The In-Situ One-Step Synthesis of a PDC Macromolecular Pro-Drug and the Fabrication of a Novel Core-Shell Micell.

Abstract

The development of slow release nano-sized carriers for efficient antineoplastic drug delivery with a biocompatible and biodegradable pectin-based macromolecular pro-drug for tumor therapy has been reported in this study. Pectin-doxorubicin conjugates (PDC), a macromolecular pro-drug, were prepared via an amide condensation reaction, and a novel amphiphilic core-shell micell based on a PDC macromolecular pro-drug (PDC-M) was self-assembled in situ, with pectin as the hydrophilic shell and doxorubicin (DOX) as the hydrophobic core. Then the chemical structure of the PDC macromolecular pro-drug was identified by both Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ((1)H-NMR), and proved that doxorubicin combined well with the pectin and formed macromolecular pro-drug. The PDC-M were observed to have an unregularly spherical shape and were uniform in size by scanning electron microscopy (SEM). The average particle size of PDC-M, further measured by a Zetasizer nanoparticle analyzer (Nano ZS, Malvern Instruments), was about 140 nm. The encapsulation efficiency and drug loading were 57.82% ± 3.7% (n = 3) and 23.852% ±2.3% (n = 3), respectively. The in vitro drug release behaviors of the resulting PDC-M were studied in a simulated tumor environment (pH 5.0), blood (pH 7.4) and a lysosome media (pH 6.8), and showed a prolonged slow release profile. Assays for antiproliferative effects and flow cytometry of the resulting PDC-M in HepG2 cell lines demonstrated greater properties of delayed and slow release as compared to free DOX. A cell viability study against endothelial cells further revealed that the resulting PDC-M possesses excellent cell compatibilities and low cytotoxicities in comparison with that of the free DOX. Hemolysis activity was investigated in rabbits, and the results also demonstrated that the PDC-M has greater compatibility in comparison with free DOX. This shows that the resulting PDC-M can ameliorate the hydrophobicity of free DOX. This work proposes a novel strategy for in-situ one-step synthesis of macromolecular pro-drugs and fabrication of a core-shell micelle, demonstrating great potential for cancer chemotherapy.

• Authors: Cui-Yun Yu, Sa Yang, Zhi-Ping Li, Can Huang, Qian Ning, Wen Huang, Wen-Tong Yang, Dongxiu He, Lichun Sun
• Journal: Current pharmaceutical design (Curr Pharm Des) Vol. 22 Issue 4 Pg. 506-13 ( 2016) ISSN: 1873-4286 [Electronic] United Arab Emirates
• PMID: 26517529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Macromolecular Substances
• Micelles
• Prodrugs
• Doxorubicin
• Pectins

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Survival (drug effects, physiology)
• Chemistry, Pharmaceutical
• Dose-Response Relationship, Drug
• Doxorubicin (chemical synthesis, pharmacology)
• Drug Carriers (chemical synthesis, pharmacology)
• Drug Delivery Systems (methods)
• Female
• Hep G2 Cells
• Humans
• Macromolecular Substances (chemical synthesis)
• Male
• Micelles
• Nanoparticles
• Pectins (chemical synthesis, pharmacology)
• Prodrugs (chemical synthesis, pharmacology)
• Rabbits