Improved antitumor activity and reduced myocardial toxicity of doxorubicin encapsulated in MPEG-PCL nanoparticles.
Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium.
Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan, P.R. China.
Chuntang
C
Sun
Department of Health Management Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
Le
L
Zhou
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
Maling
M
Gou
Institute of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
Shuai
S
Shi
Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan, P.R. China.
Tao
T
Li
Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, Sichuan, P.R. China.
Jinyi
J
Lang
D000072283:A549 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology*; D004337:Drug Carriers / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009206:Myocardium / Q000473:pathology; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy*; D011091:Polyesters / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D015027:Zebrafish
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D011092:Polyethylene Glycols; D004317:Doxorubicin