scholarly journals Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

2016 ◽  
Vol 113 (15) ◽  
pp. 4164-4169 ◽  
Author(s):  
Hong-Jun Li ◽  
Jin-Zhi Du ◽  
Xiao-Jiao Du ◽  
Cong-Fei Xu ◽  
Chun-Yang Sun ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metastatic Cancer ◽  
Cancer Drug ◽  
Target Cells ◽  
Stimuli Responsive ◽  
Tumor Penetration ◽  
Cell Internalization ◽  
High Propensity ◽  
Cancer Nanomedicine

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

scholarly journals Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2383
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Metastasis ◽  
Metastatic Cancer ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Soft Agar ◽  
Lamin A ◽  
And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

scholarly journals The In Vivo Selection Method in Breast Cancer Metastasis

2021 ◽  
Vol 22 (4) ◽  
pp. 1886
Author(s):  
Jun Nakayama ◽  
Yuxuan Han ◽  
Yuka Kuroiwa ◽  
Kazushi Azuma ◽  
Yusuke Yamamoto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Metastasis ◽  
Metastatic Cancer ◽  
Expression Patterns ◽  
Selection Method ◽  
Gene Signatures ◽  
In Vivo Selection ◽  
Metastatic Cancer Cells

Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.

scholarly journals pH-Sensitive Poly(β-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells

Nanomaterials ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 952 ◽  
Author(s):  
Mengxue Zhou ◽  
Xingcai Zhang ◽  
Jin Xie ◽  
Rongxiang Qi ◽  
Huiru Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ph Sensitive ◽  
Amino Ester ◽  
Stimuli Responsive ◽  
Glycoprotein P ◽  
Cell Internalization ◽  
Promising Tool ◽  
Intracellular Drug Delivery ◽  
Mcf 7

Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli-responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH-sensitive poly(β-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells.

scholarly journals Probe for the measurement of cell surface pH in vivo and ex vivo

2016 ◽  
Vol 113 (29) ◽  
pp. 8177-8181 ◽  
Author(s):  
Michael Anderson ◽  
Anna Moshnikova ◽  
Donald M. Engelman ◽  
Yana K. Reshetnyak ◽  
Oleg A. Andreev
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Surface Acidity ◽  
Measurement Tool ◽  
Mouse Tumor ◽  
Cell Surfaces ◽  
Surface Ph

We have developed a way to measure cell surface pH by positioning a pH-sensitive fluorescent dye, seminaphtharhodafluor (SNARF), conjugated to the pH low insertion peptide (pHLIP). It has been observed that many diseased tissues are acidic and that tumors are especially so. A combination of effects acidifies tumor cell interiors, and cells pump out lactic acid and protons to maintain intracellular pH, acidifying the extracellular space. Overexpression of carbonic anhydrases on cell surfaces further contributes to acidification. Thus, the pH near tumor cell surfaces is expected to be low and to increase with distance from the membrane, so bulk pH measurements will not report surface acidity. Our new surface pH-measurement tool was validated in cancer cells grown in spheroids, in mouse tumor models in vivo, and in excised tumors. We found that the surface pH is sensitive to cell glycolytic activity: the pH decreases in high glucose and increases if glucose is replaced with nonmetabolized deoxyglucose. For highly metastatic cancer cells, the pH measured at the surface was 6.7–6.8, when the surrounding external pH was 7.4. The approach is sensitive enough to detect 0.2–0.3 pH unit changes in vivo in tumors induced by i.p. injection of glucose. The pH at the surfaces of highly metastatic cells within tumors was found to be about 6.1–6.4, whereas in nonmetastatic tumors, it was 6.7–6.9, possibly creating a way to distinguish more aggressive from less aggressive tumors. Other biological roles of surface acidity may be found, now that targeted measurements are possible.

scholarly journals Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo

2020 ◽  
Vol 117 (37) ◽  
pp. 22910-22919
Author(s):  
Xingkang He ◽  
Xin Yin ◽  
Jing Wu ◽  
Stina L. Wickström ◽  
Yanhong Duo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Metastatic Cancer ◽  
Car T Cells ◽  
Human T Cell ◽  
Car T ◽  
Metastatic Cancer Cells

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.

