All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells

State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Journal of Controlled Release (Impact Factor: 7.71). 10/2010; 149(3):281-91. DOI: 10.1016/j.jconrel.2010.10.019
Source: PubMed


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.

26 Reads
  • Source
    • "Retinoic acid (Fig. 1) is derived from retinol and presents two biologically relevant isomers, namely the alltrans retinoic acid (ATRA) and the 9-cis-retinoic acid. In previously reported studies ATRA showed to be effective in the treatment and/or chemoprevention of several epithelial and hematological malignancies such as breast and lung cancer, promyelocytic leukemia, ovarian adenocarcinoma and human malignant gliomas [6] [7] [8] as well as diverse dermatological diseases such as acne, psoriasis and ichthyosis [3] [9]. It has also proved to play a major role in maintaining the integrity of the cornea since it induces the proliferation and differentiation of corneal epithelial cells on both normal and diseased eye [10] [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: All-trans retinoic acid (ATRA) is a derivative of retinol (or vitamin A) presenting similar benefits but considerable lower adverse toxicity, mainly in cases of high or long-term therapeutic doses. ATRA showed to be effective in the treatment and/or chemoprevention of several epithelial and hematological malignancies and diverse dermatological and eye diseases however, its low solubility in aqueous media and photosensitivity hinder its wider usage by the conventional administration methods. Supercritical fluids technologies are being widely used to enhance the in vivo bioactivity of this type of drugs both by improving their dissolution rate (using particle size reduction processes) and/or by controlling their release into the media after incorporation into solid polymeric/inorganic matrices (using supercritical impregnation/foaming processes). In both cases the solubility of the drug in the supercritical fluid (usually scCO2) is required for process optimization purposes. Therefore, in this work the solubility of ATRA in scCO2 was measured at different isotherms (308.2, 318.2 and 328.2 K) and pressures that ranged from 10 up to 30 MPa using a static analytical method. Solubility data were correlated using three commonly used density-based models, namely the Bartle, Chrastil and Méndez-Santiago-Teja models. The solubility of ATRA in scCO2 was found to be between 1.52 × 10−6 and
    Journal of Supercritical Fluids The 01/2015; 98. DOI:10.1016/j.supflu.2014.12.027 · 2.37 Impact Factor
  • Source
    • "For example, retinoic acids, derivatives of vitamin A, are known to induce cancer cell differentiation, proliferation arrest, and apoptosis. Li et al12 incorporated all-trans retinoic acid into stealth liposomes and showed that combination therapy using retinoic acid-liposomes and vinorelbine liposomes was more effective than monotherapy using vinorelbine liposomes alone in inhibiting the relapse of breast cancer arisen from breast cancer stem cells, likely because the retinoic acid-liposomes promoted the differentiation of cancer stem cells and arrested cell cycle.12 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.
    International Journal of Nanomedicine 01/2013; 8:61-71. DOI:10.2147/IJN.S37859 · 4.38 Impact Factor
  • Source
    • "Estrogen also causes BCSCs to differentiate, as demonstrated by a reduction in the number of cancer stem cells in tumors positive for estrogen receptors [59]. All-trans retinoic acid (ATRA) can prevent breast cancer recurrence by inducing BCSC differentiation and cell cycle arrest [2,60]. BCSCs may also be affected in terms of stem cell self-renewal, differentiation, motility and mesenchymal phenotype after treatment with the polyamine analog [1 N, 12 N] bis (ethyl)-cis -6.7-dehydrospermine (PG11047) [61]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs). We isolated a breast cancer cell population (CD44+CD24- cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44+CD24- phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs. Knockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs. Knockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.
    Journal of Translational Medicine 12/2011; 9(1):209. DOI:10.1186/1479-5876-9-209 · 3.93 Impact Factor
Show more