An albumin‑binding domain and targeting peptide‑based recombinant protein and its enediyne‑integrated analogue exhibit directional delivery and potent inhibitory activity on pancreatic cancer with K‑ras mutation.

Abstract

Efficient enrichment and transmembrane transport of cytotoxic reagents are considered to be effective strategies to increase the efficiency and selectivity of antitumor drugs targeting solid tumors. In the present study, a recombinant protein ABD‑LDP‑Ec consisting of the albumin‑binding domain (ABD), the apoprotein (LDP) of lidamycin (LDM) and an EGFR‑targeting oligopeptide (Ec) was prepared by DNA recombination and bacterial fermentation, and was integrated with the enediyne chromophore (AE) of lidamycin to generate its enediyne‑integrated analogue ABD‑LDP‑Ec‑AE. ABD‑LDP‑Ec exhibited high binding capacity to both albumin and EGFR‑positive pancreatic cancer cells, and was internalized into the cytoplasm through receptor‑mediated endocytosis and albumin‑driven macropinocytosis of K‑ras mutant cells. In animal experiments, ABD‑LDP‑Ec demonstrated notable selective distribution in pancreatic carcinoma xenografts by passive targeting of albumin captured in the blood and was retained in the tumor for 48 h. ABD‑LDP‑Ec and ABD‑LDP‑Ec‑AE exhibited inhibitory activity in cell proliferation and AsPC‑1 xenograft growth, and ABD‑LDP‑Ec‑AE increased the tumor growth inhibition rate by 20% compared with natural LDM. The results indicated that the introduction of ABD‑based multi‑functional drug delivery may be an effective approach to improve the efficacy of antitumor drugs, especially for K‑ras mutant cancers.

• Authors: Weijin Sheng, Jing Geng, Liang Li, Yue Shang, Min Jiang, Yongsu Zhen
• Journal: Oncology reports (Oncol Rep) Vol. 43 Issue 3 Pg. 851-863 (03 2020) ISSN: 1791-2431 [Electronic] Greece
• PMID: 32020213 (Publication Type: Journal Article)

Chemical References

• Albumins
• Aminoglycosides
• Antineoplastic Agents
• Enediynes
• KRAS protein, human
• Oligopeptides
• Peptides
• Recombinant Proteins
• C 1027
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)

Topics

• Albumins (chemistry, genetics)
• Aminoglycosides (chemistry, genetics, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Enediynes (chemistry, pharmacology)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Heterografts
• Humans
• Mice
• Mutation (genetics)
• Oligopeptides (chemistry, genetics, pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Peptides (antagonists & inhibitors, genetics)
• Protein Binding (drug effects)
• Protein Domains (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Recombinant Proteins (drug effects, genetics)
• Xenograft Model Antitumor Assays