Li-Min Mu

Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes

The recurrence of breast cancer is associated with drug-resistance of cancer stem cells (CSCs), while overexpression of cell membrane ATP-binding cassette (ABC) transporters and resistance of mitochondrial apoptosis-related proteins are responsible for the drug-resistance of CSCs. The targeting berberine liposomes were developed to modulate the resistant membrane and mitochondrial proteins of breast CSCs for the treatment and prevention of breast cancer relapse. Evaluations were performed on human breast CSCs and CSC xenografts in nude mice. The targeting berberine liposomes were shown to cross the CSC membrane, inhibit ABC transporters (ABCC1, ABCC2, ABCC3, ABCG2) and selectively accumulate in the mitochondria. Furthermore, the pro-apoptotic protein Bax was activated while the anti-apoptotic protein Bcl-2 was inhibited resulting in opening of the mitochondrial permeability transition pores, release of cytochrome c, and activation of caspase-9/caspase-3 enzymes. Significant efficacy of the administrations in mice was observed, indicating that the targeting berberine liposomes are a potential therapy for the treatment and prevention of breast cancer relapse arising from CSCs.

Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels.

Application of functional vincristine plus dasatinib liposomes to deletion of vasculogenic mimicry channels in triple-negative breast cancer.

Standard chemotherapy cannot eradicate triple-negative breast cancer (TNBC) while the residual cancer cells readily form the vasculogenic mimicry (VM) channels, which lead to the relapse of cancer after treatment. In this study, the functional vincristine plus dasatinib liposomes, modified by a targeting molecule DSPE-PEG2000-c(RGDyK), were fabricated to address this issue. The investigations were performed on TNBC MDA-MB-231 cells and MDA-MB-231 xenografts in nude mice. The liposomes exhibited the superior performances in the following aspects: the enhancement of cellular uptake via targeted action; the induction of apoptosis via activation of caspase 8, 9, and 3, increased expression of Bax, decreased expression of Mcl-1, and generation of reactive oxygen species (ROS); and the deletion of VM channels via inhibitions on the VM channel indicators, which consisted of vascular endothelial-cadherin (VE-Cad), focal adhesion kinase (FAK), phosphatidylinositide 3-kinase (PI3K), and matrix metallopeptidases (MMP-2, and MMP-9). Furthermore, the liposomes displayed the prolonged circulation time in the blood, the increased accumulation in tumor tissue, and the improved therapeutic efficacy along with deletion of VM channels in the TNBC-bearing mice. In conclusion, the nanostructured functional drug-loaded liposomes may provide a promising strategy for the treatment of invasive TNBC along with deletion of VM channels.

Dual-functional drug liposomes in treatment of resistant cancers

&NA; Efficacy of regular chemotherapy is significantly hampered by multidrug resistance (MDR) and severe systemic toxicity. The reduced toxicity has been evidenced after administration of drug liposomes, consisting of the first generation of regular drug liposomes, the second generation of long‐circulation drug liposomes, and the third generation of targeting drug liposomes. However, MDR of cancers remains as an unsolved issue. The objective of this article is to review the dual‐functional drug liposomes, which demonstrate the potential in overcoming MDR. Herein, dual‐functional drug liposomes are referring to the drug‐containing phospholipid bilayer vesicles that possess a dual‐function of providing the basic efficacy of drug and the extended effect of the drug carrier. They exhibit unique roles in treatment of resistant cancer via circumventing drug efflux caused by adenosine triphosphate binding cassette (ABC) transporters, eliminating cancer stem cells, destroying mitochondria, initiating apoptosis, regulating autophagy, destroying supply channels, utilizing microenvironment, and silencing genes of the resistant cancer. As the prospect of an estimation, dual‐functional drug liposomes would exhibit more strength in their extended function, hence deserving further investigation for clinical validation. Graphical abstract Figure. No caption available.

A nanostructure of functional targeting epirubicin liposomes dually modified with aminophenyl glucose and cyclic pentapeptide used for brain glioblastoma treatment.

The objectives of the present study were to develop functional targeting epirubicin liposomes for transferring drugs across the blood-brain barrier (BBB), treating glioblastoma, and disabling neovascularization. The studies were performed on glioblastoma cells in vitro and on glioblastoma-bearing mice. The results showed that the constructed liposomes had a high encapsulation efficiency for drugs (>95%), suitable particle size (109 nm), and less leakage in the blood component-containing system; were significantly able to be transported across the BBB; and exhibited efficacies in killing glioblastoma cells and in destroying glioblastoma neovasculature in vitro and in glioblastoma-bearing mice. The action mechanisms of functional targeting epirubicin liposomes correlated with the following features: the long circulation in the blood system, the ability to be transported across the BBB via glucose transporter-1, and the targeting effects on glioblastoma cells and on the endothelial cells of the glioblastoma neovasculature via the integrin β3 receptor. In conclusion, functional targeting epirubicin liposomes could be used as a potential therapy for treating brain glioblastoma and disabling neovascularization in brain glioblastomas.

