TY - JOUR
T1 - Cholesterol modification of an anticancer drug for efficient incorporation into a supramolecular hydrogel system
AU - Bakker, Maarten H.
AU - Grillaud, Maxime
AU - Wu, Dan Jing
AU - Fransen, Peter Paul K.H.
AU - de Hingh, Ignace H.
AU - Dankers, Patricia Y.W.
PY - 2018/9
Y1 - 2018/9
N2 - Treatment of cancer in the peritoneal cavity may be improved with macroscale drug delivery systems that offer control over intraperitoneal concentration of chemotherapeutic agents. Currently, suitable drug carriers to facilitate a sustained release of small hydrophilic drugs such as mitomycin C are lacking. For this purpose, a pH-responsive supramolecular hydrogel based on ureido-pyrimidinone (UPy) chemistry is utilized here. In order to provide a sustained release profile, a lipophilicity-increasing cholesterol conjugation strategy is proposed that enhances affinity between the modified drug (mitomycin-PEG24-cholesterol, MPC) and the hydrophobic compartments in the UPy gel. Additional advantages of cholesterol conjugation include improved chemical stability and potency of mitomycin C. In vitro the tunability of the system to obtain optimal effective concentrations over time is demonstrated with a combinatorial treatment of mitomycin C and MPC in one UPy hydrogel delivery system.
AB - Treatment of cancer in the peritoneal cavity may be improved with macroscale drug delivery systems that offer control over intraperitoneal concentration of chemotherapeutic agents. Currently, suitable drug carriers to facilitate a sustained release of small hydrophilic drugs such as mitomycin C are lacking. For this purpose, a pH-responsive supramolecular hydrogel based on ureido-pyrimidinone (UPy) chemistry is utilized here. In order to provide a sustained release profile, a lipophilicity-increasing cholesterol conjugation strategy is proposed that enhances affinity between the modified drug (mitomycin-PEG24-cholesterol, MPC) and the hydrophobic compartments in the UPy gel. Additional advantages of cholesterol conjugation include improved chemical stability and potency of mitomycin C. In vitro the tunability of the system to obtain optimal effective concentrations over time is demonstrated with a combinatorial treatment of mitomycin C and MPC in one UPy hydrogel delivery system.
KW - Cholesterol
KW - Controlled release
KW - Drug delivery
KW - Intraperitoneal chemotherapy
KW - Mitomycin C
KW - Supramolecular hydrogel
KW - Mitomycin/chemistry
KW - Cholesterol/chemistry
KW - Humans
KW - Structure-Activity Relationship
KW - Cell Survival/drug effects
KW - Dose-Response Relationship, Drug
KW - Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry
KW - Cell Death/drug effects
KW - Molecular Structure
KW - Cell Proliferation/drug effects
KW - Urea/analogs & derivatives
KW - Antibiotics, Antineoplastic/chemistry
KW - Polyethylene Glycols/chemistry
KW - Cell Line, Tumor
KW - Hydrophobic and Hydrophilic Interactions
KW - Pyrimidinones/chemistry
KW - Macromolecular Substances/chemistry
KW - Drug Screening Assays, Antitumor
KW - Hydrogen-Ion Concentration
KW - mitomycin C
KW - drug delivery
KW - intraperitoneal chemotherapy
KW - cholesterol
KW - controlled release
KW - supramolecular hydrogel
UR - http://www.scopus.com/inward/record.url?scp=85047663654&partnerID=8YFLogxK
U2 - 10.1002/marc.201800007
DO - 10.1002/marc.201800007
M3 - Article
C2 - 29806084
AN - SCOPUS:85047663654
SN - 1022-1336
VL - 39
JO - Macromolecular Rapid Communications
JF - Macromolecular Rapid Communications
IS - 17
M1 - 1800007
ER -
