title: 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.forename: Cui-Yun
authors.initials: CY
authors.lastname: Yu
authors.forename: Sa
authors.initials: S
authors.lastname: Yang
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Li
authors.forename: Can
authors.initials: C
authors.lastname: Huang
authors.forename: Qian
authors.initials: Q
authors.lastname: Ning
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.forename: Wen-Tong
authors.initials: WT
authors.lastname: Yang
authors.forename: Dongxiu
authors.initials: D
authors.lastname: He
authors.affiliation: Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China. lsun@tulane.edu.
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000138:chemical synthesis* / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis; D008297:Male; D008823:Micelles; D053758:Nanoparticles; D010368:Pectins / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D046911:Macromolecular Substances; D008823:Micelles; D011355:Prodrugs; D004317:Doxorubicin; D010368:Pectins