Research Spotlight: Targeting drug delivery systems for circumventing multidrug resistance of cancers

Multidrug resistance is a major obstacle to successful chemotherapy of cancer. To overcome multidrug resistance, our research is to develop new liposome and nanomicelle delivery systems. Investigations are focusing on certain aspects, including resistant cancer cell membranes, cancer stem cells, mitochondria, apoptosis genes, vasculogenic mimicry and heterogeneity of cancer cells. Evaluations have been performed on cancer cells, cancer spheroids and cancer animal models. These nanoscale formulations demonstrated an enhanced chemotherapy efficacy in resistant cancer and cancer stem cells in vitro and in vivo.

Lipid vesicles containing transferrin receptor binding peptide TfR-T 12 and octa-arginine conjugate stearyl-R 8 efficiently treat brain glioma along with glioma stem cells

Surgery and radiotherapy cannot fully remove brain glioma; thus, chemotherapy continues to play an important role in treatment of this illness. However, because of the restriction of the blood-brain barrier (BBB) and the regeneration of glioma stem cells, post-chemotherapy relapse usually occurs. Here, we report a potential solution to these issues that involves a type of novel multifunctional vinblastine liposomes equipped with transferrin receptor binding peptide TfR-T12 and octa-arginine conjugate stearyl-R8. Studies were performed on brain glioma and glioma stem cells in vitro and were verified in brain glioma-bearing mice. The liposomes were transported across the BBB, killing brain glioma and glioma stem cells via the induction of necrosis, apoptosis and autophagy. Furthermore, we reveal the molecular mechanisms for treating brain glioma and glioma stem cells via functionalized drug lipid vesicles.

The use of functional epirubicin liposomes to induce programmed death in refractory breast cancer

Currently, chemotherapy is less efficient in controlling the continued development of breast cancer because it cannot eliminate extrinsic and intrinsic refractory cancers. In this study, mitochondria were modified by functional epirubicin liposomes to eliminate refractory cancers through initiation of an apoptosis cascade. The efficacy and mechanism of epirubicin liposomes were investigated on human breast cancer cells in vitro and in vivo using flow cytometry, confocal microscopy, high-content screening system, in vivo imaging system, and tumor inhibition in mice. Mechanistic studies revealed that the liposomes could target the mitochondria, activate the apoptotic enzymes caspase 8, 9, and 3, upregulate the proapoptotic protein Bax while downregulating the antiapoptotic protein Mcl-1, and induce the generation of reactive oxygen species (ROS) through an apoptosis cascade. In xenografted mice bearing breast cancer, the epirubicin liposomes demonstrated prolonged blood circulation, significantly increased accumulation in tumor tissue, and robust anticancer efficacy. This study demonstrated that functional epirubicin liposomes could significantly induce programmed death of refractory breast cancer by activating caspases and ROS-related apoptotic signaling pathways, in addition to the direct killing effect of the anticancer drug itself. Thus, we present a simple nanomedicine strategy to treat refractory breast cancer.

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Efficacy in Treating Lung Metastasis of Invasive Breast Cancer with Functional Vincristine Plus Dasatinib Liposomes

Background: The metastasis of breast cancer is the leading cause of death, while lung metastasis is a major clinical phenomenon in patients with invasive breast cancer. The current treatment option comprising surgery, radiation, and standard chemotherapy cannot achieve a satisfactory effect on the treatment of lung metastasis of breast cancer. In this study, we report the potential of preventing lung metastasis of invasive breast cancer using the newly developed functional vincristine plus dasatinib liposomes. Methods: The investigations were performed on invasive breast cancer MDA-MB-231 cells in vitro and in lung metastatic model of invasive breast cancer MDA-MB-231 cells in nude mice. Results: The functional drug liposomes were able to induce cell cycle arrest at G2/M phase, induce apoptosis, inhibit adhesion, migration, and invasion of breast cancer cells in vitro, and prevent lung metastasis of breast cancer in nude mice. Conclusion: These findings indicate a potential clinical use of functional vincristine plus dasatinib liposomes for treating metastatic breast cancer.