Doxorubicin-polyphosphazene conjugate hydrogels for locally controlled delivery of cancer therapeutics.
Poly(organophosphazene)-doxorubicin (DOX) conjugate bearing hydrophobic L-isoleucine ethyl ester (IleOEt) and hydrophilic alpha-amino-omega-methoxy-poly(ethylene glycol) with molecular weight of 550 Da (AMPEG 550) along with carboxylic acid as a functional group was synthesized to create a drug delivery system, which is based on locally injectable, biodegradable, and thermosensitive hydrogels. In addition to the evaluation of the in vitro and in vivo antitumor activities, the physicochemical properties, hydrolytic degradation, and DOX release profile of the poly(organophosphazene)-DOX conjugate were determined. The aqueous solution of the polymer-DOX conjugate showed a sol-gel transition behavior depending on temperature changes. Based on the in vivo antitumor activities of the locally injected poly(organophosphazene)-DOX conjugate into the tumor-induced nude mice, the conjugate hydrogel after the local injection at the tumor site was shown to inhibit tumor growth more effectively with less toxicity and much longer than doxorubicin and saline as controls, indicating that tumor active DOX from the conjugate hydrogel is released slowly over a longer period of time and effectively accumulated locally in the tumor sites. These results suggest that the poly(organophosphazene)-doxorubicin conjugates hold great potential for use in preclinical and clinical studies as single and/or combination therapies.
Chun
Changju
C
Division of Life Science, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
Lee
Sun M
SM
Kim
Chang W
CW
Hong
Ki-Yun
KY
Kim
Sang Y
SY
Yang
Han K
HK
Song
Soo-Chang
SC
D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006868:Hydrolysis / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D044367:Phase Transition / Q000187:drug effects; D011108:Polymers / Q000737:chemistry*; D049268:Positron-Emission Tomography; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature; D023041:Xenograft Model Antitumor Assays
D020100:Hydrogels; D009943:Organophosphorus Compounds; D011108:Polymers; C108974:poly(phosphazene); D019788:Fluorodeoxyglucose F18; D004317:Doxorubicin