Programmed delivery of cyclopeptide RA-V and antisense oligonucleotides for combination therapy on hypoxic tumors and for therapeutic self-monitoring.

Abstract

Chemotherapy is a dominant treatment modality for different types and stages of cancer. However, hypoxia is one of the undesirable limitations of chemotherapy, which reduces the therapeutic efficiency in cancer treatment, ultimately leading to failure of the treatment. Herein, an ideal chemosensitization system capable of attenuating the tumor hypoxia microenvironment and enhancing chemotherapy effects in tumors was designed. This system (designated as the RA/RX Liposome) uses for the first time a pH-sensitive liposome to co-deliver cyclopeptide RA-V as chemotherapeutic drugs and antisense oligonucleotides as HIF-1α inhibitors (RX-0047) for attenuating tumor hypoxia, as well as a caspase-8 activation probe for therapeutic self-monitoring. After modification with death receptor 5-specific antibodies (anti-DR5) on the surface of the liposome, the RA/RX Liposome can successfully deliver components targeting colon tumors in vivo. This work should synergistically enhance the therapeutic effects of the treatment by successfully down-regulating HIF-1α expression against tumor hypoxia during the RA-V-induced apoptotic process. More importantly, the RA/RX Liposome can be precisely applied for therapeutic self-monitoring with the light-up fluorescence of the caspase-8 probe.

• Authors: Yongrong Yao , Li Feng , Zhe Wang , Huachao Chen , Ninghua Tan
• Journal: Biomaterials science (Biomater Sci) Vol. 8 Issue 1 Pg. 256-265 (Dec 17 2019) ISSN: 2047-4849 [Electronic] England
• PMID: 31687671 (Publication Type: Journal Article)

Chemical References

• Antibodies
• Liposomes
• Oligonucleotides
• Peptides, Cyclic
• RX 0047
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10B protein, human
• RA V
• CASP8 protein, human
• Caspase 8

Topics

• Animals
• Antibodies (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Caspase 8 (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, metabolism)
• Drug Synergism
• Female
• HCT116 Cells
• HT29 Cells
• Humans
• Liposomes
• Mice
• Oligonucleotides (administration & dosage, pharmacology)
• Peptides, Cyclic (administration & dosage, pharmacology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology)
• Tumor Hypoxia (drug effects)
• Xenograft Model Antitumor Assays