Binding and interstitial penetration of liposomes within avascular tumor spheroids

Kostarelos, Kostas; Emfietzoglou, Dimitris; Papakostas, Alexandros; Yang, Wei; Ballangrud, Åse M.; Sgouros, George

doi:10.1002/ijc.20457

Cited by 110 publications

(119 citation statements)

References 39 publications

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“…Neutral DMPC (dimyristoyl-phosphatidylcholine):cholesterol liposomes (~-9 mV) exhibited at 100 µm from the spheroid rim 49.2% diffusion compared to 2.3% and 21.4% for cationic DMPC:DOPE (dioleoylphosphatidylcholine) liposomes (~50 mV) with respectively DC-chol (3b-[N-(N′ ,N′-dimethylaminoethane)-carbamoyl]cholesterol) and DOTAP components. 57 In another study, the limited penetration of cationic DOTAP liposomes into spheroids was attributed to electrostatic interactions of this type of liposomes with spheroid cells. 20,57 However, in the same study, DOTAP liposomes accumulated to a higher extent than neutral (DOPE) or anionic (DOPS) ones, suggesting that accumulation of NPs is not fully related to their ability to penetrate in depth into spheroid.…”

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confidence: 97%

“…In this regard, 3D in vitro models and above all MCTS have been applied for evaluating the NP potential to accumulate and penetrate in depth the tumor tissue. 20,34,[56][57][58][59] Determination of free or drug-loaded NPs' distribution and concentration in spheroids can be performed by various techniques. The distribution of gold NPs in MCTS could be precisely assessed with transmission electronic microscopy (TEM), 60,61 while fluorescence microscopy was successfully applied for the detection of dye-labeled NPs.…”

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confidence: 99%

“…59,69 Estimation of drug concentration in MCTS could be done by high-performance liquid chromatography (HPLC), 20 flow cytometry or chemical extraction with successive fluorescence measurements. 43,44,57,64 After incubation, MCTS is collected and embedded in special medium as tissue-Tek before being cut in thin sections (~5 µm).…”

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confidence: 99%

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Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Millard¹,

Yakavets²,

Zorin³

et al. 2017

IJN

112

107

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The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS) model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM) components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs) play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a better comprehension of the interactions between NPs and tumor components that affect tumor drug delivery. MCTS is particularly suitable for the high-throughput screening of new nanodrugs.

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Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Millard¹,

Yakavets²,

Zorin³

et al. 2017

IJN

112

107

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“…31 The single-spheroid model produced by EW7 and M8 cells in agar-coated 96-well plates is a very useful model because of the simplicity of measuring the spheroids radii to calculate volumes. Although size and total protein measurements displayed a good correlation, in some cases the level of significance of the two methodologies differed.…”

Section: Lipofection With Hifnb Gene Displayed a Strong Cytotoxic Effmentioning

confidence: 99%

Interferon-β lipofection I. Increased efficacy of chemotherapeutic drugs on human tumor cells derived monolayers and spheroids

et al. 2012

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We evaluated the effect of hIFNb gene transfer alone or in combination with different antineoplastic drugs commonly used in cancer treatment. Five human tumor-derived cell lines were cultured as monolayers and spheroids. Four cell lines (Ewing sarcomas EW7 and COH, melanoma M8 and mammary carcinoma MCF-7) were sensitive to hIFNb gene lipofection. Although this effect appeared in both culture configurations, spheroids showed a relative multicellular resistance (insensitive colon carcinoma HT-29 excluded). EW7 and M8 hIFNb-expressing cells were exposed to different concentrations of bleomycin, bortezomib, carboplatin, doxorubicin, etoposide, methotrexate, paclitaxel and vincristine in both configuration models. In chemotherapy-sensitive EW7 monolayers, the combination of hIFNb gene and antineoplastic drugs displayed only additive or counteractive (methotrexate) effects, suggesting that cytotoxic mechanisms triggered by hIFNb gene lipofection could be saturating the signaling pathways. Conversely, in chemotherapy-resistant EW7 spheroids or M8 cells, the combination of hIFNb with drugs that mainly operate at the genotoxic level (doxorubicin, methotrexate and paclitaxel) presented only additive effects. However, drugs that also increase pro-oxidant species can complement the antitumor efficacy of the hIFNb gene and clearly caused potentiated effects (bleomycin, bortezomib, carboplatin, etoposide and vincristine). The great bystander effect induced by hIFNb gene lipofection could be among the main causes of its effectiveness, because only 1 or 2% of EW7 or M8 hIFNb-expressing cells killed more than 60 or 80% of cell population, respectively.

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“…The enhanced permeability can be attributed to the ability of the liposomal formulations to permeate across the interstitial spaces in the spheroids, and this was achieved by incorporation of fusogenic lipids like DSPC and DSPE-PEG into the lipid bilayer during their preparation. 30 Lastly, in order to investigate whether 3D arrangement of cells physically prevents drug penetration and whether upregulation of glycolytic activity in spheroids leads to further resistance to 3-BPA in terms of hexokinase inhibition and cytotoxicity, we used 3-BPA as an inhibitor of aerobic glycolysis in spheroids. Cells grown in spheroid cultures exhibited greater resistance in comparison with monolayer cell cultures when treated with 3-BPA in both solution and liposomal formulations.…”

mentioning

confidence: 99%

Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

Gandham¹,

Talekar²,

Singh³

et al. 2015

IJN

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Background The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Methods Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 µm by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions ( P <0.0001, Student’s t -test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect ( P <0.001, Student’s t -test, unpaired and two-tailed) at a dose of 50 µM than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 µM–100 µM) showed that the liposomal formulations had an enhanced cytotoxic effect of 2–5-fold ( P <0.0001, Student’s t -test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 µM and 25 µM concentrations. Conclusion SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model.

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Binding and interstitial penetration of liposomes within avascular tumor spheroids

Cited by 110 publications

References 39 publications

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Interferon-β lipofection I. Increased efficacy of chemotherapeutic drugs on human tumor cells derived monolayers and spheroids

Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

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