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.

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    • "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]. "
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    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
    Full-text · Article · Jan 2015 · Journal of Supercritical Fluids The
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    • "In vitro release of daunorubicin and quinacrine in drugs-loaded liposomes was performed by the dialysis against the release medium (PBS containing 10% fetal calf serum). Daunorubicin and quinacrine in the samples were measured by HPLC as above, and release rates of both drugs were estimated as our previous reports [32, 33]. Each assay was repeated in triplicate. "
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    ABSTRACT: Most anticancer drugs are not able to cross the blood-brain barrier (BBB) effectively while surgery and radiation therapy cannot eradicate brain glioma cells and glioma stem cells (GSCs), hence resulting in poor prognosis with high recurrence rates. In the present study, a kind of multifunctional targeting daunorubicin plus quinacrine liposomes was developed for treating brain glioma and GSCs. Evaluations were performed on in-vitro BBB model, murine glioma cells, GSCs, and GSCs bearing mice. Results showed that the multifunctional targeting daunorubicin plus quinacrine liposomes exhibited evident capabilities in crossing the BBB, in killing glioma cells and GSCs and in diminishing brain glioma in mice. Action mechanism studies indicated that the enhanced efficacy of the multifunctional targeting drugs-loaded liposomes could be due to the following aspects: evading the rapid elimination from blood circulation; crossing the BBB effectively; improving drug uptake by glioma cells and GSCs; down-regulating the overexpressed ABC transporters; inducing apoptosis of GSCs via up-regulating apoptotic receptor/ligand (Fas/Fasl), activating apoptotic enzymes (caspases 8, 9 and 3), activating pro-apoptotic proteins (Bax and Bok), activating tumor suppressor protein (P53) and suppressing anti-apoptotic proteins (Bcl-2 and Mcl-1). In conclusion, the multifunctional targeting daunorubicin plus quinacrine liposomes could be used as a potential therapy for treating brain glioma and GSCs.
    Full-text · Article · Aug 2014 · Oncotarget
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    • "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 "
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    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.
    Preview · Article · Jan 2013 · International Journal of Nanomedicine
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