Morphological Damage Induced in vivo by Lonidamine on Human Metastatic Cancer Cells

Oncology ◽  
1984 ◽  
Vol 41 (1) ◽  
pp. 94-103 ◽  
Author(s):  
C. De Martino ◽  
T. Battelli ◽  
R. Cavaliere ◽  
C. Gallo Curcio ◽  
M. Bellocci ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metastatic Cancer ◽  
Metastatic Cancer Cells

Membrane Derived Micorvesicles - Underappreciated Components of the Tumor Microenvironment That Modulate Tumor Growth, Vascularization and Metastasis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 473-473
Author(s):  
Marcin Wysoczynski ◽  
Fadhi Hayek ◽  
Janina Ratajczak ◽  
Anna Janowska-Wieczorek ◽  
Mariusz Z. Ratajczak
Keyword(s):  
Lung Cancer ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cell Surface ◽  
Cancer Cells ◽  
Lipid Raft ◽  
Membrane Lipid ◽  
Target Cells

Abstract Viable eukaryotic cells shed circular membrane fragments called microvesicles (MV) from the cell surface and secrete them from the endosomal compartments. These MV, which are different from apoptotic bodies, are enriched in lipids, proteins and mRNA. We postulate that MV play an important and underappreciated role in cell-cell communication by i) stimulating target cells with ligands that the MV express, ii) fusing with target cells and thus transferring various receptors to their surface, and iii) delivering mRNA, lipids and proteins. Since tumor cells secrete large quantities of MV we hypothesized that the latter are important constituents of the tumor microenvironment and their role in tumor progression merited investigation. First, we observed that human and murine lung cancer cell lines secrete more MV in response to non-apoptotic doses of hypoxia, irradiation and chemotherapy. The MV derived from human cancer cells chemoattracted bone marrow-, lymph node- and lung-derived fibroblasts and endothelial cells and activated in these stromal cells the phosphorylation of MAPKp42/44 and AKT. Furthermore, they also induced in bone marrow- and lung-derived fibroblasts expression of LIF, OSM, IL-11, VEGF and MMP-9. Moreover, conditioned media from marrow fibroblasts exposed to MV induced phosphorylation of STAT-3 proteins and chemoattracted lung cancer cells in a LIF- and OSM-dependent manner and, together with IL-11 and VEGF, activated osteoclasts and endothelial cells. Furthermore, MV from cancer cells embedded in Matrigel implants strongly stimulated angiogenesis. We also found that tumor-derived MV express tissue factor (TF) and activate platelets and as a result of this MV derived from activated platelets transfer several adhesion molecules from platelets to the tumor cell surface. This increases adhesiveness of lung cancer cells in endothelium and their metastatic spread in vivo after injection into syngeneic mice. Finally, we found that formation of MV depends on the formation of membrane lipid rafts. Thus we postulate that tumor- and platelet-derived MV are underappreciated constituents of the tumor microenvironment and play a pivotal role in tumor progression/metastasis and angiogenesis. As MV formation appears to be lipid raft-dependent, we suggest that inhibitors of membrane lipid raft formation (e.g, statins or polyene antibiotics) could decrease MV-dependent tumor spread/growth and we are currently testing this hypothesis in animal models in vivo.

Preparation and Characterization of Heparin-Retinoic Acid-Folic Acid Conjugates for Targeted Cancer Therapy

2010 ◽  
Vol 93-94 ◽  
pp. 324-327 ◽  
Author(s):  
Il Kyu Park ◽  
Yu Jin Kim ◽  
Kang Moo Huh ◽  
Yong Kyu Lee
Keyword(s):  
Folic Acid ◽  
Water Solubility ◽  
Drug Carrier ◽  
Ultra Violet ◽  
Proton Nuclear Magnetic Resonance ◽  
Coagulation Cascade ◽  
Cancer Drug ◽  
Great Promise ◽  
Target Cells

To make significant progress in the fight against cancer, treatment should target cells more specifically, produce fewer side effects, be easy to administer and deter tumor viability on multiple levels. We have attained dramatic in vivo tumor shrinkage and tumor vasculature disruption using a ternary biomolecular nanoparticle comprised of polymeric carrier polysaccharide heparin, anticancer drug retinoid and targeting ligand folic acid. The conjugation of retinoid and folic acid to heparin enhanced the water solubility of the drug, enabled selective targeting, and enhanced the role of heparin as anti-cancer drug carrier by eluding the coagulation cascade. This approach for targeting tumor holds great promise for treatment of various types of cancer. The folic acid linked heparin-retinoid conjugates (HFR) reactions was conjugated with ester and amide bonding which was confirmed by fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR). The ratio of HFR conjugates was measured with Ultra-Violet spectrometry (UV-spectrometry). The particle size of HFR nanoparticles was measured by dynamic light scattering (DLS), and transmission electron microscopy (TEM). HFR conjugates were spherical and showed a diameter range of 200-300 nm in size. The nanoparticles maintained their stability in serum condition for 48hrs and have the high potential for applications in biomedical field.

