Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer.

Abstract

The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5 μg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity. Graphical abstract In this work, Ara-C encapsulated with hyaluronic acid-tyramine conjugates (HA-Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.

• Authors: Juan Tang, Na Wang, JingBo Wu, PeiRong Ren, JunYang Li, LiShi Yang, XiangXiang Shi, Yue Chen, ShaoZhi Fu, Sheng Lin
• Journal: Investigational new drugs (Invest New Drugs) Vol. 37 Issue 6 Pg. 1146-1157 (12 2019) ISSN: 1573-0646 [Electronic] United States
• PMID: 30790151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• H2AX protein, mouse
• Histones
• Hydrogels
• Cytarabine
• Hyaluronic Acid

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage)
• Apoptosis
• Carcinoma, Lewis Lung (drug therapy, metabolism, radiotherapy)
• Cell Cycle
• Cell Line, Tumor
• Combined Modality Therapy
• Cytarabine (administration & dosage)
• Drug Liberation
• Drug Synergism
• Female
• Histones (metabolism)
• Hyaluronic Acid (administration & dosage)
• Hydrogels (administration & dosage)
• Injections, Intralesional
• Lung Neoplasms (drug therapy, metabolism, radiotherapy)
• Mice, Inbred C57BL