Time-staggered delivery of docetaxel and H1-S6A,F8A peptide for sequential dual-strike chemotherapy through tumor priming and nuclear targeting.

Abstract

While highly effective for slowing cancer progression in principle, the c-Myc inhibitor peptide H1-S6A,F8A (H1) has not performed well in tumor studies, in part because it does not pass efficiently through the nuclear envelope. Here we describe a dual-strike strategy in which tumor cells were treated first with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-docetaxel (DTX) conjugates (P-DTX), which arrested cells in the G2/M phase and prolonged the period when the nuclear membrane was disassembled. In the second strike, the cells were then treated with P-H1 conjugates, which entered the nucleus and efficiently inhibited c-Myc. The in vitro studies demonstrated that the combination of P-DTX and P-H1 conjugates was sequence-dependent, and P-DTX followed by P-H1 had synergism, which was significantly more effective than reverse sequential delivery, simultaneous co-delivery or monotherapy with P-DTX or P-H1 alone. The in vivo studies showed that sequential delivery of P-DTX followed by P-H1 remarkably slowed the tumor growth and improved the animal survival. This sequential, dual-strike approach provides new opportunities for nuclear-targeted anticancer drug delivery.

• Authors: Lian Li, Wei Sun, Zhirong Zhang, Yuan Huang
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 232 Pg. 62-74 (06 28 2016) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 27098443 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Peptides
• Polymethacrylic Acids
• Proto-Oncogene Proteins c-myc
• Taxoids
• Docetaxel
• Duxon

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Docetaxel
• Female
• HeLa Cells
• Humans
• Mice, Nude
• Neoplasms (drug therapy, pathology)
• Peptides (administration & dosage, chemistry, pharmacokinetics)
• Polymethacrylic Acids (administration & dosage, chemistry, pharmacokinetics)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors, metabolism)
• Taxoids (administration & dosage, chemistry, pharmacokinetics)
• Tumor Burden (drug effects)