All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells.
The relapse of cancer is mostly due to the proliferation of cancer stem cells which could not be eliminated by a standard chemotherapy. A new kind of all-trans retinoic acid stealth liposomes was developed for preventing the relapse of breast cancer and for treating the cancer in combination with a cytotoxic agent, vinorelbine stealth liposomes. In vitro studies were performed on the human breast cancer MCF-7 and MDA-MB-231 cells. In vivo evaluations were performed on the newly established relapse model with breast cancer stem cells. Results showed that the particle size of all-trans retinoic acid stealth liposomes was approximately 80nm, and the encapsulation efficiency was >90%. Breast cancer stem cells were identified with the CD44(+)/CD24(-) phenotype and characterized with properties: resistant to cytotoxic agent, stronger capability of proliferation, and stronger capability of differentiation. Inhibitory effect of all-trans retinoic acid stealth liposomes was more potent in cancer stem cells than in cancer cells. The mechanisms were defined to be two aspects: arresting breast cancer stem cells at the G(0)/G(1) phase in mitosis, and inducing the differentiation of breast cancer stem cells. The cancer relapse model was successfully established by xenografting breast cancer stem cells into NOD/SCID mice, and the formation and growth of the xenografted tumors were significantly inhibited by all-trans retinoic acid stealth liposomes. The combination therapy of all-trans retinoic acid stealth liposomes with vinorelbine stealth liposomes produced the strongest inhibitory effect to the relapse tumor model. It could be concluded that all-trans retinoic acid stealth liposomes could be used for preventing the relapse of breast cancer by differentiating cancer stem cells and arresting the cell-cycle, and for treating breast cancer as a co-therapy, thus providing a novel strategy for treating breast cancer and preventing relapse derived from breast cancer stem cells.
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Ruo-Jing
RJ
Li
Xue
X
Ying
Yan
Y
Zhang
Rui-Jun
RJ
Ju
Xiao-Xing
XX
Wang
Hong-Juan
HJ
Yao
Ying
Y
Men
Wei
W
Tian
Yang
Y
Yu
Liang
L
Zhang
Ren-Jie
RJ
Huang
Wan-Liang
WL
Lu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D012008:Recurrence; D014212:Tretinoin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D008081:Liposomes; D014212:Tretinoin; D014747:Vinblastine; D000077235:Vinorelbine