scholarly journals Chemotherapeutic Drug Functionalized Nanoparticles are Beneficial When Treating Breast Cancer Via Magnetic Hyperthermia

2018 ◽  
Author(s):  
Susann Piehler ◽  
Heidi Dähring ◽  
Julia Grandke ◽  
Julia Göring ◽  
Pierre Couleaud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Magnetic Hyperthermia ◽  
Target Cells ◽  
Chemotherapeutic Drug ◽  
Antitumor Effects ◽  
Cell Cycle Proteins

Doxorubicin (DOX) is a frequently used chemotherapeutic drug for breast cancer, but its site specificity and local internalization into tumor cells is rather low. In this paper we conjugated magnetic nanoparticles (MNPs) with DOX and/or a pseudopeptide NucAnt (N6L) as modality to enhance DOX-induced antitumor effects in breast cancer cells (BT474). In this context, we determined cellular uptake of MNP formulations, analyzed cell viability and expression of apoptotic and cell cycle proteins after magnetic hyperthermia (43°C, 1 h) in vivo and in vitro. We have shown that i) the presence of N6L on the surface of DOX-functionalized MNPs increases their internalization into a target cells and potentiates the cytotoxic potential of the anticancer drug, ii) in combination with hyperthermia, DOX functionalized MNPs influence the expression of apoptotic and cell cycle proteins, and also favors tumor regression in vivo. Our data show that intratumoral application of DOX coupled MNPs is able to overcome biological barriers to chemotherapeutic drugs, enabling them to penetrate into the target cells. Combined with hyperthermia these MNPs can be an effective method in enhancing the localised delivery and penetration of DOX into breast cancer cells.

miR-221 to modulate tumor growth in vivo and as a regulator of TGF.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23008-e23008
Author(s):  
Martin Spahn ◽  
Eugenio Zoni ◽  
Markus Krebs ◽  
Philip Herreiner ◽  
Charis Kalogirou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Bone Lesions ◽  
Zebrafish Embryos ◽  
The Impact

e23008 Background: Despite the advances in cancer therapy, when Prostate Cancer (PCa) progress to castration resistant phase, patients develop incurable bone metastases. Understanding the processes that regulate homing and survival of metastatic cancer cells in the bone is crucial for the identification of new therapies. TGF-β signaling plays a major role in bone remodeling and according to the “vicious cycle hypothesis” is a master regulator of maintenance of prostate cancer cells in lytic bone lesions. microRNAs (miRs) are a class of small non-coding RNAs that regulates many biological process. miR-221 expression has been previously associated with prostate cancer progression. Here we studied the effect of miR-221 on TGF-β signaling and the impact of miR-221 on tumor growth in vivo Methods: miR-221 was overexpressed in PC3 and RWPE-1 cells and PMEPA was monitored by RT-qPCR and western blot. Expression of miR-221 in PC3 and RWPE-1 cells was assessed by RT-qPCR. Luciferase assay was used to investigate the interaction between miR-221 and PMEPA1. For zebrafish experiment, fluorescently labelled PC-3M-Pro4 cells overexpressing miR-221 were injected in the Duct of Cuvier (DC) of zebrafish embryos. Results: miR-221 overexpression resulted in decreased PMEPA1 mRNA and protein in PC-3 cells. Luciferase reporter assay indicated that miR-221 can directly interact with PMEPA1 3’ UTR. We show an enhancement of the proliferative effect of TGF-β in PC-3 cells, following miR-221 overexpression. In conclusion, we observed increased Smad2 activation upon TGF-β treatment in miR-221 overexpressing PC-3 cells. Inoculation of PC-3M-Pro4 cells overexpressing miR-221 in the DC of zebrafish embryos resulted reduced tumor burden compared to control. Finally, we observed inverse correlation between miR-221 and PMEPA1 expression in normal vs. tumor tissue collected from PCa patients. Conclusions: Our results indicate that miR-221 is a regulator of TGF-β signaling via modulation of PMEPA1 and miR-221 overexpression can reduce tumor growth in vivo.

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