydrogels kept a higher amount of drug delivery at the tumor site for a long time compared with free drug injection. Low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. Combination of IFN-α2b-loaded hydrogels (Gel-IFN) with T cells and LDI exhibited higher efficacy to eradicate human gastric cancer xenograted tumors with less proliferating cells and more necrotic regions compared with IFN-α2b or T cells alone.

DISCUSSION:

HPC hydrogels kept the activity of IFN-α2b and stably release of IFN-α2b to stimulate T cells for a long time. At the same time, low-dose radiation recruits T cells into tumors. This innovative integration mode of IFN-α2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the therapeutic outcome of T cell therapy.

• Authors: Qin Liu, Dinghu Zhang, Hanqing Qian, Yanhong Chu, Yan Yang, Jie Shao, Qiuping Xu, Baorui Liu
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 15 Pg. 3669-3680 ( 2020) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 32547021 (Publication Type: Journal Article)
• Copyright: © 2020 Liu et al.

Chemical References

• Antineoplastic Agents
• Cross-Linking Reagents
• Hydrogels
• Interferon alpha-2
• Interferon-alpha
• Interferon-alpha2b
• Cellulose
• hydroxypropylcellulose

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellulose (analogs & derivatives, chemistry)
• Cross-Linking Reagents (chemistry)
• Dose-Response Relationship, Radiation
• Electrons
• Humans
• Hydrogels (chemistry)
• Interferon alpha-2
• Interferon-alpha (pharmacology, therapeutic use)
• Light
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Stomach Neoplasms (drug therapy, radiotherapy)
• T-Lymphocytes (drug effects, immunology)
• Xenograft Model Antitumor Assays